Omega-3 Research papers – Reference

No human clinical trial data are reported for supplementation benefits of omega-3 fatty acids in patients with either the traumatic brain injury or ischemic reperfusion injury.  Although supplementation benefits of omega-3 fatty acids in patients with brain injuries have not been reported, data from several preclinical trials suggest that either pre- or post-supplementation of omega-3 fatty acids could benefit patients with brain injuries. The following is a list of relevant papers from NIH’s PubMed:

1. Lipids Health Dis. 2013 Feb 11;12(1):16. [Epub ahead of print]

Modulating the inflammatory properties of activated microglia with
Docosahexaenoic acid and Aspirin.

Pettit LK, Varsanyi C, Tadros J, Vassiliou E.

ABSTRACT: BACKGROUND: Microglia are considered the "resident macrophages" of the 
brain. When in their resting state, microglia perform routine maintenance and
immune surveillance. Once activated, either by injury or an immune stimulus,
microglia secrete a variety of pro-inflammatory molecules, such as Nitric Oxide, 
superoxide, and inflammatory cytokines. Up-regulation of pro-inflammatory
molecules is transient, and does not cause neurodegeneration. However, if
up-regulation lasts for an extended period of time, neurodegeneration ensues.Many
neurodegenerative diseases are characterized by chronic inflammation due to
microglial activation. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) have been
proposed as possible preventative treatments for neurodegenerative diseases, due 
to their anti-inflammatory properties. Docosahexaenoic Acid (DHA) is an omega-3
polyunsaturated fatty acid (PUFA) that has potent anti-inflammatory
properties.This research work sought to elucidate whether microglial activation
can be modulated by combining Aspirin, a classical NSAID, with Docosahexaenoic
Acid, a natural anti-inflammatory agent. The combined ability of Aspirin and DHA 
to modulate microglial activation was determined in the context of
pro-inflammatory cytokines, Nitric Oxide levels, as well as total Glutathione
levels. RESULTS: Docosahexaenoic Acid increased total Glutathione levels in
microglia cells and enhanced their anti-oxidative capacity. It reduced production
of the pro-inflammatory cytokines TNF-alpha and IL-6 induced through TLR-3 and
TLR-4 activation. Furthermore, it reduced production of Nitric Oxide. Aspirin
showed similar anti-inflammatory effects with respect to TNF-alpha during TLR-3
and TLR-7 stimulation. Aspirin did not show any redection in terms of Nitric
Oxide production. Combination of Aspirin and Docosahexaenoic Acid showed
augmentation in total Glutathione production during TLR-7 stimulation as well as 
a reduction in IL-6, TNF-alpha and Nitric Oxide. CONCLUSIONS: Collectively, these
findings highlight the combination of Docosahexaenoic Acid and Aspirin as a
possible measure against inflammation of the nervous system, thus leading to
protection against neurodegenerative diseases with an inflammatory etiology.

PMID: 23398903  [PubMed - as supplied by publisher]

2. J Neurotrauma. 2013 Jan 30. [Epub ahead of print]

OMEGA-3 FATTY ACIDS FOR TREATMENT OF TRAUMATIC BRAIN INJURY.

Hasadsri L, Wang BH, Lee JV, Erdman JW, Llano DA, Barbey AK, Wszalek T, Sharrock 
MF, Wang H.

Mayo Clinic, Laboratory Medicine and Pathology, Rochester, Minnesota, United
States; hasadsri@life.illinois.edu.

Traumatic Brain Injury (TBI) is a global public health epidemic. In the US alone,
more than 3 million people sustain a TBI annually. It is one of the most
disabling injuries as it results in motor and sensory deficits as well as severe 
cognitive, emotional, and psychosocial impairment, crippling many vital areas of 
higher functioning. Fueled by the recognition of TBI as the "signature injury" in
our wounded soldiers in Iraq and Afghanistan and its often devastating impact on 
athletes playing contact sports, interest in TBI and TBI research has increased
dramatically. Unfortunately, despite increased awareness of its detrimental
consequences, there has been little progress in developing effective TBI
interventions. Recent evidence, however, strongly indicates that nutritional
intervention may provide a unique opportunity to enhance the neuronal repair
process after TBI. To date, two omega-3 fatty acids, docosahexaenoic acid (DHA)
and eicosapentaenoic acid (EPA), have the most promising laboratory evidence for 
their neuro-restorative capacities in TBI. Although both animal models and human 
studies of brain injuries suggest they may provide benefits, there has been no
human trial evaluating the effects of n-3 fatty acids on resilience to, or
treatment of, TBI. This paper reviews the known functions of n-3 fatty acids in
the brain and their specific role in the cellular and biochemical pathways
underlying neurotraumatic injury. We also highlight recent studies on the
therapeutic impact of enhanced omega 3 intake in vivo, and how this may be a
particularly promising approach to improving functional outcome in patients with 
TBI.

PMID: 23363551  [PubMed - as supplied by publisher]

3. Am J Emerg Med. 2013 Jan;31(1):273.e5-8. doi: 10.1016/j.ajem.2012.05.014. Epub
2012 Aug 3.

Therapeutic use of omega-3 fatty acids in severe head trauma.

Lewis M, Ghassemi P, Hibbeln J.

Brain Health Education and Research Foundation, Arlington, VA, USA.
dr.michael.lewis@gmail.com

Traumatic brain injury (TBI) has long been recognized as the leading cause of
traumatic death and disability. Tremendous advances in surgical and intensive
care unit management of the primary injury, including maintaining adequate
oxygenation, controlling intracranial pressure, and ensuring proper cerebral
perfusion pressure, have resulted in reduced mortality. However, the secondary
injury phase of TBI is a prolonged pathogenic process characterized by
neuroinflammation, excitatory amino acids, free radicals, and ion imbalance.
There are no approved therapies to directly address these underlying processes.
Here, we present a case that was intentionally treated with substantial amounts
of omega-3 fatty acids (n-3FA) to provide the nutritional foundation for the
brain to begin the healing process following severe TBI. Recent animal research
supports the use of n-3FA, and clinical experience suggests that benefits may be 
possible from substantially and aggressively adding n-3FA to optimize the
nutritional foundation of severe TBI patients and must be in place if the brain
is to be given the opportunity to repair itself to the best possible extent.
Administration early in the course of treatment, in the emergency department or
sooner, has the potential to improve outcomes from this potentially devastating
public health problem.

Copyright © 2013 Elsevier Inc. All rights reserved.

PMCID: PMC3518659
PMID: 22867826  [PubMed - in process]

4. PLoS One. 2013;8(1):e51543. doi: 10.1371/journal.pone.0051543. Epub 2013 Jan 4.

Low vitamin D status and suicide: a case-control study of active duty military
service members.

Umhau JC, George DT, Heaney RP, Lewis MD, Ursano RJ, Heilig M, Hibbeln JR,
Schwandt ML.

National Institute on Alcohol Abuse and Alcoholism, National Institutes of
Health, Bethesda, MD, USA. umhau@jhu.edu

OBJECTIVE: Considering that epidemiological studies show that suicide rates in
many countries are highest in the spring when vitamin D status is lowest, and
that low vitamin D status can affect brain function, we sought to evaluate if a
low level of 25-hydroxyvitamin D [25(OH)D] could be a predisposing factor for
suicide.
METHOD: We conducted a prospective, nested, case-control study using serum
samples stored in the Department of Defense Serum Repository. Participants were
previously deployed active duty US military personnel (2002-2008) who had a
recent archived serum sample available for analysis. Vitamin D status was
estimated by measuring 25(OH) D levels in serum samples drawn within 24 months of
the suicide. Each verified suicide case (n = 495) was matched to a control (n =
495) by rank, age and sex. We calculated odds ratio of suicide associated with
categorical levels (octiles) of 25(OH) D, adjusted by season of serum collection.
FINDINGS: More than 30% of all subjects had 25(OH)D values below 20 ng/mL.
Although mean serum 25(OH)D concentrations did not differ between suicide cases
and controls, risk estimates indicated that subjects in the lowest octile of
season-adjusted 25(OH)D (<15.5 ng/mL) had the highest risk of suicide, with
subjects in the subsequent higher octiles showing approximately the same level of
decreased risk (combined odds ratio compared to lowest octile = 0.49; 95% C.I.:
0.315-0.768).
CONCLUSIONS: Low vitamin D status is common in active duty service members. The
lowest 25(OH)D levels are associated with an increased risk for suicide. Future
studies could determine if additional sunlight exposure and vitamin D
supplementation might reduce suicide by increasing 25(OH) D levels.

PMCID: PMC3537724
PMID: 23308099  [PubMed - in process]

5. Prostaglandins Leukot Essent Fatty Acids. 2013 Jan;88(1):97-103. doi:
10.1016/j.plefa.2012.05.008. Epub 2012 Jul 4.

n-3 Polyunsaturated fatty acids in animal models with neuroinflammation.

Orr SK, Trépanier MO, Bazinet RP.

Department of Nutritional Sciences, Faculty of Medicine, University of Toronto,
Toronto, ON, Canada M5S 3E2.

Neuroinflammation is present in the majority of acute and chronic neurological
disorders. Excess or prolonged inflammation in the brain is thought to exacerbate
neuronal damage and loss. Identifying modulators of neuroinflammation is an
active area of study since it may lead to novel therapies. Omega-3
polyunsaturated fatty acids (n-3 PUFA) are anti-inflammatory in many non-neural
tissues; their role in neuroinflammation is less studied. This review summarizes 
the relationship between n-3 PUFA and brain inflammation in animal models of
brain injury and aging. Evidence by and large shows protective effects of n-3
PUFA in models of sickness behavior, stroke, aging, depression, Parkinson's
disease, diabetes, and cytokine- and irradiation-induced cognitive impairments.
However, rigorous studies that test the direct effects of n-3 PUFA in
neuroinflammation in vivo are lacking. Future research in this area is necessary 
to determine if, and if so which, n-3 PUFA directly target brain inflammatory
pathways. n-3 PUFA bioactive metabolites may provide novel therapeutic targets
for neurological disorders with a neuroinflammatory component.

Copyright © 2012 Elsevier Ltd. All rights reserved.

PMID: 22770766  [PubMed - in process]

6. J Spec Oper Med. 2012 Fall;12(3):5-7.

Omega-3 Fatty Acid Ingestion as a TBI Prophylactic.

Barringer N, Conkright W.

Given the hazardous nature of combat operations and training exercises (e.g.
airborne operations) conducted by the United States military, servicemembers are 
at high risk for sustaining a traumatic brain injury (TBI). Since the beginning
of the Iraq and Afghanistan wars, almost a quarter of a million servicemembers
have sustained a TBI.1 A large number of TBIs are a result of the concussive
forces generated by improvised explosive devices (IED). A smaller number are a
result of penetrating head wounds. Others may be caused by activities resulting
in powerful acceleration, deceleration, or rotational forces. Therapies for
treating TBI thus far have been limited. Much of the research conducted to date
has focused on post-injury pharmacological interventions.2 Additionally, better
protective equipment could help in preventing TBIs; however, these issues are
outside the scope of this paper. A relatively new area of research is
investigating prophylactic measures taken to lessen the effects of TBI. One such 
measure involves nutritional interventions and their effects on TBI severity.
Therefore, the purpose of this paper is to elucidate the potential benefits of
omega-3 fatty acid intake as it relates to TBI severity.

2012.

PMID: 23032313  [PubMed - in process]

7. Exp Transl Stroke Med. 2012 Sep 14;4(1):19. doi: 10.1186/2040-7378-4-19.

Docosahexaenoic acid complexed to human albumin in experimental stroke:
neuroprotective efficacy with a wide therapeutic window.

Eady TN, Khoutorova L, Atkins KD, Bazan NG, Belayev L.

Neuroscience Center of Excellence, School of Medicine, Louisiana State University
Health New Orleans, New Orleans, LA, 70112, USA. lbelay@lsuhsc.edu.

BACKGROUND: Docosahexaenoic acid (DHA) complexed to human serum albumin (Alb) is 
neuroprotective after experimental stroke. Here we tested using lower
concentrations of albumin as part of the complex to achieve neuroprotection. We
found that lower Alb concentrations extend the therapeutic window of protection
beyond 5 h after stroke onset.
METHODS: Sprague-Dawley rats were received 2 h middle cerebral artery occlusion
(MCAo). The behavior was evaluated on day 1, 2, 3 and 7 after MCAo. In the
dose-response study, animals were given either DHA (5mg/kg), Alb (0.63g/kg),
DHA-Alb (5mg/kg + 0.32, 0.63 or 1.25 g/kg) or saline, i.v. 3 h after onset of
stroke (n=6-8 per group). In the therapeutic window study, DHA-Alb (5mg/kg +
1.25g/kg) was administered i.v. at either 3, 4, 5, 6 or 7 h after onset of stroke
(n=7-9 per group). Alb (1.25g/kg) was given at 3 h or 5 h and saline at 3h after 
onset of reperfusion. Seven days after MCAo, infarct volumes and number of GFAP, 
ED-1, NeuN, SMI-71 positive cells and vessels were counted.
RESULTS: Moderate DHA-Alb doses (0.63 and 1.25 g/kg) improved neurological scores
compared to albumin-treated rats on days 1, 2, 3 and 7. All DHA-Alb doses (0.32, 
0.63 and 1.25 g/kg) markedly reduced cortical (by 65-70%), striatal (by 52-63%)
and total infarct volumes (by 60-64%) compared to native Alb group. In the
therapeutic window study DHA-Alb led to improved neurological score and
significant reductions of infarct volumes (especially in the cortical or
penumbral region), even when treatment was initiated as late as 7 hours after
onset of MCAo.
CONCLUSIONS: The DHA-Alb complex affords high-grade neurobehavioral
neuroprotection in focal cerebral ischemia, equaling or exceeding that afforded
by native Alb or DHA, at considerably moderate doses. It has a broad therapeutic 
window extending to 7 h after stroke onset. Taken together, these finding support
the potential clinical feasibility of administering DHA-Alb therapy to patients
with acute ischemic stroke.

PMCID: PMC3540001
PMID: 22980673  [PubMed]

8. J Neurosurg Spine. 2012 Aug;17(2):134-40. doi: 10.3171/2012.5.SPINE1216. Epub
2012 Jun 26.

Dietary therapy to promote neuroprotection in chronic spinal cord injury.

Holly LT, Blaskiewicz D, Wu A, Feng C, Ying Z, Gomez-Pinilla F.

Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles,
CA 90095-6901, USA. lholly@mednet.ucla.edu

OBJECT: The pathogenesis of cervical spondylotic myelopathy (CSM) is related to
both primary mechanical and secondary biological injury. The authors of this
study explored a novel, noninvasive method of promoting neuroprotection in
myelopathy by using curcumin to minimize oxidative cellular injury and the
capacity of omega-3 fatty acids to support membrane structure and improve
neurotransmission.
METHODS: An animal model of CSM was created using a nonresorbable expandable
polymer placed in the thoracic epidural space, which induced delayed myelopathy. 
Animals that underwent placement of the expandable polymer were exposed to either
a diet rich in docosahexaenoic acid and curcumin (DHA-Cur) or a standard Western 
diet (WD). Twenty-seven animals underwent serial gait testing, and spinal cord
molecular assessments were performed after the 6-week study period.
RESULTS: At the conclusion of the study period, gait analysis revealed
significantly worse function in the WD group than in the DHA-Cur group. Levels of
brain-derived neurotrophic factor (BDNF), syntaxin-3, and 4-hydroxynonenal
(4-HNE) were measured in the thoracic region affected by compression and lumbar
enlargement. Results showed that BDNF levels in the DHA-Cur group were not
significantly different from those in the intact animals but were significantly
greater than in the WD group. Significantly higher lumbar enlargement syntaxin-3 
in the DHA-Cur animals combined with a reduction in lipid peroxidation (4-HNE)
indicated a possible healing effect on the plasma membrane.
CONCLUSIONS: Data in this study demonstrated that DHA-Cur can promote spinal cord
neuroprotection and neutralize the clinical and biochemical effects of
myelopathy.

PMID: 22735048  [PubMed - indexed for MEDLINE]

9. Neurotoxicology. 2012 Aug;33(4):780-8. doi: 10.1016/j.neuro.2012.02.018. Epub
2012 Mar 8.

n-3 polyunsaturated fatty acids inhibit lipopolysaccharide-induced microglial
activation and dopaminergic injury in rats.

Ji A, Diao H, Wang X, Yang R, Zhang J, Luo W, Cao R, Cao Z, Wang F, Cai T.

Department of Nutrition & Food Hygiene and the Ministry of Education Key Lab of
Hazard Assessment and Control in Special Operational Environment, School of
Public Health, Fourth Military Medical University, Xi'an 710032, China.

Increasing evidence indicates that neuroinflammation plays an important role in
neurotoxins-induced neurodegenerations. Microglia are a type of glial cells in
the brain and play as the first and main form of active immune defense in the
central nervous system. Accumulated data suggest that the activation of microglia
plays a critical role in neurotoxicities induced by environmental toxicants. So
the inhibition of microglia has been proven to be an effective strategy against
neurotoxic effects. In the present study, we found that n-3 polyunsaturated fatty
acids can inhibit both microglial activation and dopaminergic injury in the
substantia nigra of Sprague-Dawley rats induced by lipopolysaccharide, one of the
major constituents of the outer membrane of Gram-negative bacteria. Moreover, n-3
polyunsaturated fatty acids inhibited lipopolysaccharide-induced activation of
nuclear factor-κB, an important transcription factor involved in microglial
activation. Taken together, our results provided the first in vivo evidence that 
n-3 polyunsaturated fatty acids can inhibit the damage of dopaminergic neurons
induced by lipopolysaccharide through their inhibitory effects on nuclear
factor-κB-dependent microglial activation.

Copyright © 2012 Elsevier Inc. All rights reserved.

PMID: 22406923  [PubMed - indexed for MEDLINE]

10. Exp Neurol. 2012 Jul;236(1):122-30. doi: 10.1016/j.expneurol.2012.04.007. Epub
2012 Apr 19.

Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury
after experimental stroke.

Bazan NG, Eady TN, Khoutorova L, Atkins KD, Hong S, Lu Y, Zhang C, Jun B, Obenaus
A, Fredman G, Zhu M, Winkler JW, Petasis NA, Serhan CN, Belayev L.

Neuroscience Center of Excellence, School of Medicine, Louisiana State University
Health Sciences Center, New Orleans, LA 70112, USA. nbazan@lsuhsc.edu

Acute ischemic stroke triggers complex neurovascular, neuroinflammatory and
synaptic alterations. Aspirin and docosahexaenoic acid (DHA), an omega-3
essential fatty acid family member, have beneficial effects on cerebrovascular
diseases. DHA is the precursor of neuroprotectin D1 (NPD1), which downregulates
apoptosis and, in turn, promotes cell survival. Here we have tested the effect of
aspirin plus DHA administration and discovered the synthesis of aspirin-triggered
NPD1 (AT-NPD1) in the brain. Then we performed the total chemical synthesis of
this molecule and tested in the setting of 2h middle cerebral artery occlusion
(MCAo) in Sprague-Dawley rats. Neurological status was evaluated at 24h, 48 h, 72
h, and 7 days. At 3h post-stroke onset, an intravenous administration of 333
μg/kg of AT-NPD1 sodium salt (AT-NPD1-SS) or methyl-ester (AT-NPD1-ME) or vehicle
(saline) as treatment was given. On day 7, ex vivo magnetic resonance imaging
(MRI) of the brains was conducted on 11.7 T MRI. T2WI, 3D volumes, and apparent
diffusion coefficient (ADC) maps were generated. In addition, infarct volumes and
number of GFAP (reactive astrocytes), ED-1 (activated microglia/macrophages) and 
SMI-71-positive vessels were counted in the cortex and striatum at the level of
the central lesion. All animals showed similar values for rectal and cranial
temperatures, arterial blood gases, and plasma glucose during and after MCAo.
Treatment with both AT-NPD1-SS and AT-NPD1-ME significantly improved neurological
scores compared to saline treatment at 24h, 48 h, 72 h and 7 days. Total lesion
volumes computed from T2WI images were significantly reduced by both AT-NPD1-SS
and AT-NPD1-ME treatment in the cortex (by 44% and 81%), striatum (by 61% and
77%) and total infarct (by 48% and 78%, respectively). Brain edema, computed from
T2WI in the cortex (penumbra) and striatum (core), was elevated in the saline
group. In contrast, both AT-NPD1 decreased water content in the striatum on day
7. 3D volumes, computed from T2WI, were dramatically reduced with both AT-NPD1
and the lesion was mostly localized in the subcortical areas. Treatment with both
AT-NPD1-SS and AT-NPD1-ME significantly reduced cortical (by 76% and 96%),
subcortical (by 61% and 70%) and total (69% and 84%, respectively) infarct
volumes as defined by histopathology. In conclusion, a novel biosynthetic pathway
that leads to the formation of AT-NPD1 mediator in the brain was discovered. In
addition, administration of synthetic AT-NPD1, in either its sodium salt or as
the methyl ester, was able to attenuate cerebral ischemic injury which leads to a
novel approach for pharmaceutical intervention and clinical translation.

Copyright © 2012 Elsevier Inc. All rights reserved.

PMCID: PMC3409566 [Available on 2013/7/1]
PMID: 22542947  [PubMed - indexed for MEDLINE]

11. Int J Dev Neurosci. 2012 Jun;30(4):315-23. doi: 10.1016/j.ijdevneu.2012.01.007.
Epub 2012 Jan 28.

Maternal prenatal omega-3 fatty acid supplementation attenuates hyperoxia-induced
apoptosis in the developing rat brain.

Tuzun F, Kumral A, Ozbal S, Dilek M, Tugyan K, Duman N, Ozkan H.

Department of Neonatology, School of Medicine, Dokuz Eylul University, Turkey.

Supraphysiologic amounts of oxygen negatively influences brain maturation and
development. The aim of the present study was to evaluate whether maternal ω-3
long-chain polyunsaturated fatty acid (ω-3 FA) supplementation during pregnancy
protects the developing brain against hyperoxic injury. Thirty-six rat pups from 
six different dams were divided into six groups according to the diet
modifications and hyperoxia exposure. The groups were: a control group (standard 
diet+room air), a hyperoxia group (standard diet+80% O₂ exposure), a
hyperoxia+high-dose ω-3 FA-supplemented group, a hyperoxia+low-dose ω-3
FA-supplemented group, a room air+low-dose ω-3 FA-supplemented+group, and a room 
air+high dose ω-3 FA-supplemented group. The ω-3 FA's were supplemented as a
mixture of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) from the
second day of pregnancy until birth. Rat pups in the hyperoxic groups were
exposed to 80% oxygen from birth until postnatal day 5 (P5). At P5, all animals
were sacrificed. Neuronal cell death and apoptosis were evaluated by cell count, 
TUNEL, and active Caspase-3 immunohistochemistry. Histopathological examination
showed that maternally ω-3 FA deficient diet and postnatal hyperoxia exposure
were associated with significantly lower neuronal counts and significantly higher
apoptotic cell death in the selected brain regions. Ω-3 FA treatment
significantly diminished apoptosis, in the selected brain regions, in a dose
dependent manner. Our results suggest that the maternal ω-3 FA supply may protect
the developing brain against hyperoxic injury.

Copyright © 2012 ISDN. Published by Elsevier Ltd. All rights reserved.

PMID: 22342579  [PubMed - indexed for MEDLINE]

12. J Matern Fetal Neonatal Med. 2012 Jun;25(6):849-54. doi:
10.3109/14767058.2011.587917. Epub 2011 Sep 6.

Maternal omega-3 fatty acid supplementation protects against
lipopolysaccharide-induced white matter injury in the neonatal rat brain.

Tuzun F, Kumral A, Dilek M, Ozbal S, Ergur B, Yesilirmak DC, Duman N, Yilmaz O,
Ozkan H.

Department of Pediatrics, Division of Neonatology, Dokuz Eylul University, Izmir,
Turkey.

OBJECTIVES: Periventricular leukomalacia (PVL) is the predominant form of brain
injury in premature infants, and no specific treatment currently exists for this 
condition. We have evaluated whether maternal omega-3 fatty acid (ω3 FA)
treatment reduces endotoxin-induced PVL in the developing rat brain.
METHODS: Wistar rats with dated pregnancies were fed a standard diet or a diet
enriched in ω3 FA (70% docosahexaenoic acid + 30% eicosapentaenoic acid mixture) 
during gestation. Intraperitoneal injection of lipopolysaccharide (LPS) was
administered consecutively on the 18th and 19th embryonic days to establish the
endotoxin-induced PVL rat model. The animals were divided into four groups: (i)
control, (ii) PVL, (iii) PVL+low-dose ω3 FA and (iv) PVL+high-dose ω3 FA. At day 
P7, apoptosis and hypomyelination in periventricular white matter were evaluated 
by immunohistochemical assessments.
RESULTS: High-dose maternal ω3 FA treatment reduced brain weight loss. Maternal
ω3 FA treatment given either in low or high doses greatly decreased caspase-3
immunoreactivity and increased myelin basic protein immunoreactivity, indicating 
a decrease in apoptosis and hypomyelination.
CONCLUSION: Considering that no specific treatment is available for PVL, maternal
ω3 FA supplementation may provide a nutritional strategy to limit periventricular
white matter damage caused by infections during pregnancy.

PMID: 21892882  [PubMed - indexed for MEDLINE]

13. J Neurochem. 2012 Jun;121(5):738-50. doi: 10.1111/j.1471-4159.2012.07726.x. Epub 
2012 Apr 12.

Docosahexaenoic acid, but not eicosapentaenoic acid, reduces the early
inflammatory response following compression spinal cord injury in the rat.

Hall JC, Priestley JV, Perry VH, Michael-Titus AT.

Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, OH 
43210, USA. jodie.hall@osumc.edu

Docosahexaenoic acid (DHA, 22 : 6) and eicosapentaenoic acid (EPA, 20 : 5) are
omega-3 polyunsaturated fatty acids (n-3 PUFAs) with distinct anti-inflammatory
properties. Both have neuroprotective effects acutely following spinal cord
injury (SCI). We examined the effect of intravenous DHA and EPA on early
inflammatory events after SCI. Saline, DHA or EPA (both 250 nmol/kg) were
administered 30 min after T12 compression SCI, to female Sprague-Dawley rats. DHA
significantly reduced the number of neutrophils to some areas of the injured
epicentre at 4 h and 24 h. DHA also reduced C-reactive protein plasma levels,
whereas EPA did not significantly reduce neutrophils or C-reactive protein.
Laminectomy and SCI elicited a sustained inflammatory response in the liver,
which was not reversed by the PUFAs. The chemokine KC/GRO/CINC and the cytokine
IL-6 provide gradients for chemotaxis of neutrophils to the epicentre. At 4 h
after injury, there was a significant increase in IL-6, KC/GRO/CINC, IL-1β and
tumour necrosis factor-α in the epicentre, with a return to baseline at 24 h.
Neither DHA nor EPA returned their levels to control values. These results
indicate that the acute neuroprotective effects of n-3 PUFAs in rat compression
SCI may be only partly attributed to reduction of some of the early inflammatory 
events occurring after injury.

© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for
Neurochemistry.

PMID: 22404382  [PubMed - indexed for MEDLINE]

14. Stroke. 2012 Mar;43(3):691-6. doi: 10.1161/STROKEAHA.111.636035. Epub 2012 Jan
26.

Free Fatty acids and delayed cerebral ischemia after subarachnoid hemorrhage.

Badjatia N, Seres D, Carpenter A, Schmidt JM, Lee K, Mayer SA, Claassen J,
Connolly ES, Elkind MS.

Neurological Institute of New York, 177 Fort Washington Avenue, New York, NY
10032, USA. nb2217@columbia.edu

BACKGROUND AND PURPOSE: The purpose of this study was to understand factors
related to increases in serum free fatty acid (FFA) levels and association with
delayed cerebral ischemia (DCI) after subarachnoid hemorrhage.
METHODS: We performed serial measurement of systemic oxygen consumption by
indirect calorimetry and FFA levels by liquid chromatography/mass spectrometry in
the first 14 days after ictus in 50 consecutive patients with subarachnoid
hemorrhage. Multivariable generalized estimating equation models identified
associations with FFA levels in the first 14 days after SAH and Cox proportional 
hazards model used to identified associations with time to DCI.
RESULTS: There were 187 measurements in 50 patients with subarachnoid hemorrhage 
(mean age, 56±14 years old; 66% women) with a median Hunt-Hess score of 3.
Adjusting for Hunt-Hess grade and daily caloric intake, n-6 and n-3 FFA levels
were both associated with oxygen consumption and the modified Fisher score.
Fourteen (28%) patients developed DCI on median postbleed Day 7. The modified
Fisher score (P=0.01), mean n-6:n-3 FFA ratio (P=0.02), and mean oxygen
consumption level (P=0.04) were higher in patients who developed DCI. In a Cox
proportional hazards model, the mean n-6:n-3 FFA ratio (P<0.001), younger age
(P=0.05), and modified Fisher scale (P=0.004) were associated with time to DCI.
CONCLUSIONS: Injury severity and oxygen consumption hypermetabolism are
associated with higher n-FFA levels and an increased n-6:n-3 FFA ratio is
associated with DCI. This may indicate a role for interventions that modulate
both oxygen consumption and FFA levels to reduce the occurrence of DCI.

PMID: 22282893  [PubMed - indexed for MEDLINE]

15. Transl Stroke Res. 2012 Mar;3(1):154-163. Epub 2011 Oct 27.

Superior Neuroprotective Efficacy of LAU-0901, a Novel Platelet-Activating Factor
Antagonist, in Experimental Stroke.

Belayev L, Eady TN, Khoutorova L, Atkins KD, Obenaus A, Cordoba M, Vaquero JJ,
Alvarez-Builla J, Bazan NG.

Platelet-activating factor (PAF) accumulates during cerebral ischemia, and
inhibition of this process plays a critical role in neuronal survival. Recently, 
we demonstrated that LAU-0901, a novel PAF receptor antagonist, is
neuroprotective in experimental stroke. We used magnetic resonance imaging in
conjunction with behavior and immunohistopathology to expand our understanding of
this novel therapeutic approach. Sprague-Dawley rats received 2 h middle cerebral
artery occlusion (MCAo) and were treated with LAU-0901 (60 mg/kg) or vehicle 2 h 
from MCAo onset. Behavioral function, T2-weighted imaging (T2WI), and apparent
diffusion coefficients were performed on days 1, 3, and 7 after MCAo. Infarct
volume and number of GFAP, ED-1, and NeuN-positive cells were conducted on day 7.
Behavioral deficit was significantly improved by LAU-0901 treatment compared to
vehicle on days 1, 3, and 7. Total lesion volumes computed from T2WI were
significantly reduced by LAU-0901 on days 1, 3, and 7 (by 83%, 90%, and 96%,
respectively), which was consistent with decreased edema formation.
Histopathology revealed that LAU-0901 treatment resulted in significant reduction
of cortical and subcortical infarct volumes, attenuated microglial infiltration, 
and promoted astrocytic and neuronal survival. These findings suggest LAU-0901 is
a promising neuroprotectant and provide the basis for future therapeutics in
patients suffering ischemic stroke.

PMCID: PMC3284672
PMID: 22408693  [PubMed]

16. PLoS One. 2012;7(10):e46151. doi: 10.1371/journal.pone.0046151. Epub 2012 Oct 30.

Docosahexaenoic acid signaling modulates cell survival in experimental ischemic
stroke penumbra and initiates long-term repair in young and aged rats.

Eady TN, Belayev L, Khoutorova L, Atkins KD, Zhang C, Bazan NG.

Neuroscience Center of Excellence, Louisiana State University Health Sciences
Center, New Orleans, Louisiana, United States of America.

BACKGROUND: Docosahexaenoic acid, a major omega-3 essential fatty acid family
member, improves behavioral deficit and reduces infarct volume and edema after
experimental focal cerebral ischemia. We hypothesize that DHA elicits
neuroprotection by inducing AKT/p70S6K phosphorylation, which in turn leads to
cell survival and protects against ischemic stroke in young and aged rats.
METHODS AND RESULTS: Rats underwent 2 h of middle cerebral artery occlusion
(MCAo). DHA, neuroprotectin D1 (NPD1) or vehicle (saline) was administered 3 h
after onset of stroke. Neurological function was evaluated on days 1, 2, 3, and
7. DHA treatment improved functional recovery and reduced cortical, subcortical
and total infarct volumes 7 days after stroke. DHA also reduced microglia
infiltration and increased the number of astrocytes and neurons when compared to 
vehicle on days 1 and 7. Increases in p473 AKT and p308 AKT
phosphorylation/activation were observed in animals treated with DHA 4 h after
MCAo. Activation of other members of the AKT signaling pathway were also observed
in DHA treated animals including increases in pS6 at 4 h and pGSK at 24 h. DHA or
NPD1 remarkably reduced total and cortical infarct in aged rats. Moreover, we
show that in young and aged rats DHA treatment after MCAo potentiates NPD1
biosynthesis. The phosphorylation of p308 AKT or pGSK was not different between
groups in aged rats. However, pS6 expression was increased with DHA or NPD1
treatment when compared to vehicle.
CONCLUSIONS: We suggest that DHA induces cell survival, modulates the
neuroinflammatory response and triggers long term restoration of synaptic
circuits. Both DHA and NPD1 elicited remarkable protection in aged animals.
Accordingly, activation of DHA signaling might provide benefits in the management
of ischemic stroke both acutely as well as long term to limit ensuing
disabilities.

PMCID: PMC3484151
PMID: 23118851  [PubMed - in process]

17. J Clin Psychiatry. 2011 Dec;72(12):1585-90. doi: 10.4088/JCP.11m06879. Epub 2011 
Aug 23.

Suicide deaths of active-duty US military and omega-3 fatty-acid status: a
case-control comparison.

Lewis MD, Hibbeln JR, Johnson JE, Lin YH, Hyun DY, Loewke JD.

Department of Preventive Medicine and Biometrics, Uniformed Services University
of the Health Sciences Bethesda, Maryland, USA.

Comment in
    J Clin Psychiatry. 2011 Dec;72(12):1574-6.

BACKGROUND: The recent escalation of US military suicide deaths to record numbers
has been a sentinel for impaired force efficacy and has accelerated the search
for reversible risk factors.
OBJECTIVE: To determine whether deficiencies of neuroactive, highly unsaturated
omega-3 essential fatty acids (n-3 HUFAs), in particular docosahexaenoic acid
(DHA), are associated with increased risk of suicide death among a large random
sample of active-duty US military.
METHOD: In this retrospective case-control study, serum fatty acids were
quantified as a percentage of total fatty acids among US military suicide deaths 
(n = 800) and controls (n = 800) matched for age, date of collection of sera,
sex, rank, and year of incident. Participants were active-duty US military
personnel (2002-2008). For cases, age at death ranged from 17-59 years (mean =
27.3 years, SD = 7.3 years). Outcome measures included death by suicide,
postdeployment health assessment questionnaire (Department of Defense Form 2796),
and ICD-9 mental health diagnosis data.
RESULTS: Risk of suicide death was 14% higher per SD of lower DHA percentage (OR 
= 1.14; 95% CI, 1.02-1.27; P < .03) in adjusted logistic regressions. Among men, 
risk of suicide death was 62% greater with low serum DHA status (adjusted OR =
1.62; 95% CI, 1.12-2.34; P < .01, comparing DHA below 1.75% [n = 1,389] to DHA of
1.75% and above [n = 141]). Risk of suicide death was 52% greater in those who
reported having seen wounded, dead, or killed coalition personnel (OR = 1.52; 95%
CI, 1.11-2.09; P < .01).
CONCLUSION: This US military population had a very low and narrow range of n-3
HUFA status. Although these data suggest that low serum DHA may be a risk factor 
for suicide, well-designed intervention trials are needed to evaluate causality.

© Copyright 2011 Physicians Postgraduate Press, Inc.

PMCID: PMC3259251
PMID: 21903029  [PubMed - indexed for MEDLINE]

18. J Trauma. 2011 Nov;71(5):1211-8. doi: 10.1097/TA.0b013e3182092c62.

Lipid mediators in cerebral spinal fluid of traumatic brain injured patients.

Farias SE, Heidenreich KA, Wohlauer MV, Murphy RC, Moore EE.

Department of Pharmacology, University of Colorado at Denver, Anschutz Medical
Campus, Aurora, CO, USA.

BACKGROUND: Enzymatic and nonenzymatic oxidation of polyunsaturated fatty acids
leads to the formation of biologically active products known as lipid mediators. 
In the brain, lipid mediators play an important role in supporting homeostasis
and normal function. Thus, levels of these metabolites in normal and pathologic
conditions in the brain are particularly relevant in understanding the transition
to disease.
METHODS: In this study, liquid chromatography tandem mass spectrometry was used
to analyze lipid mediators in cerebrospinal fluid (CSF) of controls and traumatic
brain injured (TBI) patients.
RESULTS: Our results showed that the levels of arachidonic acid (AA),
docosahexaenoic acid (DHA), 5- and 12- eicosatetraenoic acid (HETE) were
significantly increased in the CSF of TBI patients. The magnitude of increase was
10-fold for AA, DHA, and 5-HETE and 17-fold for 12-HETE. Prostaglandins and
leukotrienes were not detected in CSF of either control or brain injured
patients. Furthermore, this study found that isoprostanes and thromboxanes are
present in CSF of brain injured patients.
CONCLUSIONS: This study clearly shows that certain lipid mediators accumulate in 
the CSF of TBI patient. This study also suggests the potential use of DHA, AA, 5-
and 12-HETE as biochemical markers of brain injury and to monitor the impact of
interventions.

PMID: 21427623  [PubMed - indexed for MEDLINE]

19. J Neurotrauma. 2011 Oct;28(10):2113-22. doi: 10.1089/neu.2011.1872. Epub 2011 Oct
4.

The salutary effects of DHA dietary supplementation on cognition,
neuroplasticity, and membrane homeostasis after brain trauma.

Wu A, Ying Z, Gomez-Pinilla F.

Department of Integrative Biology and Physiology, University of California at Los
Angeles (UCLA), Los Angeles, California 90095, USA.

The pathology of traumatic brain injury (TBI) is characterized by the decreased
capacity of neurons to metabolize energy and sustain synaptic function, likely
resulting in cognitive and emotional disorders. Based on the broad nature of the 
pathology, we have assessed the potential of the omega-3 fatty acid
docosahexaenoic acid (DHA) to counteract the effects of concussive injury on
important aspects of neuronal function and cognition. Fluid percussion injury
(FPI) or sham injury was performed, and rats were then maintained on a diet high 
in DHA (1.2% DHA) for 12 days. We found that DHA supplementation, which elevates 
brain DHA content, normalized levels of brain-derived neurotrophic factor (BDNF),
synapsin I (Syn-1), cAMP-responsive element-binding protein (CREB), and
calcium/calmodulin-dependent kinase II (CaMKII), and improved learning ability in
FPI rats. It is known that BDNF facilitates synaptic transmission and learning
ability by modulating Syn-I, CREB, and CaMKII signaling. The DHA diet also
counteracted the FPI-reduced manganese superoxide dismutase (SOD) and Sir2 (a
NAD+-dependent deacetylase). Given the involvement of SOD and Sir2 in promoting
metabolic homeostasis, DHA may help the injured brain by providing resistance to 
oxidative stress. Furthermore, DHA normalized levels of calcium-independent
phospholipase A2 (iPLA2) and syntaxin-3, which may help preserve membrane
homeostasis and function after FPI. The overall results emphasize the potential
of dietary DHA to counteract broad and fundamental aspects of TBI pathology that 
may translate into preserved cognitive capacity.

PMCID: PMC3191367
PMID: 21851229  [PubMed - indexed for MEDLINE]

20. Mil Med. 2011 Oct;176(10):1120-7.

Neuroprotection for the warrior: dietary supplementation with omega-3 fatty
acids.

Lewis MD, Bailes J.

Defense and Veterans Brain Injury Center, 11300 Rockville Pike Suite 1100,
Rockville, MD 20812, USA.

Nutrition has traditionally involved in supplying energy and hydration. An
emerging concept developed by the authors is the concept of using omega-3 fatty
acids (n-3 FAs) to increase the resilience of the brain. The n-3 FAs have
numerous proven benefits including support of cardiovascular and psychiatric
health. Docosahexaenoic acid in particular, is found in high concentrations in
the brain. N-3 FAs provide benefits by exerting a protective mechanism at the
cellular and neuronal levels including the modulation of inflammatory cascade
following traumatic brain injury. Promising research and evolving clinical
experience now indicate that n-3 FA is useful and effective for recovery
following traumatic brain injury. More exciting is that new laboratory research
shows the beneficial effects extend to when n-3 FA is given before injury. Given 
the safety profile, availability, and affordability of n-3 FA, Generally
Recognized As Safe amounts of eicosapentaenoic acid and docosahexaenoic acid (up 
to 3,000 mg daily) should be considered for the athlete and soldier, not only for
its general health benefits, but particularly also for those at risk or high
exposure to brain impacts. A comprehensive, coordinated research program to
evaluate the multiple uses of n-3 FA should be a high priority for the Department
of Defense.

PMID: 22128646  [PubMed - indexed for MEDLINE]

21. Mol Neurobiol. 2011 Oct;44(2):216-22. doi: 10.1007/s12035-011-8200-6. Epub 2011
Sep 15.

Endogenous signaling by omega-3 docosahexaenoic acid-derived mediators sustains
homeostatic synaptic and circuitry integrity.

Bazan NG, Musto AE, Knott EJ.

Neuroscience Center of Excellence, Louisiana State University Health Sciences
Center, 2020 Gravier Street, Suite D, New Orleans, LA, 70112, USA,
nbazan@lsuhsc.edu.

The harmony and function of the complex brain circuits and synapses are sustained
mainly by excitatory and inhibitory neurotransmission, neurotrophins, gene
regulation, and factors, many of which are incompletely understood. A common
feature of brain circuit components, such as dendrites, synaptic membranes, and
other membranes of the nervous system, is that they are richly endowed in
docosahexaenoic acid (DHA), the main member of the omega-3 essential fatty acid
family. DHA is avidly retained and concentrated in the nervous system and known
to play a role in neuroprotection, memory, and vision. Only recently has it
become apparent why the surprisingly rapid increases in free (unesterified) DHA
pool size take place at the onset of seizures or brain injury. This phenomenon
began to be clarified by the discovery of neuroprotectin D1 (NPD1), the
first-uncovered bioactive docosanoid formed from free DHA through
15-lipoxygenase-1 (15-LOX-1). NPD1 synthesis includes, as agonists, oxidative
stress and neurotrophins. The evolving concept is that DHA-derived docosanoids
set in motion endogenous signaling to sustain homeostatic synaptic and circuit
integrity. NPD1 is anti-inflammatory, displays inflammatory resolving activities,
and induces cell survival, which is in contrast to the pro-inflammatory actions
of the many of omega-6 fatty acid family members. We highlight here studies
relevant to the ability of DHA to sustain neuronal function and protect synapses 
and circuits in the context of DHA signalolipidomics. DHA signalolipidomics
comprises the integration of the cellular/tissue mechanism of DHA uptake, its
distribution among cellular compartments, the organization and function of
membrane domains containing DHA phospholipids, and the precise cellular and
molecular events revealed by the uncovering of signaling pathways regulated by
docosanoids endowed with prohomeostatic and cell survival bioactivity. Therefore,
this approach offers emerging targets for prevention, pharmaceutical
intervention, and clinical translation involving DHA-mediated signaling.

PMCID: PMC3180614
PMID: 21918832  [PubMed - indexed for MEDLINE]

22. Stroke. 2011 Oct;42(10):2903-9. doi: 10.1161/STROKEAHA.111.620856. Epub 2011 Aug 
18.

Accumulation of dietary docosahexaenoic acid in the brain attenuates acute immune
response and development of postischemic neuronal damage.

Lalancette-Hébert M, Julien C, Cordeau P, Bohacek I, Weng YC, Calon F, Kriz J.

Department of Psychiatry and Neuroscience, Faculty of Medicine, University Laval,
2705 boul. Laurier, Quebec City, QC, G1V 4G2 Canada.

BACKGROUND AND PURPOSE: Consumption of fish has been shown to reduce risk of
coronary heart disease and, possibly, of ischemic stroke. Because docosahexaenoic
acid (DHA) is the most likely neuroactive component within fish oil, we
hypothesized that exposing mice to a DHA-enriched diet may reduce inflammation
and protect neurons against ischemic injury.
METHODS: To visualize the effects of DHA on neuroinflammation after stroke,
TLR2-fluc-GFP transgenic mice were exposed to either a control diet, a diet
depleted in n-3 polyunsaturated fatty acid, or a diet enriched in DHA during 3
months. Real-time biophotonic/bioluminescence imaging of the TLR2 response was
performed before and after middle cerebral artery occlusion, whereas cytokines
concentrations and stroke area analyses were performed at 3 and 7 days after
middle cerebral artery occlusion, respectively.
RESULTS: We show that a 3-month DHA treatment prevented microglial activation
after ischemic injury, reduced the ischemic lesion size, and increased levels of 
the antiapoptotic molecule Bcl-2 in the brain. Additional analysis revealed a
significant decrease in the levels of COX2 and IL-1β, but not in other
proinflammatory cytokines. Importantly, long-term DHA supplementation
significantly changed the n-3:n-6 polyunsaturated fatty acid ratio in the brain.
CONCLUSIONS: Collectively, these data indicate that diet-induced accumulation of 
DHA in the brain protects against postischemic inflammation and injury. Because
DHA is widely available at low cost and has an excellent safety profile, our data
suggest that increased DHA intake may provide protection against acute immune
response/brain damage in ischemic stroke.

PMID: 21852616  [PubMed - indexed for MEDLINE]

23. JPEN J Parenter Enteral Nutr. 2011 Sep;35(5):556-9. doi:
10.1177/0148607111416122.

Nutrition and traumatic brain injury: a perspective from the Institute of
Medicine report.

Bistrian BR, Askew W, Erdman JW Jr, Oria MP.

Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
bbistria@bidmc.harvard.edu

PMID: 21881010  [PubMed - indexed for MEDLINE]

24. Chem Biol. 2011 Aug 26;18(8):976-87. doi: 10.1016/j.chembiol.2011.06.008.

Novel proresolving aspirin-triggered DHA pathway.

Serhan CN, Fredman G, Yang R, Karamnov S, Belayev LS, Bazan NG, Zhu M, Winkler
JW, Petasis NA.

Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes
of Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine,
Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA. 
cnserhan@zeus.bwh.harvard.edu

Comment in
    Chem Biol. 2011 Oct 28;18(10):1208-9.

Endogenous mechanisms in the resolution of acute inflammation are of interest
because excessive inflammation underlies many pathologic abnormalities. We report
an aspirin-triggered DHA metabolome that biosynthesizes a potent product in
inflammatory exudates and human leukocytes, namely aspirin-triggered
Neuroprotectin D1/Protectin D1 [AT-(NPD1/PD1)]. The complete stereochemistry of
AT-(NPD1/PD1) proved to be
10R,17R-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid. The chirality of
hydroxyl groups and geometry of the conjugated triene system essential for
bioactivity were established by matching biological materials with
stereochemically pure isomers prepared by organic synthesis. AT-(NPD1/PD1)
reduced neutrophil (PMN) recruitment in murine peritonitis in a dose-dependent
fashion whereby neither a Δ(15)-trans-isomer nor DHA was effective. With human
cells, AT-(NPD1/PD1) decreased transendothelial PMN migration as well as enhanced
efferocytosis of apoptotic human PMN by macrophages. These results indicate that 
AT-(NPD1/PD1) is a potent anti-inflammatory proresolving molecule.

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMCID: PMC3164791
PMID: 21867913  [PubMed - indexed for MEDLINE]

25. Neurosci Lett. 2011 Jun 8;496(3):168-71. doi: 10.1016/j.neulet.2011.04.009. Epub 
2011 Apr 14.

Oral fish oil restores striatal dopamine release after traumatic brain injury.

Shin SS, Dixon CE.

Brain Trauma Research Center, Department of Neurosurgery, University of
Pittsburgh, 3434 Fifth Ave, Suite 201, Pittsburgh, PA 15260, USA.

Omega-3 fatty acid administration can affect the release of neurotransmitters and
reduce inflammation and oxidative stress, but its use in traumatic brain injury
(TBI) has not been described extensively. We investigated the effect of 7 day
oral fish oil treatment in the recovery of potassium evoked dopamine release
after TBI. Sham rats and TBI rats were given either olive oil or fish oil by oral
gavage and were subject to cerebral microdialysis. Olive oil treated TBI rats
showed significant dopamine release deficit compared to sham rats, and this
deficit was restored with oral fish oil treatment. There was no effect of fish
oil treatment on extracellular levels of dopamine metabolites such as
3,4-dihydroxyphenylacetic acid and homovanillic acid. These results suggest the
therapeutic potential of omega-3 fatty acids in restoring dopamine
neurotransmission deficits after TBI.

Published by Elsevier Ireland Ltd.

PMID: 21514362  [PubMed - indexed for MEDLINE]

26. Prev Med. 2011 Jun;52 Suppl 1:S75-80. doi: 10.1016/j.ypmed.2011.01.023. Epub 2011
Jan 31.

The combined effects of exercise and foods in preventing neurological and
cognitive disorders.

Gomez-Pinilla F.

Dept. of Integrative Biology and Physiology, and Dept. of Neurosurgery,
University of California Los Angeles, Los Angeles, CA 90095, USA.
fgomezpi@ucla.edu

OBJECTIVE: Exercise and select diets have important influences on health and
plasticity of the nervous system, and the molecular mechanisms involved with
these actions are starting to be elucidated. New evidence indicates that
exercise, in combination with dietary factors, exerts its effects by affecting
molecular events related to the management of energy metabolism and synaptic
plasticity.
METHODS: Published studies in animals and humans describing the effects of
exercise and diets in brain plasticity and cognitive abilities are discussed.
RESULTS: New evidence indicates that exercise and select diets exert their
effects by affecting molecular events related to the management of energy
metabolism and synaptic plasticity. An important instigator in the molecular
machinery stimulated by exercise is brain-derived neurotrophic factor (BDNF),
which acts at the interface of metabolism and plasticity.
CONCLUSIONS: Recent studies show that selected dietary factors share similar
mechanisms with exercise, and in some cases they can complement the action of
exercise. Therefore, exercise and dietary management appear as a non-invasive and
effective strategy to counteract neurological and cognitive disorders.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMCID: PMC3258093
PMID: 21281667  [PubMed - indexed for MEDLINE]

27. J Stroke Cerebrovasc Dis. 2011 May-Jun;20(3):188-95. doi:
10.1016/j.jstrokecerebrovasdis.2009.11.016. Epub 2010 Jul 10.

Eicosapentaenoic acid prevents memory impairment after ischemia by inhibiting
inflammatory response and oxidative damage.

Okabe N, Nakamura T, Toyoshima T, Miyamoto O, Lu F, Itano T.

Department of Neurobiology, Kagawa University Faculty of Medicine, 1750-1
Ikenobe, Miki, Kagawa, Japan.

Previous studies have demonstrated that the generation of reactive oxygen species
and an excessive inflammatory reaction are involved in the progression of neural 
damage following brain ischemia. In this study, we focused on the
anti-inflammatory and antioxidant properties of eicosapentaenoic acid (EPA).
Gerbils were treated intraperitoneally with 500 mg/kg of EPA ethyl for 4 weeks
until the day of forebrain ischemia, which was induced by occluding the bilateral
common carotid artery for 5 minutes. In the first part of the 2-part experiment, 
the effect of EPA treatment was evaluated using hematoxylin and eosin staining
and deoxynucleotidyl transferase-mediated dUTP nick-end labeling as a marker of
cell death (n=3 per group). The inflammatory reaction was evaluated using
anti-Iba1 immunohistochemistry, a marker of microglial activation (n=3 per
group), and detection of 8-hydroxyl-2'-deoxyguanosine, a marker of oxidative DNA 
damage (n=4 per group). In the second part of the experiment, the effect of EPA
treatment on memory function was examined using an 8-arm radial maze (n=6 per
group). EPA treatment significantly inhibited DNA oxidative damage (P < .05) and 
accumulation of Iba1-positive cells in the CA1 area at 12 and 72 hours after the 
induction of ischemia, and also decreased apoptotic neurons and neuronal death (P
< .001) at 72 hours after ischemia. EPA treatment also significantly improved
memory function (P < .05). These findings suggest that EPA inhibits the
inflammatory reaction and oxidative damage occurring after ischemic brain injury,
and also may contribute to the prevention of neural damage and memory impairment 
following such injury.

Copyright © 2011 National Stroke Association. Published by Elsevier Inc. All
rights reserved.

PMID: 20621517  [PubMed - indexed for MEDLINE]

28. Curr Opin Clin Nutr Metab Care. 2011 Mar;14(2):158-67. doi:
10.1097/MCO.0b013e328342cba5.

Docosahexaenoic acid: brain accretion and roles in neuroprotection after brain
hypoxia and ischemia.

Mayurasakorn K, Williams JJ, Ten VS, Deckelbaum RJ.

Institute of Human Nutrition, Department of Pediatrics, College of Physicians and
Surgeons of Columbia University, New York, New York 10032, USA.

PURPOSE OF REVIEW: With important effects on neuronal lipid composition,
neurochemical signaling and cerebrovascular pathobiology, docosahexaenoic acid
(DHA), a n-3 polyunsaturated fatty acid, may emerge as a neuroprotective agent
against cerebrovascular disease. This paper examines pathways for DHA accretion
in brain and evidence for possible roles of DHA in prophylactic and therapeutic
approaches for cerebrovascular disease.
RECENT FINDINGS: DHA is a major n-3 fatty acid in the mammalian central nervous
system and enhances synaptic activities in neuronal cells. DHA can be obtained
through diet or to a limited extent via conversion from its precursor,
α-linolenic acid (α-LNA). DHA attenuates brain necrosis after hypoxic ischemic
injury, principally by modulating membrane biophysical properties and maintaining
integrity in functions between presynaptic and postsynaptic areas, resulting in
better stabilizing intracellular ion balance in hypoxic-ischemic insult.
Additionally, DHA alleviates brain apoptosis, by inducing antiapoptotic
activities such as decreasing responses to reactive oxygen species, upregulating 
antiapoptotic protein expression, downregulating apoptotic protein expression,
and maintaining mitochondrial integrity and function.
SUMMARY: DHA in brain relates to a number of efficient delivery and accretion
pathways. In animal models DHA renders neuroprotection after hypoxic-ischemic
injury by regulating multiple molecular pathways and gene expression.

PMID: 21178607  [PubMed - indexed for MEDLINE]

29. Transl Stroke Res. 2011 Mar;2(1):33-41. Epub 2010 Nov 4.

Docosahexaenoic Acid Therapy of Experimental Ischemic Stroke.

Belayev L, Khoutorova L, Atkins KD, Eady TN, Hong S, Lu Y, Obenaus A, Bazan NG.

We examined the neuroprotective efficacy of docosahexaenoic acid (DHA), an
omega-3 essential fatty acid family member, in acute ischemic stroke; studied the
therapeutic window; and investigated whether DHA administration after an ischemic
stroke is able to salvage the penumbra. In each series described below, SD rats
underwent 2 h of middle cerebral artery occlusion (MCAo). In series 1, DHA or
saline was administered i.v. at 3, 4, 5, or 6 h after stroke. In series 2, MRI
was conducted on days 1, 3 and 7. In series 3, DHA or saline was administered at 
3 h, and lipidomic analysis was conducted on day 3. Treatment with DHA
significantly improved behavior and reduced total infarct volume by a mean of 40%
when administered at 3 h, by 66% at 4 h, and by 59% at 5 h. Total lesion volumes 
computed from T2-weighted images were reduced in the DHA group at all time
points. Lipidomic analysis showed that DHA treatment potentiates neuroprotectin
D1 (NPD1) synthesis in the penumbra 3 days after MCAo. DHA administration
provides neurobehavioral recovery, reduces brain infarction and edema, and
activates NPD1 synthesis in the penumbra when administered up to 5 h after focal 
cerebral ischemia in rats.

PMCID: PMC3037476
PMID: 21423332  [PubMed]

30. Neurosurgery. 2011 Feb;68(2):474-81; discussion 481. doi:
10.1227/NEU.0b013e3181ff692b.

Dietary supplementation with the omega-3 fatty acid docosahexaenoic acid in
traumatic brain injury.

Mills JD, Hadley K, Bailes JE.

Department of Neurosurgery, West Virginia University School of Medicine,
Morgantown, West Virginia, USA.

BACKGROUND: Although various strategies for prevention of brain disease have been
implemented, no substance has been found to be advantageous for prophylaxis
against brain injury.
OBJECTIVE: While previous work in our laboratory and others have shown positive
effects using the omega-3 fatty acid docosahexaenoic acid (DHA) in post-injury
treatment following traumatic and ischemic insults, we wished to test its effects
when given prior to injury. We have attempted to measure anatomical, cellular,
and behavioral outcomes with a prophylactic administration of DHA.
METHODS: Five groups of 16 adult male Sprague-Dawley rats were subjected to an
impact acceleration traumatic brain after having received a prior administration 
of DHA in doses of 3, 12, and 40 mg/kg for 30 days prior. Serum fatty acid levels
were determined from isolated plasma phospholipids at baseline and at the end of 
30 days supplementation. Following sacrifice 1 week after injury, brainstem white
matter tracts underwent fluorescent immunohistochemical processing for labeling
of beta amyloid precursor protein (APP), an anatomical marker of brain injury, as
well as measurements of CD68 and caspase-3 levels, and water maze testing was
used for behavioral assessment.
RESULTS: Dietary supplementation with DHA resulted in increased serum DHA levels 
proportionate with the escalating dosage. Immunohistochemical analysis revealed
significantly (P < .05) decreased numbers of APP levels in all groups of animals 
receiving pre-injury supplementation with DHA of 4, 12, and 40 mg/kg at 13955,
4186, and 2827 axons per mm³, respectively, vs 37442 in unsupplemented animals,
as measured by stereological methodology. Using a selective measuring technique, 
only the highest dosage group, 40 mg/kg showed significantly (P < .05) decreased 
numbers of APP positive axons, at 1.15 axons per high power field vs 6.78 in
unsupplemented animals. CD-68, caspase-3, and water maze testing all were
significantly (P < .05) improved in the high dose group.
CONCLUSION: Dietary supplementation with DHA increases serum levels and, if given
prior to traumatic brain injury, reduces the injury response, as measured by
axonal injury counts, markers for cellular injury and apoptosis, and memory
assessment by water maze testing. This uniform response was seen for the highest 
dosage group, 40 mg/kg given over 30 days prior to injury, but when measured by
stereological counting methodology there was a positive response to anatomical
injury across low to high doses of DHA. The potential for DHA to provide
prophylactic benefit to the brain against traumatic injury appears promising and 
requires further investigation.

PMID: 21135750  [PubMed - indexed for MEDLINE]

31. Acta Cir Bras. 2011;26 Suppl 1:32-7.

Preconditioning with oil mixes of high ratio Omega-9: Omega-6 and a low ratio
Omega-6:Omega-3 in rats subjected to brain ischemia/reperfusion.

Pinheiro PM, Campelo AP, Guimarães SB, Patrocínio RM, Valença Junior JT,
Vasconcelos PR.

Department of Surgery, Federal University of Ceara, Fortaleza-CE, Brazil.

PURPOSE: This study aimed to assess the effects of preconditioning with mixtures 
of oils containing high/low ratio of ω-6/ω-3 and ω-9/ω-6, respectively, in an
experimental model of cerebral ischemia-reperfusion (I/R).
METHODS: Forty-two Wistar rats were randomly distributed into two groups: control
(n=24) and test (n=18). Control group was subdivided in 4 subgroups (n=6): G1:
Sham-Water; G2: I/R-Water; G3: Sham-Isolipidic and G4: I/R-Isolipid. The animals 
received water or a isolipid mixture containing ω-3 oils (8:1 ratio) and ω-9/ω-6 
(0.4:1 ratio) by gavage for seven days. Test group included 3 subgroups (n=6) G5:
I/R-Mix1, G: 6 I/R-Mix2 and G7: I/R-Mix3. Test group animals received oily
mixtures of ω-3 (1.4:1 ratio) and ω-6 (3.4:1 ratio), differing only in source of 
ω-3: G5 (alpha-linolenic acid); G6 (alpha-linolenic, docosahexaenoic and
eicosapentaenoic acids), and G7 (alpha-linolenic and docosahexaenoic acids). On
day 7 I/R rats underwent cerebral ischemia with bilateral occlusion of common
carotid arteries for 1 hour followed by reperfusion for 3 hours. G1 and G3
animals underwent sham operation. Concluded the experiment, animals were
decapitated and their brains sliced for red neurons (RN) count in CA3 area of the
hippocampus. Variables were compared using ANOVA-Tukey test.
RESULTS: The use of different mix preparations promoted a decrease in red cell
count in all three groups (G5/G6/G7), compared with G2/G4, confirming the
protective effect of different oil blends, regardless of ω-3 source.
CONCLUSION: Pre-conditioning with mixtures of oils containing high ratio ω-6/ω-3 
and low ω-9/ω-6 relationship protects brain neurons against I/R injury in an
experimental model.

PMID: 21971654  [PubMed - indexed for MEDLINE]

32. Clin Neurosurg. 2011;58:51-6.

Concussion management at the NFL, college, high school, and youth sports levels.

Maroon JC, Bost J.

University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

PMID: 21916127  [PubMed - indexed for MEDLINE]

33. J Neurosurg. 2011 Jan;114(1):77-84. doi: 10.3171/2010.5.JNS08914. Epub 2010 Jul
16.

Omega-3 fatty acid supplementation and reduction of traumatic axonal injury in a 
rodent head injury model.

Mills JD, Bailes JE, Sedney CL, Hutchins H, Sears B.

Department of Neurosurgery, West Virginia University School of Medicine,
Morgantown, West Virginia, USA. jmills@hsc.wvu.edu

OBJECT: Traumatic brain injury remains the most common cause of death in persons 
under 45 years of age in the Western world. Recent evidence from animal studies
suggests that supplementation with omega-3 fatty acid (O3FA) (particularly
eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) improves functional
outcomes following focal neural injury. The purpose of this study is to determine
the benefits of O3FA supplementation following diffuse axonal injury in rats.
METHODS: Forty adult male Sprague-Dawley rats were used. Three groups of 10 rats 
were subjected to an impact acceleration injury and the remaining group underwent
a sham-injury procedure (surgery, but no impact injury). Two of the groups
subjected to the injury were supplemented with 10 or 40 mg/kg/day of O3FA; the
third injured group served as an unsupplemented control group. The sham-injured
rats likewise received no O3FA supplementation. Serum fatty acid levels were
determined from the isolated plasma phospholipids prior to the injury and at the 
end of the 30 days of supplementation. After the animals had been killed,
immunohistochemical analysis of brainstem white matter tracts was performed to
assess the presence of β-amyloid precursor protein (APP), a marker of axonal
injury. Immunohistochemical analyses of axonal injury mechanisms-including
analysis for caspase-3, a marker of apoptosis; RMO-14, a marker of neurofilament 
compaction; and cytochrome c, a marker of mitochondrial injury-were performed.
RESULTS: Dietary supplementation with a fish oil concentrate rich in EPA and DHA 
for 30 days resulted in significant increases in O3FA serum levels: 11.6% ± 4.9% 
over initial levels in the 10 mg/kg/day group and 30.7% ± 3.6% in the 40
mg/kg/day group. Immunohistochemical analysis revealed significantly (p < 0.05)
decreased numbers of APP-positive axons in animals receiving O3FA
supplementation: 7.7 ± 14.4 axons per mm(2) in the 10 mg/kg/day group and 6.2 ±
11.4 axons per mm(2) in the 40 mg/kg/day group, versus 182.2 ± 44.6 axons per
mm(2) in unsupplemented animals. Sham-injured animals had 4.1 ± 1.3 APP-positive 
axons per mm(2). Similarly, immunohistochemical analysis of caspase-3 expression 
demonstrated significant (p < 0.05) reduction in animals receiving O3FA
supplementation, 18.5 ± 28.3 axons per mm(2) in the 10 mg/kg/day group and 13.8 ±
18.9 axons per mm(2) in the 40 mg/kg/day group, versus 129.3 ± 49.1 axons per
mm(2) in unsupplemented animals.
CONCLUSIONS: Dietary supplementation with a fish oil concentrate rich in the
O3FAs EPA and DHA increases serum levels of these same fatty acids in a
dose-response effect. Omega-3 fatty acid supplementation significantly reduces
the number of APP-positive axons at 30 days postinjury to levels similar to those
in uninjured animals. Omega-3 fatty acids are safe, affordable, and readily
available worldwide to potentially reduce the burden of traumatic brain injury.

PMID: 20635852  [PubMed - indexed for MEDLINE]

34. Nutr Health. 2011;20(3-4):165-9.

Collaborative effects of diet and exercise on cognitive enhancement.

Gomez-Pinilla F.

Department of Integrative Biology and Physiology, University of California Los
Angeles, Los Angeles, CA 90095, USA. fgomezpi@ucla.edu

Certain dietary factors, such as omega-3 fatty acids and curcumin, are reviewed
in their context of stimulating molecular systems that serve synaptic function,
while diets rich in saturated fats do the opposite. In turn, exercise, using
similar mechanisms as healthy diets, displays healing effects on the brain such
as counteracting the mental decline associated with age and facilitating
functional recovery resulting from brain injury and disease. Diet and exercise
are two noninvasive approaches that used together may enhance neural repair.
Omega 3 fatty acids and curcumin elevate levels of molecules important for
synaptic plasticity such as brain-derived neurotrophic factor (BDNF), thus
benefiting normal brain function and recovery events following brain insults.

PMCID: PMC3258096
PMID: 22141190  [PubMed - indexed for MEDLINE]

35. Neuropathology. 2010 Dec;30(6):597-605. doi: 10.1111/j.1440-1789.2010.01114.x.

Maternal docosahexaenoic acid-enriched diet prevents neonatal brain injury.

Suganuma H, Arai Y, Kitamura Y, Hayashi M, Okumura A, Shimizu T.

Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan.
hsuganu@med.juntendo.ac.jp

Hypoxic-ischemic encephalopathy due to neonatal asphyxia is one of the most
important causes of delayed neurological development. Prolonged neuronal
apoptosis plays an important role in the processes contributing to neuronal
degeneration. Docosahexaenoic acid (DHA), a major component of brain membrane
phospholipids, prevents neuronal cell apoptosis and plays an important role as an
anti-oxidant agent. We investigated the neuroprotective and anti-oxidant effects 
of maternal DHA supplementation during pregnancy in a model of neonatal
hypoxic-ischemic encephalopathy. Pregnant rats were randomly assigned to two
experimental groups: a control group or a DHA-enriched diet group.
Hypoxic-ischemic encephalopathy was produced by left common carotid artery
occlusion and exposure to 8% oxygen for 1.5 h. TUNEL assay, immunohistochemistry 
for caspase-3 and 8-hydroxy-deoxyguanosine (8-OHdG), and Western blot for
caspase-3 were performed at postnatal days 8, 10 and 14. Fatty acid composition
of brain was estimated on postnatal day 7. Maternal diet clearly influenced brain
fatty acid composition in pups. Numbers of apoptotic neuronal cells and 8-OHdG
immunoreactivity were significantly decreased in the DHA-enriched group. Our
findings indicate that maternal DHA-enriched diet during pregnancy provides
neuroprotection by inhibiting oxidative stress and apoptotic neuronal death.
Dietary supplementation of DHA during pregnancy may thus be beneficial in
preventing neonatal brain injury.

© 2010 Japanese Society of Neuropathology.

PMID: 20408962  [PubMed - indexed for MEDLINE]

36. Stroke. 2010 Oct;41(10):2341-7. doi: 10.1161/STROKEAHA.110.586081. Epub 2010 Aug 
12.

Omega-3 polyunsaturated fatty acid supplementation confers long-term
neuroprotection against neonatal hypoxic-ischemic brain injury through
anti-inflammatory actions.

Zhang W, Hu X, Yang W, Gao Y, Chen J.

Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh,
PA 15213, USA. chenj2@upmc.edu

BACKGROUND AND PURPOSE: Current available therapies for neonatal hypoxia/ischemia
(H/I) brain injury are rather limited. Here, we investigated the effect of
omega-3 polyunsaturated fatty acids on brain damage and long-term neurological
function after H/I in neonates.
METHODS: Female rats were treated with or without an omega-3 polyunsaturated
fatty acids-enriched diet from the second day of pregnancy until 14 days after
parturition. Seven-day-old neonates were subjected to H/I and euthanized 5 weeks 
later for evaluation of tissue loss. Neurological impairment was assessed
progressively for 5 weeks after H/I by grid walking, foot fault, and Morris water
maze. Activation of microglia and production of inflammatory mediators were
examined up to 7 days after H/I.
RESULTS: Omega-3 polyunsaturated fatty acid supplementation significantly reduced
brain damage and improved long-term neurological outcomes up to 5 weeks after
neonatal H/I injury. Omega-3 polyunsaturated fatty acids exerted an
anti-inflammatory effect in microglia both in an in vivo model of H/I and in in
vitro microglial cultures subjected to inflammatory stimuli by inhibiting NF-κB
activation and subsequent release of inflammatory mediators.
CONCLUSIONS: Our results suggest that omega-3 polyunsaturated fatty acids confer 
potent neuroprotection against neonatal H/I brain injury through, at least
partially, suppressing a microglial-mediated inflammatory response.

PMCID: PMC3021248
PMID: 20705927  [PubMed - indexed for MEDLINE]

37. J Neurotrauma. 2010 Sep;27(9):1617-24. doi: 10.1089/neu.2009.1239.

Docosahexaenoic acid reduces traumatic axonal injury in a rodent head injury
model.

Bailes JE, Mills JD.

Department of Neurosurgery, West Virginia University School of Medicine,
Morgantown, West Virginia 26506, USA. jbailes@hsc.wvu.edu

Traumatic brain injury (TBI) remains the most common cause of death in persons
under age 45 in the Western world. Recent evidence from animal studies suggests
that supplementation with omega-3 fatty acids (O3FA) improves functional outcomes
following focal neural injury. The purpose of this study is to determine the
benefits of DHA supplementation following diffuse axonal injury in rats. Four
groups of 10 adult male Sprague-Dawley rats were subjected to an impact
acceleration injury and then received 30 days of supplementation with either
10 mg/kg/d or 40 mg/kg/d of docosahexaenoic acid (DHA). Serum fatty acid levels
were determined from the isolated plasma phospholipids prior to injury and at the
end of the 30 days of DHA supplementation. Following sacrifice, brainstem white
matter tracts underwent fluorescent immunohistochemical processing for labeling
of β-amyloid precursor protein (APP), a marker of axonal injury. Dietary
supplementation with either 10 mg/kg/d or 40 mg/kg/d of DHA for 30 days results
in significantly (p < 0.05) increased DHA serum levels of 123% and 175% over
baseline, respectively. Immunohistochemical analysis reveals significantly
(p < 0.05) decreased numbers of APP-positive axons in animals receiving dietary
supplementation with DHA, 26.1 (SD 5.3) for 10 mg/kg/d, and 19.6 (SD 4.7) for
40 mg/kg/d axons per mm(2), versus 147.7 (SD 7.1) axons in unsupplemented
animals. Sham-injured animals had 6.4 (SD 13.9) APP positive axons per mm(2).
Dietary supplementation with DHA increases serum levels in a dose-dependent
manner. DHA supplementation significantly reduces the number of APP-positive
axons at 30 days post-injury, to levels similar to seen those in uninjured
animals. DHA is safe, affordable, and readily available worldwide to potentially 
reduce the burden of TBI.

PMID: 20597639  [PubMed - indexed for MEDLINE]

38. Mol Neurobiol. 2010 Jun;41(2-3):367-74. doi: 10.1007/s12035-010-8139-z. Epub 2010
May 14.

Omega-3 essential fatty acids modulate initiation and progression of
neurodegenerative disease.

Palacios-Pelaez R, Lukiw WJ, Bazan NG.

Diater Laboratorios, 28918, Leganes, Madrid, Spain. r.palacios@diater.com

The significance of the selective enrichment in omega-3 essential fatty acids in 
photoreceptors and synaptic membranes of the nervous system has remained, until
recently, incompletely understood. While studying mechanisms of cell survival in 
neural degeneration, we discovered a docosanoid synthesized from unesterified
docosahexaenoic acid (DHA) by a 15-lipoxygenase (15-LOX), which we called
neuroprotectin D1 (NPD1; 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15E,19Z hexaenoic
acid). This lipid mediator is a docosanoid because it is derived from the 22
carbon (22C) precursor DHA, unlike eicosanoids, which are derived from the 20
carbon (20C) arachidonic acid (AA) family member of essential fatty acids. We
discovered that NPD1 is promptly made in response to oxidative stress, as a
response to brain ischemia-reperfusion, and in the presence of neurotrophins.
NPD1 is neuroprotective in experimental brain damage, in oxidative-stressed
retinal pigment epithelial (RPE) cells, and in human brain cells exposed to
amyloid-beta (Abeta) peptides. We thus envision NPD1 as a protective sentinel,
one of the very first defenses activated when cell homeostasis is threatened by
imbalances in normal neural function. We provide here, in three sections, recent 
experimental examples that highlight the specificity and potency of NPD1 spanning
beneficial bioactivity during initiation and early progression of
neurodegeneration: (1) during retinal signal phototransduction, (2) during brain 
ischemia-reperfusion, and (3) in Alzheimer's disease (AD) and stressed human
brain cell models of AD. From this experimental evidence, we conclude that
DHA-derived NPD1 regulation targets upstream events of brain cell apoptosis, as
well as neuro-inflammatory signaling, promoting and maintaining cellular
homeostasis, and restoring neural and retinal cell integrity.

PMID: 20467837  [PubMed - indexed for MEDLINE]

39. Am J Obstet Gynecol. 2010 May;202(5):469.e1-6. doi: 10.1016/j.ajog.2010.01.076.
Epub 2010 Mar 31.

Docosahexaenoic acid confers neuroprotection in a rat model of perinatal
hypoxia-ischemia potentiated by Escherichia coli lipopolysaccharide-induced
systemic inflammation.

Berman DR, Liu YQ, Barks J, Mozurkewich E.

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology,
University of Michigan Medical School, Ann Arbor, MI.

OBJECTIVE: Lipopolysaccharide pretreatment potentiates hypoxic ischemic injury.
We hypothesized that docosahexaenoic acid pretreatment would improve function and
reduce brain volume loss in this rat model of perinatal brain injury and
inflammation.
STUDY DESIGN: Seven-day-old rats were divided into 3 groups: intraperitoneal
docosahexaenoic acid 1 mg/kg and lipopolysaccharide 0.1 mg/kg, 25% albumin and
lipopolysaccharide, and normal saline. Injections were given 2.5 hours before
carotid ligation, followed by 90 minutes 8% O2. Rats underwent sensorimotor
function testing and brain volume loss assessment on postnatal day 14.
RESULTS: Docosahexaenoic acid pretreatment improved vibrissae forepaw placing
scores compared with albumin/lipopolysaccharide (mean+/-standard deviation
weighted score/20: 17.72+/-0.92 docosahexaenoic acid/lipopolysaccharide vs
13.83+/-0.82 albumin/lipopolysaccharide; P<.007). Albumin/lipopolysaccharide rats
scores were worse than those of the normal saline/normal saline rats
(13.83+/-0.82 vs 17.21+/-0.71; P=.076). No significant differences in brain
volume loss were observed among groups.
CONCLUSION: Lipopolysaccharide inflammatory stimulation in conjunction with
hypoxic ischemic resulted in poorer function than hypoxic ischemic alone.
Docosahexaenoic acid pretreatment had significantly improved function in neonatal
rats exposed to lipopolysaccharide and hypoxic ischemic.

Copyright (c) 2010 Mosby, Inc. All rights reserved.

PMCID: PMC3535291
PMID: 20356570  [PubMed - indexed for MEDLINE]

40. Prostaglandins Other Lipid Mediat. 2010 Apr;91(3-4):85-9. doi:
10.1016/j.prostaglandins.2009.09.005. Epub 2009 Oct 3.

Docosahexaenoic acid neurolipidomics.

Niemoller TD, Bazan NG.

Neuroscience Center of Excellence, Louisiana State University Health Sciences
Center, School of Medicine, New Orleans, LA 70112, USA.

Mediator lipidomics is a field of study concerned with the characterization,
structural elucidation and bioactivity of lipid derivatives actively generated by
enzymatic activity. It is well known that omega-3 fatty acids are beneficial for 
brain function. Docosahexaenoic acid [DHA; 4 22:6(n-3)] is the most abundant
essential omega-3 fatty acid present in the brain and it has multiple mechanisms 
of exerting protective effects after cellular injury. Certain lipid species
produced from DHA early during the reperfusion stage of brain
ischemia-reperfusion injury are generated in order to help the cell cope as the
injury progresses. We explore these newly discovered lipid mediators in order to 
understand their role in the cell. We have identified one of these potentially
protective lipid mediators as a novel stereospecific DHA-derived fatty acid,
called neuroprotectin D1 (NPD1; 10R,17S-dihydroxy-docosa-4Z,7Z,11E,15E,19Z
hexaenoic acid). DHA also has important roles in pro-survival signaling cascades 
after ischemia-reperfusion in injury. It has been shown to accelerate AKT
translocation and activation and has binding affinity with an important
PPAR-gamma family of ligand-activated nuclear receptors that have been implicated
in various aspects of lipid metabolism and have been shown to have
anti-inflammatory actions. Here we present an overview of these mechanisms and
discuss the potential of using DHA signaling in the development of treatments for
the large population of patients suffering from the devastating consequences of
stroke.

Copyright 2009. Published by Elsevier Inc.

PMCID: PMC2905848
PMID: 19804838  [PubMed - indexed for MEDLINE]

41. Acta Neurol Taiwan. 2009 Dec;18(4):231-41.

Essential fatty acids and human brain.

Chang CY, Ke DS, Chen JY.

Department of Neurology, Chi-Mei Medical Center, Tainan Taiwan.
chiayu.chang7@msa.hinet.net

The human brain is nearly 60 percent fat. We've learned in recent years that
fatty acids are among the most crucial molecules that determine your brain's
integrity and ability to perform. Essential fatty acids (EFAs) are required for
maintenance of optimal health but they can not synthesized by the body and must
be obtained from dietary sources. Clinical observation studies has related
imbalance dietary intake of fatty acids to impaired brain performance and
diseases. Most of the brain growth is completed by 5-6 years of age. The EFAs,
particularly the omega-3 fatty acids, are important for brain development during 
both the fetal and postnatal period. Dietary decosahexaenoic acid (DHA) is needed
for the optimum functional maturation of the retina and visual cortex, with
visual acuity and mental development seemingly improved by extra DHA. Beyond
their important role in building the brain structure, EFAs, as messengers, are
involved in the synthesis and functions of brain neurotransmitters, and in the
molecules of the immune system. Neuronal membranes contain phospholipid pools
that are the reservoirs for the synthesis of specific lipid messengers on
neuronal stimulation or injury. These messengers in turn participate in signaling
cascades that can either promote neuronal injury or neuroprotection. The goal of 
this review is to give a new understanding of how EFAs determine our brain's
integrity and performance, and to recall the neuropsychiatric disorders that may 
be influenced by them. As we further unlock the mystery of how fatty acids affect
the brain and better understand the brain's critical dependence on specific EFAs,
correct intake of the appropriate diet or supplements becomes one of the tasks we
undertake in pursuit of optimal wellness.

PMID: 20329590  [PubMed - indexed for MEDLINE]

42. J Nutr Biochem. 2009 Sep;20(9):715-25. doi: 10.1016/j.jnutbio.2008.06.014. Epub
2008 Sep 20.

Protective effect of docosahexaenoic acid against brain injury in ischemic rats.

Pan HC, Kao TK, Ou YC, Yang DY, Yen YJ, Wang CC, Chuang YH, Liao SL, Raung SL, Wu
CW, Chiang AN, Chen CJ.

Chung Hwa University of Medical Technology, Tainan, Taiwan.

Evidence suggests that inactivation of cell-damaging mechanisms and/or activation
of cell-survival mechanisms may provide effective preventive or therapeutic
interventions to reduce cerebral ischemia/reperfusion (I/R) injuries.
Docosahexaenoic acid (DHA) is an essential polyunsaturated fatty acid in the
central nervous system that has been shown to possess neuroprotective effects. We
examined whether different preadministrative protocols of DHA have effects on
brain injury after focal cerebral I/R and investigated the potential neuroactive 
mechanisms involved. Sprague-Dawley rats were intraperitoneally pretreated with
DHA once 1 h or 3 days being subjected to focal cerebral I/R or daily for 6 weeks
before being subjected to focal cerebral I/R. Reduction of brain infarction was
found in all three DHA-pretreated groups. The beneficial effect of DHA on the
treatment groups was accompanied by decreases in blood-brain barrier disruption, 
brain edema, malondialdehyde (MDA) production, inflammatory cell infiltration,
interleukin-6 (IL-6) expression and caspase-3 activity. Elevation of
antioxidative capacity, as evidenced by decreased MDA level and increased
superoxide dismutase activity and glutathione level, was detected only in the
chronic daily-administration group. The two single-administration groups showed
increased phosphorylation of extracellular-signal-regulated kinase (ERK).
Elevation of Bcl-2 expression was detected in the chronic daily-administration
and 3-day-administration groups. In vitro study demonstrated that DHA attenuated 
IL-6 production from stimulated glial cells involving nuclear factor kappaB
inactivation. Therefore, the data suggest that the neuroprotective mechanisms of 
DHA pretreatment are, in part, mediated by attenuating damaging mechanisms
through reduction of cytotoxic factor production and by strengthening survival
mechanisms through ERK-mediated and/or Bcl-2-mediated prosurvival cascade.

PMID: 18805685  [PubMed - indexed for MEDLINE]

43. Stroke. 2009 Sep;40(9):3121-6. doi: 10.1161/STROKEAHA.109.555979. Epub 2009 Jun
18.

Robust docosahexaenoic acid-mediated neuroprotection in a rat model of transient,
focal cerebral ischemia.

Belayev L, Khoutorova L, Atkins KD, Bazan NG.

Neuroscience Center of Excellence, Louisiana State University Health Sciences
Center, New Orleans, LA 70112, USA. lbelay@lsuhsc.edu

BACKGROUND AND PURPOSE: Docosahexaenoic acid (DHA; 22:6n-3), an omega-3 essential
fatty acid family member, is the precursor of neuroprotectin D1, which
downregulates apoptosis and, in turn, promotes cell survival. This study was
conducted to assess whether DHA would show neuroprotective efficacy when
systemically administered in different doses after middle cerebral artery
occlusion (MCAo) in rats.
METHODS: Sprague-Dawley rats were anesthetized with isoflurane and subjected to 2
hour of MCAo. Animals were treated with either DHA (low doses=3.5 or 7 mg/kg;
medium doses=16 or 35 mg/kg; and high dose=70 mg/kg) or an equivalent volume of
saline intravenously 3 hours after MCAo onset. Neurologic status was evaluated
during occlusion (60 minutes) and on days 1, 2, 3, and 7 after MCAo. Seven days
after MCAo, brains were perfusion-fixed, and infarct areas and volumes were
determined.
RESULTS: Only the low and medium doses of DHA significantly improved the
neurologic score compared with vehicle-treated rats at 24 hours, 48 hours, 72
hours, and 7 days. DHA markedly reduced total corrected infarct volume in all
treated groups compared with vehicle-treated rats (3.5 mg/kg, 26+/-9 mm(3); 7
mg/kg, 46+/-12 mm(3); 16 mg/kg, 37+/-5 mm(3); and 35 mg/kg, 34+/-15 mm(3) vs
vehicle, 94+/-12 mm(3)). Cortical and striatal infarct volumes were also
significantly reduced by treatment with DHA. No neuroprotective effects were
observed with 70 mg/kg DHA.
CONCLUSIONS: We conclude that DHA experimental therapy at low and medium doses
improves neurologic and histologic outcomes after focal cerebral ischemia and
might provide benefits in patients after ischemic stroke.

PMCID: PMC2745047
PMID: 19542051  [PubMed - indexed for MEDLINE]

44. Prostaglandins Leukot Essent Fatty Acids. 2009 Aug-Sep;81(2-3):205-11. doi:
10.1016/j.plefa.2009.05.024. Epub 2009 Jun 11.

Cellular and molecular events mediated by docosahexaenoic acid-derived
neuroprotectin D1 signaling in photoreceptor cell survival and brain protection.

Bazan NG.

Neuroscience Center of Excellence and Department of Ophthalmology, School of
Medicine, Louisiana State University Health Sciences Center, 2020 Gravier Street,
Suite D, New Orleans, LA 70112, USA. nbazan@lsuhsc.edu

Deficiency in docosahexaenoic acid (DHA) is associated with impaired visual and
neurological postnatal development, cognitive decline, macular degeneration, and 
other neurodegenerative diseases. DHA is an omega-3 polyunsaturated fatty acyl
chain concentrated in phospholipids of brain and retina, with photoreceptor cells
displaying the highest content of DHA of all cell membranes. The identification
and characterization of neuroprotectin D1 (NPD1, 10R,
17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid) contributes in
understanding the biological significance of DHA. In oxidative stress-challenged 
human retinal pigment epithelial (RPE) cells, human brain cells, or rat brains
undergoing ischemia-reperfusion, NPD1 synthesis is enhanced as a response for
sustaining homeostasis. Thus, neurotrophins, Abeta peptide 42 (Abeta42), calcium 
ionophore A23187, interleukin (IL)-1beta, or DHA supply enhances NPD1 synthesis. 
NPD1, in turn, up-regulates the antiapoptotic proteins of the Bcl-2 family and
decreases the expression of proapoptotic Bcl-2 family members. Moreover, NPD1
inhibits IL-1beta-stimulated expression of cyclooxygenase-2 (COX-2). Because both
RPE and photoreceptors are damaged and then die in retinal degenerations,
elucidating how NPD1 signaling contributes to retinal cell survival may lead to a
new understanding of disease mechanisms. In human neural cells, DHA attenuates
amyloid-beta (Abeta) secretion, resulting in concomitant formation of NPD1. NPD1 
was found to be reduced in the Alzheimer's disease (AD) cornu ammonis region 1
(CA1) hippocampal region, but not in other areas of the brain. The expression of 
key enzymes for NPD1 biosynthesis, cytosolic phospholipase A(2) (cPLA(2)), and
15-lipoxygenase (15-LOX) was found altered in the AD hippocampal CA1 region. NPD1
repressed Abeta42-triggered activation of pro-inflammatory genes and upregulated 
the antiapoptotic genes encoding Bcl-2, Bcl-xl, and Bfl-1(A1) in human brain
cells in culture. Overall, these results support the concept that NPD1 promotes
brain and retina cell survival via the induction of antiapoptotic and
neuroprotective gene-expression programs that suppress Abeta42-induced
neurotoxicity and other forms of cell injury, which in turn fosters homeostasis
during development in aging, as well as during the initiation and progression of 
neurodegenerative diseases.

PMCID: PMC2756692
PMID: 19520558  [PubMed - indexed for MEDLINE]

45. Altern Med Rev. 2009 Mar;14(1):14-35.

Integrated brain restoration after ischemic stroke--medical management, risk
factors, nutrients, and other interventions for managing inflammation and
enhancing brain plasticity.

Kidd PM.

Brain injury from ischemic stroke can be devastating, but full brain restoration 
is feasible. Time until treatment is critical; rapid rate of injury progression, 
logistical and personnel constraints on neurological and cardiovascular
assessment, limitations of recombinant tissue plasminogen activator (rtPA) for
thrombolysis, anticoagulation and antiplatelet interventions, and neuroprotection
all affect outcome. Promising acute neuroprotectant measures include albumin,
magnesium, and hypothermia. Long-term hyperbaric oxygen therapy (HBOT) is safe
and holds great promise. Eicosanoid and cytokine down-regulation by omega-3
nutrients docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) may help
quench stroke inflammation. C-reactive protein (CRP), an inflammatory biomarker
and stroke-recurrence predictor, responds favorably to krill oil (a
phospholipid-DHA/EPA-astaxanthin complex). High homocysteine (Hcy) is a proven
predictor of stroke recurrence and responds to folic acid and vitamin B12.
Vitamin E may lower recurrence for individuals experiencing high oxidative
stress. Citicoline shows promise for acute neuroprotection. Glycerophosphocholine
(GPC) is neuroprotective and supports neuroplasticity via nerve growth factor
(NGF) receptors. Stem cells have shown promise for neuronal restoration in
randomized trials. Endogenous brain stem cells can migrate to an ischemic injury 
zone; exogenous stem cells once transplanted can migrate (home) to the stroke
lesion and provide trophic support for cortical neuroplasticity. The
hematopoietic growth factors erythropoietin (EPO) and granulocyte-colony
stimulating factor (G-CSF) have shown promise in preliminary trials, with
manageable adverse effects. Physical and mental exercises, including
constraint-induced movement therapy (CIMT) and interactive learning aids, further
support brain restoration following ischemic stroke. Brain plasticity underpins
the function-driven brain restoration that can occur following stroke.

PMID: 19364191  [PubMed - indexed for MEDLINE]

46. Brain Res. 2009 Feb 9;1253:184-90. doi: 10.1016/j.brainres.2008.11.074. Epub 2008
Dec 3.

LAU-0901, a novel platelet-activating factor receptor antagonist, confers
enduring neuroprotection in experimental focal cerebral ischemia in the rat.

Belayev L, Khoutorova L, Atkins K, Cherqui A, Alvarez-Builla J, Bazan NG.

Neuroscience Center of Excellence, Louisiana State University Health Science
Center, New Orleans, LA 70112, USA. lbelay@lsuhsc.edu

LAU-0901, a novel platelet-activating factor (PAF) receptor antagonist, is highly
neuroprotective in a rodent model of cerebral ischemia. This study was conducted 
to establish whether the neuroprotection induced by LAU-0901 persists with
chronic survival. Male Sprague-Dawley rats were anesthetized with isoflurane and 
subjected to 2 h of temporary middle cerebral artery occlusion (MCAo) induced by 
means of a poly-L-lisine-coated intraluminal nylon suture. Animals were treated
with either LAU-0901 (60 mg/kg) or vehicle (45% cyclodextran) administered i.p.
at 2 h from onset of MCAo. They received neurobehavioral examinations during MCAo
(60 min) and then at 1, 2, 3, 7, 14, 21 and 28 days followed by histopathology at
30 days. LAU-0901 significantly improved the behavior compared to the vehicle
group, beginning on day 1 (by 29%, p=0.00007) and persisting throughout a 30-day 
survival period (42%, p=0.0001). Compared with vehicle treatment, LAU-0901
treatment significantly increased volume of non-infarcted brain tissue loss
relative to the unlesioned hemisphere (16.3 +/- 4.6% vs. 46.0 +/- 10.3%,
respectively). These results establish that LAU-0901 confers enduring ischemic
neuroprotection.

PMCID: PMC2637461
PMID: 19070607  [PubMed - indexed for MEDLINE]

47. World Rev Nutr Diet. 2009;99:46-54. doi: 10.1159/000192994. Epub 2009 Jan 9.

Omega-3 fatty acid docosahexaenoic acid is the precursor of neuroprotectin D1 in 
the nervous system.

Niemoller TD, Stark DT, Bazan NG.

Neuroscience Center of Excellence and Department of Ophthalmology, Louisiana
State University Health Sciences Center, School of Medicine, New Orleans, La
70112, USA.

PMID: 19136838  [PubMed - indexed for MEDLINE]

48. Exp Neurol. 2008 Dec;214(2):253-8. doi: 10.1016/j.expneurol.2008.08.009. Epub
2008 Aug 28.

LAU-0901, a novel platelet-activating factor antagonist, is highly
neuroprotective in cerebral ischemia.

Belayev L, Khoutorova L, Atkins K, Gordon WC, Alvarez-Builla J, Bazan NG.

Neuroscience Center of Excellence, School of Medicine, Louisiana State University
Health Sciences Center, New Orleans, LA 70112, USA. lbelay@lsuhsc.edu

Platelet-activating factor (PAF) is a bioactive phospholipid that accumulates
during ischemia-reperfusion and is involved in the activation of platelets,
neutrophils, and pro-inflammatory signaling. PAF has been suggested to enhance
brain ischemia-reperfusion damage. LAU-0901, a novel PAF receptor antagonist, was
examined in models of focal cerebral ischemia in rats and mice. Sprague-Dawley
rats were anesthetized and received 2-hour middle cerebral artery occlusion
(MCAo) by intraluminal suture. LAU-0901 (30, 60, 90 mg/kg; n=9-11) or vehicle
(n=11) was administered i.p. at 2 h after onset of MCAo. The neurological status 
was evaluated at 60 min, and on days 1, 2, 3 and 7 after MCAo. In the
dose-response study in mice, C57BL/6 mice were anesthetized and received 1 h MCAo
by intraluminal suture. LAU-0901 (15, 30, 60 mg/kg; n=7-9) or vehicle (n=8) was
given i.p. at 1 h after onset of MCAo. Local cerebral blood flow (LCBF) was
measured at 1, 2, 4, and 6 h after MCAo in mice. LAU-0901 treated rats showed
improved neurological score throughout the 7-day survival period. LAU-0901
treatment (30, 60 and 90 mg/kg) reduced total corrected infarct volume compared
to vehicle rats by 76, 88 and 90%, respectively. Mice treated with LAU-0901 (30
and 60 mg/kg) reduced total infarction by 29% and 66%, respectively. LCBF was
improved by treatment with LAU-0901 (30 mg/kg) by 77% of baseline at 6 h. In
conclusion, we demonstrate for the first time that LAU-0901 improves behavioral
scores, LCBF and reduces infarct volume after focal cerebral ischemia in rats and
mice. Thus, this PAF receptor antagonist exhibits potent and sustained
neuroprotection that may be of value for the design of stroke therapies.

PMCID: PMC2647717
PMID: 18793637  [PubMed - indexed for MEDLINE]

49. J Neurotrauma. 2008 Dec;25(12):1499.

Omega-3 and BDNF regulation: eicosapentaenoic acid may play a key role in
limitation of CNS injury.

Logan AC.

Comment on
    J Neurotrauma. 2004 Oct;21(10):1457-67.

PMID: 19378461  [PubMed - indexed for MEDLINE]

50. Epilepsy Behav. 2008 Jul;13(1):36-42. doi: 10.1016/j.yebeh.2008.01.001. Epub 2008
Mar 4.

Neuroprotective activity of omega-3 fatty acids against epilepsy-induced
hippocampal damage: Quantification with immunohistochemical for calcium-binding
proteins.

Ferrari D, Cysneiros RM, Scorza CA, Arida RM, Cavalheiro EA, de Almeida AC,
Scorza FA.

Disciplina de Neurologia Experimental, Universidade Federal de São Paulo, Escola 
Paulista de Medicina, São Paulo, Brasil.

To investigate whether n-3 polyunsaturated fatty acids (n-3 PUFAs) would promote 
different morphological changes in the hippocampal formation of rats with
epilepsy, we performed an immunocytochemical study using parvalbumin (PV) and
calretinin (CR) distribution as a marker. Animals subjected to the experimental
model of epilepsy with a single dose of pilocarpine were randomly divided into
the following groups: animals with epilepsy treated daily with vehicle (EV) and
animals with epilepsy treated daily with 85 mg/kg n-3 PUFAs (EW). Control animals
administered saline were also randomly divided into two other groups: animals
treated daily with vehicle (CV) and animals treated daily with 85 mg/kg n-3 PUFAs
(CW). A larger number of PV-positive neurons were observed in EW when compared
with EV, CV, and CW. Similarly, there were significantly more CR-positive neurons
in EW than in EV. These findings demonstrate that omega-3 fatty acids prevent
status epilepticus-associated neuropathological changes in the hippocampal
formation of rats with epilepsy.

PMID: 18295545  [PubMed - indexed for MEDLINE]

51. Neurol Sci. 2008 Jun;29(3):147-52. doi: 10.1007/s10072-008-0926-1. Epub 2008 Jul 
9.

The protective effect of fish n-3 fatty acids on cerebral ischemia in rat
prefrontal cortex.

Ozen OA, Cosar M, Sahin O, Fidan H, Eser O, Mollaoglu H, Alkoc O, Yaman M, Songur
A.

Kocatepe University, School of Medicine, Department of Anatomy, Afyonkarahisar,
Turkey.

This study presents neuroprotective effects of fish n-3 EFA on the prefrontal
cortex after cerebral ischemia and reperfusion. Eighteen rats divided into three 
groups. Group A rats were used as control. Cerebral ischemia and reperfusion was 
produced in rats either on a standard diet (Group B) or a standard diet plus fish
n-3 EFA for 14 days (Group C). The malondialdehyde (MDA) levels and activities of
superoxide dismutase (SOD) and catalase (CAT) were measured and the number of
apoptotic neurons was counted. The levels of MDA and activities of SOD increased 
in Group B rats as compared to Group A rats, and decreased in Group C rats as
compared to Group B rats. The activities of CAT increased in Group C as compared 
to Group B rats. The number of apoptotic neurons in the prefrontal cortex was
lower in Group C as compared to Group B rats.

PMID: 18612761  [PubMed - indexed for MEDLINE]

52. Alzheimers Dement. 2008 Jan;4(1 Suppl 1):S153-68. doi:
10.1016/j.jalz.2007.10.005. Epub 2007 Dec 21.

Oral administration of circulating precursors for membrane phosphatides can
promote the synthesis of new brain synapses.

Cansev M, Wurtman RJ, Sakamoto T, Ulus IH.

Department of Brain and Cognitive Sciences, Massachusetts Institute of
Technology, Cambridge, MA, USA.

Although cognitive performance in humans and experimental animals can be improved
by administering omega-3 fatty acid docosahexaenoic acid (DHA), the neurochemical
mechanisms underlying this effect remain uncertain. In general, nutrients or
drugs that modify brain function or behavior do so by affecting synaptic
transmission, usually by changing the quantities of particular neurotransmitters 
present within synaptic clefts or by acting directly on neurotransmitter
receptors or signal-transduction molecules. We find that DHA also affects
synaptic transmission in mammalian brain. Brain cells of gerbils or rats
receiving this fatty acid manifest increased levels of phosphatides and of
specific presynaptic or postsynaptic proteins. They also exhibit increased
numbers of dendritic spines on postsynaptic neurons. These actions are markedly
enhanced in animals that have also received the other two circulating precursors 
for phosphatidylcholine, uridine (which gives rise to brain uridine diphosphate
and cytidine triphosphate) and choline (which gives rise to phosphocholine). The 
actions of DHA aere reproduced by eicosapentaenoic acid, another omega-3
compound, but not by omega-6 fatty acid arachidonic acid. Administration of
circulating phosphatide precursors can also increase neurotransmitter release
(acetylcholine, dopamine) and affect animal behavior. Conceivably, this treatment
might have use in patients with the synaptic loss that characterizes Alzheimer's 
disease or other neurodegenerative diseases or occurs after stroke or brain
injury.

PMCID: PMC2344157
PMID: 18631994  [PubMed - indexed for MEDLINE]

53. Neuromolecular Med. 2008;10(4):219-35. doi: 10.1007/s12017-008-8036-z. Epub 2008 
Jun 10.

Neurological benefits of omega-3 fatty acids.

Dyall SC, Michael-Titus AT.

British College of Osteopathic Medicine, Lief House, 120-122 Finchley Road, NW5
5HR, London, UK. sdyall@bcom.ac.uk

The central nervous system is highly enriched in long-chain polyunsaturated fatty
acid (PUFA) of the omega-6 and omega-3 series. The presence of these fatty acids 
as structural components of neuronal membranes influences cellular function both 
directly, through effects on membrane properties, and also by acting as a
precursor pool for lipid-derived messengers. An adequate intake of omega-3 PUFA
is essential for optimal visual function and neural development. Furthermore,
there is increasing evidence that increased intake of the long-chain omega-3
PUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may confer
benefits in a variety of psychiatric and neurological disorders, and in
particular neurodegenerative conditions. However, the mechanisms underlying these
beneficial effects are still poorly understood. Recent evidence also indicates
that in addition to the positive effects seen in chronic neurodegenerative
conditions, omega-3 PUFA may also have significant neuroprotective potential in
acute neurological injury. Thus, these compounds offer an intriguing prospect as 
potentially new therapeutic approaches in both chronic and acute conditions. The 
purpose of this article is to review the current evidence of the neurological
benefits of omega-3 PUFA, looking specifically at neurodegenerative conditions
and acute neurological injury.

PMID: 18543124  [PubMed - indexed for MEDLINE]

54. Brain Res Rev. 2007 Dec;56(2):443-71. Epub 2007 Oct 23.

Comparison of biochemical effects of statins and fish oil in brain: the battle of
the titans.

Farooqui AA, Ong WY, Horrocks LA, Chen P, Farooqui T.

Department of Molecular and Cellular Biochemistry, The Ohio State University,
1645 Neil Avenue, Columbus, OH 43210, USA. farooqui.1@osu.edu

Neural membranes are composed of glycerophospholipids, sphingolipids, cholesterol
and proteins. The distribution of these lipids within the neural membrane is not 
random but organized. Neural membranes contain lipid rafts or microdomains that
are enriched in sphingolipids and cholesterol. These rafts act as platforms for
the generation of glycerophospholipid-, sphingolipid-, and cholesterol-derived
second messengers, lipid mediators that are necessary for normal cellular
function. Glycerophospholipid-derived lipid mediators include eicosanoids,
docosanoids, lipoxins, and platelet-activating factor. Sphingolipid-derived lipid
mediators include ceramides, ceramide 1-phosphates, and sphingosine 1-phosphate. 
Cholesterol-derived lipid mediators include 24-hydroxycholesterol,
25-hydroxycholesterol, and 7-ketocholesterol. Abnormal signal transduction
processes and enhanced production of lipid mediators cause oxidative stress and
inflammation. These processes are closely associated with the pathogenesis of
acute neural trauma (stroke, spinal cord injury, and head injury) and
neurodegenerative diseases such as Alzheimer disease. Statins, the HMG-CoA
reductase inhibitors, are effective lipid lowering agents that significantly
reduce risk for cardiovascular and cerebrovascular diseases. Beneficial effects
of statins in neurological diseases are due to their anti-excitotoxic,
antioxidant, and anti-inflammatory properties. Fish oil omega-3 fatty acids,
eicosapentaenoic acid and docosahexaenoic acid, have similar anti-excitotoxic,
antioxidant and anti-inflammatory effects in brain tissue. Thus the lipid
mediators, resolvins, protectins, and neuroprotectins, derived from
eicosapentaenoic acid and docosahexaenoic acid retard neuroinflammation,
oxidative stress, and apoptotic cell death in brain tissue. Like statins,
ingredients of fish oil inhibit generation of beta-amyloid and provide protection
from oxidative stress and inflammatory processes. Collective evidence suggests
that antioxidant, anti-inflammatory, and anti-apoptotic properties of statins and
fish oil contribute to the clinical efficacy of treating neurological disorders
with statins and fish oil. We speculate that there is an overlap between
neurochemical events associated with neural cell injury in stroke and
neurodegenerative diseases. This commentary compares the neurochemical effects of
statins with those of fish oil.

PMID: 17959252  [PubMed - indexed for MEDLINE]

55. Brain. 2007 Nov;130(Pt 11):3004-19. Epub 2007 Sep 27.

A combination of intravenous and dietary docosahexaenoic acid significantly
improves outcome after spinal cord injury.

Huang WL, King VR, Curran OE, Dyall SC, Ward RE, Lal N, Priestley JV,
Michael-Titus AT.

Neuroscience Centre, Institute of Cell & Molecular Science, Queen Mary University
of London, UK. w.huang@qmul.ac.uk

Previous studies have shown that omega-3 polyunsaturated fatty acids such as
alpha-linolenic acid and docosahexaenoic acid (DHA) are neuroprotective in models
of spinal cord injury (SCI) in rodents. However, the mechanism of action
underlying these effects has not been elucidated, and the optimum treatment
regime remains to be defined. We have therefore carried out a detailed analysis
of the effects of DHA in adult rats subject to thoracic compression SCI. Saline
or DHA (250 nmol/kg) was administered intravenously (i.v.) 30 min after
compression. After injury, the saline group received a standard control diet for 
1 or 6 weeks, whereas DHA-injected animals received either a control or a
DHA-enriched diet (400 mg/kg/day) for 1 or 6 weeks. Other groups received a
DHA-enriched diet only for 1 week following injury, or received acute DHA (250
nmol/kg; i.v.) treatment delayed up to 3 h after injury. We also assessed
oxidative stress and the inflammatory reaction at the injury site, neuronal and
oligodendrocyte survival and axonal damage and the locomotor recovery. At 24 h,
lipid peroxidation, protein oxidation, RNA/DNA oxidation and the induction of
cyclooxygenase-2 were all significantly reduced by i.v. DHA administration. At 1 
week and 6 weeks, macrophage recruitment was reduced and neuronal and
oligodendrocyte survival was substantially increased. Axonal injury was reduced
at 6 weeks. Locomotor recovery was improved from day 4, and sustained up to 6
weeks. Rats treated with a DHA-enriched diet in addition to the acute DHA
injection were not significantly different from the acute DHA-treated animals at 
1 week, but at 6 weeks showed additional improvements in both functional and
histological outcomes. DHA treatment was ineffective if the acute injection was
delayed until 3 h post-injury, or if the DHA was administered for 1 week solely
by diet. Our results in a clinically relevant model of SCI show that significant 
neuroprotection can be obtained by combining an initial acute i.v. injection of
DHA with a sustained dietary supplementation. Given that the safety and
tolerability of preparations enriched in omega-3 fatty acids is already
well-documented, such a combined DHA treatment regime deserves consideration as a
very promising approach to SCI management.

PMID: 17901087  [PubMed - indexed for MEDLINE]

56. Neurotoxicology. 2007 Nov;28(6):1220-9. Epub 2007 Aug 10.

Detrimental effects of post-treatment with fatty acids on brain injury in
ischemic rats.

Yang DY, Pan HC, Yen YJ, Wang CC, Chuang YH, Chen SY, Lin SY, Liao SL, Raung SL, 
Wu CW, Chou MC, Chiang AN, Chen CJ.

Chang Bing Show Chwan Memorial Hospital, Changhua 542, Taiwan.

Studies have illustrated that fatty acids, especially polyunsaturated fatty acids
(PUFA), have a role in regulating oxidative stress via the enhancement of
antioxidative defense capacity or the augmentation of oxidative burden. Elevated 
oxidative stress has been implicated in the pathogenesis of brain injury
associated with cerebral ischemia/reperfusion (I/R). The objective of this study 
was to assess whether treatment with fatty acids after focal cerebral I/R induced
by occlusion of the common carotid arteries and the middle cerebral artery has
effects on brain injury in a rat model. PUFA, including arachidonic acid (AA) and
docosahexaenoic acid (DHA), and the saturated fatty acid, stearic acid (SA), were
administrated 60 min after reperfusion via intraperitoneal injection. AA and DHA 
aggravated cerebral ischemic injury, which manifested as enlargement of areas of 
cerebral infarction and increased impairment of motor activity, in a
concentration-dependent manner. However, there were no remarkable differences in 
post-ischemic alterations between the SA and saline groups. The post-ischemic
augmentation of injury in AA and DHA treatment groups was accompanied by
increases in the permeability of the blood-brain barrier (BBB), brain edema,
metalloproteinase (MMP) activity, inflammatory cell infiltration, cyclooxygenase 
2 (COX-2) expression, caspase 3 activity, and malondialdehyde (MDA) production,
and by a decrease in the brain glutathione (GSH) content. Furthermore, we found
that either AA or DHA alone had little effect on free radical generation in
neuroglia, but they greatly increased the hydrogen peroxide-induced oxidative
burden. Taken together, these findings demonstrate the detrimental effect of PUFA
such as AA and DHA in post-ischemic progression and brain injury after cerebral
I/R is associated with augmentation of cerebral I/R-induced alterations,
including oxidative changes.

PMID: 17854901  [PubMed - indexed for MEDLINE]

57. J Neurotrauma. 2007 Oct;24(10):1587-95.

Omega-3 fatty acids supplementation restores mechanisms that maintain brain
homeostasis in traumatic brain injury.

Wu A, Ying Z, Gomez-Pinilla F.

Department of Physiological Science, University of California at Los Angeles
(UCLA), Los Angeles, California 90095, USA.

Traumatic brain injury (TBI) produces a state of vulnerability that reduces the
brain capacity to cope with secondary insults. The silent information regulator 2
(Sir2) has been implicated with maintaining genomic stability and cellular
homeostasis under challenging situation. Here we explore the possibility that the
action of Sir2alpha (mammalian Sir2) in the brain can extend to serve neuronal
plasticity. We provide novel evidence showing that mild TBI reduces the
expression of Sir2alpha in the hippocampus, in proportion to increased levels of 
protein oxidation. In addition, we show that dietary supplementation of omega-3
fatty acids that ameliorates protein oxidation was effective to reverse the
reduction of Sir2alpha level in injured rats. Given that oxidative stress is a
subproduct of dysfunctional energy homeostasis, we measured AMP-activated protein
kinase (AMPK) and phosphorylated-AMPK (p-AMPK) to have an indication of the
energy status of cells. Hippocampal levels of total and phosphorylated AMPK were 
reduced after TBI and levels were normalized by omega-3 fatty acts supplements.
Further, we found that TBI reduced ubiquitous mitochondrial creatine kinase
(uMtCK), an enzyme implicated in the energetic regulation of Ca2+-pumps and in
the maintenance of Ca2+-homeostasis. Omega-3 fatty acids supplements normalized
the levels of uMtCK after lesion. Furthermore, we found that the correlation
between Sir2alpha and AMPK or p-AMPK was disrupted by TBI, but restored by
omega-3 fatty acids supplements. Our results suggest that TBI may compromise
neuronal protective mechanisms by involving the action of Sir2alpha. In addition,
results show the capacity of omega-3 fatty acids to counteract some of the
effects of TBI by normalizing levels of molecular systems associated with energy 
homeostasis.

PMID: 17970622  [PubMed - indexed for MEDLINE]

58. Neurochem Int. 2007 Feb;50(3):548-54. Epub 2006 Dec 21.

The protective effect of fish n-3 fatty acids on cerebral ischemia in rat
hippocampus.

Bas O, Songur A, Sahin O, Mollaoglu H, Ozen OA, Yaman M, Eser O, Fidan H,
Yagmurca M.

Kocatepe University, School of Medicine, Department of Anatomy, Afyonkarahisar,
Turkey. orhanbas55@hotmail.com

Reactive oxygen species (ROS) have been implicated in the pathogenesis of
cerebral injury after ischemia-reperfusion (I/R). Fish n-3 essential fatty acids 
(EFA), contain eicosapentaenoic acids (EPA) and docosahexoenoic acids (DHA),
exhibit antioxidant properties. DHA is an important component of brain membrane
phospholipids and is necessary for the continuity of neuronal functions. EPA
prevents platelet aggregation and inhibits the conversion of arachidonic acid
into thromboxane A(2) and prostaglandins. They have been suggested to be
protective agents against neurological and neuropsychiatric disorders. In this
study, the neuroprotective effects of fish n-3 EFA on oxidant-antioxidant systems
and number of apoptotic neurons of the hippocampal formation (HF) subjected to
cerebral I/R injury was investigated in Sprague-Dawley rats. Six rats were used
as control (Group I). Cerebral ischemia was produced by occlusion of both the
common carotid arteries combined with hypotension for 45 min, followed by
reperfusion for 30 min, in rats either on a standard diet (Group II) or a
standard diet plus fish n-3 EFA (Marincap((R)), 0.4 g/kg/day, by gavage) for 14
days (Group III). At the end of procedures, the rats were sacrificed and their
brains were removed immediately. The levels of malonedialdehyde (MDA) and nitric 
oxide (NO) and activities of superoxide dismutase (SOD) and catalase (CAT) were
measured in left HF. In addition, the number of apoptotic neurons was counted by 
terminal transferase dUTP nick end labelling (TUNEL) assay in histological
samples of the right HF. We found that SOD activities and MDA levels increased in
Group III rats compared with Group II rats. On the other hand, CAT activities and
NO levels were found to be decreased in Group III rats compared with Group II
rats. Additionally, the number of apoptotic neurons was lower in Group III in
comparison with Group II rats. The present findings suggest that fish n-3 EFA
could decrease the oxidative status and apoptotic changes in ischemic rat
hippocampal formation. Dietary supplementation of n-3 EFA may be beneficial to
preserve or ameliorate ischemic cerebral vascular disease.

PMID: 17187901  [PubMed - indexed for MEDLINE]

59. J Am Soc Mass Spectrom. 2007 Jan;18(1):128-44. Epub 2006 Oct 19.

Resolvin D1, protectin D1, and related docosahexaenoic acid-derived products:
Analysis via electrospray/low energy tandem mass spectrometry based on spectra
and fragmentation mechanisms.

Hong S, Lu Y, Yang R, Gotlinger KH, Petasis NA, Serhan CN.

Analytical Core, Center for Experimental Therapeutics and Reperfusion Injury,
Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and
Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Resolvin D1 (RvD1) and protectin D1 (Neuroprotectin D1, PD1/NPD1) are newly
identified anti-inflammatory lipid mediators biosynthesized from docosahexaenoic 
acid (DHA). In this report, the spectra-structure correlations and fragmentation 
mechanisms were studied using electrospray low-energy collision-induced
dissociation tandem mass spectrometry (MS/MS) for biogenic RvD1 and PD1, as well 
as mono-hydroxy-DHA and related hydroperoxy-DHA. The loss of H2O and CO2 in the
spectra indicates the number of functional group(s). Chain-cut ions are the
signature of the positions and numbers of functional groups and double bonds. The
observed chain-cut ion is equivalent to a hypothetical homolytic-segment (cc, cm,
mc, or mm) with addition or extraction of up to 2 protons (H). The alpha-cleavage
ions are equivalent to: [cc + H], with H from the hydroxyl through a beta-ene or 
gamma-ene rearrangement; [cm - 2H], with 2H from hydroxyls of PD1 through a
gamma-ene rearrangement, or 1H from the hydroxyl and the other H from the
alpha-carbon of mono-HDHA through an alpha-H-beta-ene rearrangement; [mc - H],
with H from hydroxyl through a beta-ene or gamma-ene rearrangement, or from the
alpha-carbon through an alpha-H-beta-ene rearrangement; or [mm] through
charge-direct fragmentations. The beta-ene or gamma-ene facilitates the H shift
to gamma position and alpha-cleavage. Deuterium labeling confirmed the assignment
of MS/MS ions and the fragmentation mechanisms. Based on the MS/MS spectra and
fragmentation mechanisms, we identified RvD1, PD1, and mono-hydroxy-DHA products 
in human neutrophils and blood, trout head-kidney, and stroke-injury murine
brain-tissue.

PMCID: PMC2763184
PMID: 17055291  [PubMed - indexed for MEDLINE]

60. Methods Enzymol. 2007;433:127-43.

Measurement of products of docosahexaenoic acid peroxidation, neuroprostanes, and
neurofurans.

Arneson KO, Roberts LJ 2nd.

Division of Clinical Pharmacology, Vanderbilt University School of Medicine,
Nashville, Tennessee, USA.

Free radicals derived primarily from oxygen have been implicated in the
pathophysiology of a wide variety of human diseases. Quantification of products
of free radical damage in biological systems is necessary to understand the role 
of free radicals in disease states. Measures of lipid peroxidation are often used
to quantitate oxidative damage though many of these measures have inherent
problems with sensitivity and specificity especially when used to quantitate in
vivo oxidative injury. The discovery of the F(2)-isoprostanes (F(2)-IsoPs),
prostaglandin F(2)-like compounds derived by the free radical peroxidation of
arachidonic acid (AA, C20:4, omega-6) has largely overcome these limitations. The
measurement of the F(2)-IsoPs has been shown to be one of the most accurate
approaches to quantifying oxidative damage in vivo. We have extended our studies 
of lipid peroxidation and the F(2)-IsoPs to docosahexaenoic acid (DHA, C22:6,
omega-3) and its peroxidation products. We have found that DHA oxidizes both in
vitro and in vivo to form F(2)-IsoP-like compounds termed F(4)-neuroprostanes
(F(4)-NPs). DHA is specifically enriched in neuronal membranes making the
F(4)-NPs sensitive and specific markers of neuronal oxidative damage. Adapting
the methodology used to quantitate the F(2)-IsoPs, we utilize stable isotope
dilution, negative ion chemical ionization, gas chromatography mass spectrometry 
(GC/MS) to quantitate the F(4)-NPs with a limit of detection in the low picomolar
range. Methods have been developed to quantitate both the F(4)-NPs and the
neurofurans (NFs), DHA derived peroxidation products containing a substituted
tetrahydrofuran ring, in brain tissue and cerebrospinal fluid. This review
outlines in detail proper sample handling, extraction and hydrolysis of the
F(4)-NPs and NFs from tissue membrane phospholipids or biological fluids, and
purification and derivatization of the compounds for analysis by GC/MS.

PMID: 17954232  [PubMed - indexed for MEDLINE]

61. Neurosci Res. 2006 Oct;56(2):159-64. Epub 2006 Aug 14.

Dietary supplementation of arachidonic and docosahexaenoic acids improves
cognitive dysfunction.

Kotani S, Sakaguchi E, Warashina S, Matsukawa N, Ishikura Y, Kiso Y, Sakakibara
M, Yoshimoto T, Guo J, Yamashima T.

Department of Neurosurgery, Minami-gaoka Hospital, Kanazawa, Ishikawa, Japan.

Age-dependent increase of peroxidation of membrane fatty acids such as
arachidonic acid (ARA) and docosahexaenoic acid (DHA) in neurons was reported to 
cause a decline of the hippocampal long-term potentiation (LTP) and cognitive
dysfunction in rodents. Although supplementation of ARA and DHA can improve LTP
and cognitive function in rodents, their effects in humans are unknown. The
present work was undertaken to study whether ARA and DHA have beneficial effects 
in human amnesic patients. The subjects were 21 mild cognitive dysfunction (12
MCI-A with supplementation and 9 MIC-P with placebo), 10 organic brain lesions
(organic), and 8 Alzheimer's disease (AD). The cognitive functions were evaluated
using Japanese version of repeatable battery for assessment of neuropsychological
status (RBANS) at two time points: before and 90 days after the supplementation
of 240 mg/day ARA and DHA, or 240 mg/day of olive oil, respectively. MCI-A group 
showed a significant improvement of the immediate memory and attention score. In 
addition, organic group showed a significant improvement of immediate and delayed
memories. However, there were no significant improvements of each score in AD and
MCI-P groups. It is suggested from these data that ARA and DHA supplementation
can improve the cognitive dysfunction due to organic brain damages or aging.

PMID: 16905216  [PubMed - indexed for MEDLINE]

62. Cell Mol Neurobiol. 2006 Jul-Aug;26(4-6):901-13. Epub 2006 Aug 1.

The onset of brain injury and neurodegeneration triggers the synthesis of
docosanoid neuroprotective signaling.

Bazan NG.

LSU Neuroscience Center and Department of Ophthalmology, Louisiana State
University Health Sciences Center School of Medicine in New Orleans, New Orleans 
70112, USA. nbazan@lsuhsc.edu

Bioactive lipid messengers are formed through phospholipase-mediated cleavage of 
specific phospholipids from membrane reservoirs. Effectors that activate the
synthesis of lipid messengers, include ion channels, neurotransmitters, membrane 
depolarization, cytokines, and neurotrophic factors. In turn, lipid messengers
regulate and interact with multiple pathways, participating in the development,
differentiation, function (e.g., long-term potentiation and memory), protection, 
and repair of cells of the nervous system. Overall, bioactive lipids participate 
in the regulation of synaptic function and dysfunction. Platelet-activating
factor (PAF) and COX-2-synthesized PGE(2) modulate synaptic plasticity and
memory. Oxidative stress disrupts lipid signaling, fosters lipid peroxidation,
and initiates and propagates neurodegeneration. Lipid messengers participate in
the interactions among neurons, astrocytes, oligodendrocytes, microglia, cells of
the microvasculature, and other cells. A conglomerate of interrelated cells
comprises the neurovascular unit. Signaling at the neurovascular unit is clearly 
altered in the early stages of cerebrovascular disease as well as in
neurodegenerations. Here we will provide examples of how signaling by lipids
regulates critical events essential for neuronal survival. We will highlight a
newly identified, DHA-derived messenger, neuroprotectin D1, which attenuates
oxidative stress-induced apoptosis. The specificity and potency of this novel
docosanoid (neuroprotectin D1) indicate a potentially important target for
therapeutic intervention.

PMID: 16897369  [PubMed - indexed for MEDLINE]

63. Neuroscience. 2006;137(1):241-51. Epub 2005 Nov 14.

Alpha-linolenic acid and riluzole treatment confer cerebral protection and
improve survival after focal brain ischemia.

Heurteaux C, Laigle C, Blondeau N, Jarretou G, Lazdunski M.

Institut de Pharmacologie Moléculaire et Cellulaire, UMR 6097, CNRS Université de
Nice Sophia Antipolis, Institut Paul Hamel, 660 Route des Lucioles,
Sophia-Antipolis, 06560 Valbonne, France. heurteau@ipmc.cnrs.fr

We investigated here the effects of alpha-linolenic acid and riluzole, both
activators of the 2P-domain K+ channel family TREK/TRAAK, in a model of focal
ischemia clinically relevant to stroke, not only assessing neuronal protection,
but also long term survival. Moreover, all the drug treatments were initiated
post-ischemia. Mice were subjected to transient middle cerebral artery occlusion 
(1 h) and reperfusion according to the intraluminal filament model. Drugs were
injected into the jugular vein according to three protocols: (i) a single dose of
4 mg/kg riluzole or 500 nmol/kg alpha-linolenic acid at different reperfusion
time; (ii) a three-day therapy (a single dose of 2 mg/kg riluzole and 250 nmol/kg
alpha-linolenic acid given 1-2, 48 and 72 h after reperfusion); (iii) a
three-week therapy (a single dose of 2 mg/kg riluzole and 250 nmol/kg
alpha-linolenic acid given once a week during three weeks after reperfusion. A
combined treatment with 2mg/kg riluzole+250 nmol/kg alpha-linolenic acid injected
2 h after reperfusion was also tested. A single dose of riluzole (4 mg/kg) or
alpha-linolenic acid (500 nmol/kg) injected up to 3 h after reperfusion reduced
drastically the stroke volume by 75% and 86%, respectively. Neurological deficits
24 h after ischemia were significantly improved by alpha-linolenic acid500 or
riluzole4 with a neurological score of 1.8 as compared with 2.5 observed in
vehicle-treated mice. Alpha-linolenic acid- and riluzole treatment were
associated with a reduction in cytopathological features of cell injury,
including DNA fragmentation and Bax expression in the cortex and the caudate
putamen. With regard to the survival rate at 30 days, the best protections were
obtained with the alpha-linolenic acid-injection in the three-week therapy as
well as with a single dose of the combined treatment (2 mg/kg riluzole+250
nmol/kg alpha-linolenic acid). Palmitic acid, a saturated fatty acid that does
not activate the 2P-domain K-channel TREK/TRAAK family, did not provide any
neuroprotection. Taken together, these data suggest that the TREK/TRAAK K-channel
family may be a promising target for neuroprotection, and that riluzole and
alpha-linolenic acid could be of therapeutic value against focal
ischemia/reperfusion injury to the brain.

PMID: 16289892  [PubMed - indexed for MEDLINE]

64. Nutr Health. 2006;18(3):277-84.

The impact of diet and exercise on brain plasticity and disease.

Pinilla FG.

Department of Neurosurgery, Brain Injury Research Center, UCLA School of
Medicine, Los Angeles, California 90095, USA. Fgomezpi@ucla.ed

Lifestyle involves our preference to engage in behaviors that can remarkably
influence the fitness level of our body and brain. Dietary factors are a powerful
means to influence brain function on a daily basis. We have shown that the
consumption of a diet rich in saturated fat decreases learning and memory and
increases metabolic distress. Conversely, diets supplemented either with omega-3 
fatty acids, vitamin E or the curry spice curcumin benefit cognitive function.
Equally impressive is the action of exercise on cognitive function as documented 
by studies showing that exercise enhances learning and memory. The beneficial
action of exercise on the brain can be used therapeutically to overcome the
effects of consuming a poor diet. We suggest that the managed use of diet and
exercise can help the brain to cope with several types of insults and ultimately 
benefit brain function.

PMID: 17180873  [PubMed - indexed for MEDLINE]

65. J Biol Chem. 2005 Dec 30;280(52):43079-86. Epub 2005 Oct 10.

The docosatriene protectin D1 is produced by TH2 skewing and promotes human T
cell apoptosis via lipid raft clustering.

Ariel A, Li PL, Wang W, Tang WX, Fredman G, Hong S, Gotlinger KH, Serhan CN.

Center for Experimental Therapeutics and Reperfusion Injury, Department of
Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and
Harvard Medical School, Boston, Massachusetts 02115, USA.

Docosahexaenoic acid, a major omega-3 fatty acid in human brain, synapses,
retina, and other neural tissues, displays beneficial actions in neuronal
development, cancer, and inflammatory diseases by mechanisms that remain to be
elucidated. In this study we found, using lipid mediator informatics employing
liquid chromatography-tandem mass spectrometry, that
(10,17S)-docosatriene/neuroprotectin D1, now termed protectin D1 (PD1), is
generated from docosahexaenoic acid by T helper type 2-skewed peripheral blood
mononuclear cells in a lipoxygenase-dependent manner. PD1 blocked T cell
migration in vivo, inhibited tumor necrosis factor alpha and interferon-gamma
secretion, and promoted apoptosis mediated by raft clustering. These results
demonstrated novel anti-inflammatory roles for PD1 in regulating events
associated with inflammation and resolution.

PMID: 16216871  [PubMed - indexed for MEDLINE]

66. Ann N Y Acad Sci. 2005 Aug;1053:137-47.

Brain response to injury and neurodegeneration: endogenous neuroprotective
signaling.

Bazan NG, Marcheselli VL, Cole-Edwards K.

LSU Neuroscience Center and Department of Ophthalmology, Louisiana State
University Health Sciences Center School of Medicine, 2020 Gravier Street, Suite 
D, New Orleans, Louisiana 70112, USA. nbazan@lsuhsc.edu

Synaptic activity and ischemia/injury promote lipid messenger formation through
phospholipase-mediated cleavage of specific phospholipids from membrane
reservoirs. Lipid messengers modulate signaling cascades, contributing to
development, differentiation, function (e.g., memory), protection, regeneration, 
and repair of neurons and overall regulation of neuronal, glial, and endothelial 
cell functional integrity. Oxidative stress disrupts lipid signaling and promotes
lipid peroxidation and neurodegeneration. Lipid signaling at the neurovascular
unit (neurons, astrocytes, oligodendrocytes, microglia, and cells of the
microvasculature) is altered in early cerebrovascular and neurodegenerative
disease. We discuss how lipid signaling regulates critical events in neuronal
survival. Aberrant synaptic plasticity (e.g., epileptogenesis) is highlighted to 
show how gene expression may drive synaptic circuitry formation in the "wrong"
direction. Docosahexaenoic acid has been implicated in memory, photoreceptor cell
biogenesis and function, and neuroprotection. Free docosahexaenoic acid released 
in the brain during experimental stroke leads to the synthesis of stereospecific 
messengers through oxygenation pathways. One messenger, 10,17S-docosatriene
(neuroprotectin D1; NPD1), counteracts leukocyte infiltration and proinflammatory
gene expression in brain ischemia-reperfusion. In retina, photoreceptor survival 
depends on retinal pigment epithelial (RPE) cell integrity. NPD1 is synthesized
in RPE cells undergoing oxidative stress, potently counteracts oxidative
stress-triggered apoptotic DNA damage in RPE, upregulates antiapoptotic proteins 
Bcl-2 and Bcl-x(L), and decreases proapoptotic Bax and Bad expression. These
findings expand our understanding of how the nervous system counteracts redox
disturbances, mitochondrial dysfunction, and proinflammatory conditions. The
specificity and potency of NPD1 indicate a potential target for therapeutic
intervention for stroke, age-related macular degeneration, spinal cord injury,
and other neuroinflammatory or neurodegenerative diseases.

PMID: 16179516  [PubMed - indexed for MEDLINE]

67. Brain Pathol. 2005 Apr;15(2):159-66.

Neuroprotectin D1 (NPD1): a DHA-derived mediator that protects brain and retina
against cell injury-induced oxidative stress.

Bazan NG.

LSU Neuroscience Center and Department of Opthamology, Louisiana State University
Health Sciences Center School of Medicine, New Orleans 70112, USA.
nbazan@lsuhsc.edu

The biosynthesis of oxygenated arachidonic acid messengers triggered by cerebral 
ischemia-reperfusion is preceded by an early and rapid phospholipase A2
activation reflected in free arachidonic and docosahexaenoic acid (DHA)
accumulation. These fatty acids are released from membrane phospholipids. Both
fatty acids are derived from dietary essential fatty acids; however, only DHA,
the omega-3 polyunsaturated fatty acyl chain, is concentrated in phospholipids of
various cells of brain and retina. Synaptic membranes and photoreceptors share
the highest content of DHA of all cell membranes. DHA is involved in memory
formation, excitable membrane function, photoreceptor cell biogenesis and
function, and neuronal signaling, and has been implicated in neuroprotection. In 
addition, this fatty acid is required for retinal pigment epithelium cell (RPE)
functional integrity. Here we provide an overview of the recent elucidation of a 
specific mediator generated from DHA that contributes at least in part to its
biological significance. In oxidative stress-challenged human RPE cells and rat
brain undergoing ischemia-reperfusion, 10,17S-docosatriene (neuroprotectin D1,
NPD1) synthesis evolves. In addition, calcium ionophore A23187, IL-1beta, or the 
supply of DHA enhances NPD1 synthesis. A time-dependent release of endogenous
free DHA followed by NPD1 formation occurs, suggesting that a phospholipase A2
releases the mediator's precursor. When NPD1 is infused during
ischemia-reperfusion or added to RPE cells during oxidative stress, apoptotic DNA
damage is down-regulated. NPD1 also up-regulates the anti-apoptotic Bcl-2
proteins Bcl-2 and BclxL and decreases pro-apoptotic Bax and Bad expression.
Moreover, NPD1 inhibits oxidative stress-induced caspase-3 activation. NPD1 also 
inhibits IL-1beta-stimulated expression of COX-2. Overall, NPD1 protects cells
from oxidative stress-induced apoptosis. Because photoreceptors are progressively
impaired after RPE cell damage in retinal degenerative diseases, understanding of
how these signals contribute to retinal cell survival may lead to the development
of new therapeutic strategies. Moreover, NPD1 bioactivity demonstrates that DHA
is not only a target of lipid peroxidation, but rather is the precursor to a
neuroprotective signaling response to ischemia-reperfusion, thus opening newer
avenues of therapeutic exploration in stroke, neurotrauma, spinal cord injury,
and neurodegenerative diseases, such as Alzheimer disease, aiming to up-regulate 
this novel cell-survival signaling.

PMID: 15912889  [PubMed - indexed for MEDLINE]

68. Stroke. 2005 Jan;36(1):118-23. Epub 2004 Nov 29.

Docosahexaenoic acid complexed to albumin elicits high-grade ischemic
neuroprotection.

Belayev L, Marcheselli VL, Khoutorova L, Rodriguez de Turco EB, Busto R, Ginsberg
MD, Bazan NG.

Cerebral Vascular Disease Research Center, Department of Neurology, University of
Miami School of Medicine, Miami, FL 33101, USA.

BACKGROUND AND PURPOSE: High-dose human albumin therapy is strongly
neuroprotective in models of brain ischemia and trauma and is currently being
studied in a pilot-phase clinical stroke trial. Among its actions in ischemia,
albumin induces the systemic mobilization of n-3 polyunsaturated fatty acids and 
may help to replenish polyunsaturated fatty acids lost from neural membranes.
METHODS: We complexed 25% human albumin to docosahexaenoic acid (DHA; 22:6n-3)
and compared its neuroprotective efficacy with that of native albumin in rats
with 2-hour focal ischemia produced by intraluminal suture-occlusion of the
middle cerebral artery.
RESULTS: In animals treated with DHA-albumin, 0.63 g/kg, the improvement in
neurobehavioral scores at 72 hours significantly exceeded that of other treatment
groups, and the extent of histological protection (86% reduction in cortical
infarction) was highly significant and tended to surpass the degree of cortical
protection produced by native albumin at 1.25 g/kg (65%). DHA-albumin 0.63 g/kg, 
but not native albumin, also significantly reduced subcortical infarction and
markedly diminished brain swelling. Lipidomic analysis of DHA-albumin-treated
postischemic brains revealed a large accumulation of the neuroprotective DHA
metabolite, 10,17S-docosatriene, in the ipsilateral hemisphere.
CONCLUSIONS: The high-grade neuroprotection afforded by the DHA-albumin complex
at relatively low albumin doses is clinically advantageous in that it might
reduce the likelihood of acute intravascular volume overload and congestive heart
failure sometimes induced when patients with compromised cardiovascular function 
are treated with high-dose albumin.

PMID: 15569878  [PubMed - indexed for MEDLINE]

69. Pharmacol Biochem Behav. 2004 Dec;79(4):651-9.

Protective effect of chronic ethyl docosahexaenoate administration on brain
injury in ischemic gerbils.

Cao DH, Xu JF, Xue RH, Zheng WF, Liu ZL.

Department of Biology, Nanjing University, 22 Hankou Road, Jiangsu 210093, PR
China.

There is evidence that the excessive generation of reactive oxygen free radicals 
contributes to the brain injury associated with cerebral ischemia. In the present
study, the protective effect of chronic administration of ethyl docosahexaenoate 
(E-DHA) against oxidative brain injury was evaluated in the gerbil model of
transient cerebral ischemia. Weanling male gerbils were orally pretreated with
either E-DHA (200 mg/kg) or vehicle, once a day, for 10 weeks and subjected to
bilateral occlusion of common carotid arteries for 10 min. At the different
reperfusion times, E-DHA pretreatment significantly inhibited the increases in
the production of brain salicylate-derived 2,5-dihydroxybenzoic acid (2,5-DHBA)
and content of brain malonildialdehyde (MDA). The superoxide dismutase (SOD)
activity was not modified; however, pretreatment with E-DHA significantly
prevented the level of brain-reduced glutathione (GSH) and activities of brain
glutathione peroxidase (GSH-P(X)) and catalase (CAT) from declines caused by
cerebral ischemia. Moreover, ischemia and reperfusion-induced delayed neuronal
loss in the hippocampus CA1 sector and locomotor hyperactivity were also
significantly attenuated by pretreatment with E-DHA. These results suggested that
the neuroprotective effect of E-DHA might be due to its antioxidant property.

PMID: 15582673  [PubMed - indexed for MEDLINE]

70. J Neurochem. 2004 Oct;91(1):20-9.

Neuroprotective actions of eicosapentaenoic acid on lipopolysaccharide-induced
dysfunction in rat hippocampus.

Lonergan PE, Martin DS, Horrobin DF, Lynch MA.

Trinity College Institute of Neuroscience, Department of Physiology, Trinity
College, Dublin, Ireland.

Eicosapentaenoic acid (EPA) protects hippocampus from age-related and
irradiation-induced changes that lead to impairment in synaptic function; the
evidence suggests that this is due to its anti-inflammatory effects, specifically
preventing changes induced by the proinflammatory cytokine, interleukin-1beta
(IL-1beta). In this study, we have investigated the possibility that EPA may
prevent the effects of lipopolysaccharide (LPS) administration, which have been
shown to lead to deterioration of synaptic function in rat hippocampus. The data 
indicate that treatment of hippocampal neurones with EPA abrogated the
LPS-induced increases in phosphorylation of the mitogen-activated protein kinase,
c-Jun N-terminal kinase (JNK), the transcription factor, c-Jun and the
mitochondrial protein, Bcl-2. In parallel, we report that intraperitoneal
administration of LPS to adult rats increases phosphorylation of JNK, c-Jun and
Bcl-2 in hippocampal tissue and that these changes are coupled with increased
IL-1beta concentration. Treatment of rats with EPA abrogates these effects and
also blocks the LPS-induced impairment in long-term potentiation in perforant
path-granule cell synapses that accompanies these changes. We propose that the
neuroprotective effect of EPA may be dependent on its ability to inhibit the
downstream consequences of JNK activation.

PMID: 15379883  [PubMed - indexed for MEDLINE]

71. J Neurotrauma. 2004 Oct;21(10):1457-67.

Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and
counteract learning disability after traumatic brain injury in rats.

Wu A, Ying Z, Gomez-Pinilla F.

Department of Physiological Science, University of California at Los Angeles,
90095, USA.

Comment in
    J Neurotrauma. 2008 Dec;25(12):1499.

Omega-3 fatty acids (i.e., docosahexaenoic acid; DHA) regulate signal
transduction and gene expression, and protect neurons from death. In this study
we examined the capacity of dietary omega3 fatty acids supplementation to help
the brain to cope with the effects of traumatic injury. Rats were fed a regular
diet or an experimental diet supplemented with omega-3 fatty acids, for 4 weeks
before a mild fluid percussion injury (FPI) was performed. FPI increased
oxidative stress, and impaired learning ability in the Morris water maze. This
type of lesion also reduced levels of brain-derived neurotrophic factor (BDNF),
synapsin I, and cAMP responsive element-binding protein (CREB). It is known that 
BDNF facilitates synaptic transmission and learning ability by modulating
synapsin I and CREB. Supplementation of omega-3 fatty acids in the diet
counteracted all of the studied effects of FPI, that is, normalized levels of
BDNF and associated synapsin I and CREB, reduced oxidative damage, and
counteracted learning disability. The reduction of oxidative stress indicates a
benevolent effect of this diet on mechanisms that maintain neuronal function and 
plasticity. These results imply that omega-3 enriched dietary supplements can
provide protection against reduced plasticity and impaired learning ability after
traumatic brain injury.

PMID: 15672635  [PubMed - indexed for MEDLINE]

72. J Neurochem. 2003 Dec;87(6):1518-26.

Pharmacologic suppression of neuronal oxidative damage and dendritic degeneration
following direct activation of glial innate immunity in mouse cerebrum.

Milatovic D, Zaja-Milatovic S, Montine KS, Horner PJ, Montine TJ.

Department of Pathology, University of Washington, Harborview Medical Center,
Seattle, Washington 98104, USA.

Activation of glial innate immunity is widely proposed to contribute to a number 
of degenerative and destructive diseases of brain. However, the precise role of
activated innate immunity has been difficult to define in vivo because of
multiple simultaneous pathogenic processes and responses to injury that confound 
interpretation of results from complex models of disease. Here, we used the model
of intracerebroventricular (ICV) injection of lipopolysaccharide (LPS) to test
the hypothesis that directly activated glial innate immunity leads to
neurodegeneration in cerebrum and to establish the molecular determinants of and 
neuroprotectants from such innate immunity-mediated neuronal damage. Our results 
showed that ICV LPS induced delayed, reversible oxidative damage to cerebral
neuronal membranes as measured by F4-neuroprostanes that was coincident with
degeneration of the hippocampal pyramidal neuron dendritic system, but not neuron
death, in adult mice. Both neuronal oxidative damage and dendritic degeneration
were NF-kappaB and iNOS dependent and were completely suppressed by ibuprofen and
alpha-tocopherol, but not naproxen or gamma-tocopherol. These results prove that 
activation of glial innate immunity can lead to neurodegeneration independent of 
other pathologic processes, closely associate oxidative damage to neuronal
membranes with degeneration of the dendritic system, and provide a possible
explanation for the varying efficacy of neuroprotectants that have been suggested
in observational studies of dementia.

PMID: 14713307  [PubMed - indexed for MEDLINE]

73. J Biol Chem. 2003 Oct 31;278(44):43807-17. Epub 2003 Aug 15.

Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte
infiltration and pro-inflammatory gene expression.

Marcheselli VL, Hong S, Lukiw WJ, Tian XH, Gronert K, Musto A, Hardy M, Gimenez
JM, Chiang N, Serhan CN, Bazan NG.

Neuroscience Center of Excellence and Department of Ophthalmology, Louisiana
State University Health Sciences Center, New Orleans, Louisiana 70112, USA.

Erratum in
    J Biol Chem. 2003 Dec 19;278(51):51974.

Ischemic stroke triggers lipid peroxidation and neuronal injury. Docosahexaenoic 
acid released from membrane phospholipids during brain ischemia is a major source
of lipid peroxides. Leukocyte infiltration and pro-inflammatory gene expression
also contribute to stroke damage. In this study using lipidomic analysis, we have
identified stereospecific messengers from docosahexaenoate-oxygenation pathways
in a mouse stroke model. Aspirin, widely used to prevent cerebrovascular disease,
activates an additional pathway, which includes the 17R-resolvins. The newly
discovered brain messenger 10,17S-docosatriene potently inhibited leukocyte
infiltration, NFkappaB, and cyclooxygenase-2 induction in experimental stroke and
elicited neuroprotection. In addition, in neural cells in culture, this lipid
messenger also inhibited both interleukin 1-beta-induced NFkappaB activation and 
cyclooxygenase-2 expression. Thus, the specific novel bioactive docosanoids
generated in vivo counteract leukocyte-mediated injury as well as
pro-inflammatory gene induction. These results challenge the view that
docosahexaenoate only participates in brain damage and demonstrate that this
fatty acid is also the endogenous precursor to a neuroprotective signaling
response to ischemia-reperfusion.

PMID: 12923200  [PubMed - indexed for MEDLINE]

74. Neurosci Lett. 2003 Oct 2;349(2):136-8.

Free fatty acids in cerebrospinal fluids from patients with traumatic brain
injury.

Pilitsis JG, Coplin WM, O'Regan MH, Wellwood JM, Diaz FG, Fairfax MR, Michael DB,
Phillis JW.

Department of Neurosurgery, Wayne State University School of Medicine, UHC-6E,
4201 St. Antoine, Detroit, MI 48201, USA.

Free fatty acid (FFA) concentrations in cerebrospinal fluid (CSF) are recognized 
as markers of brain damage in animal studies. There is, however, relatively
little information regarding FFA concentrations in human CSF in normal and
pathological conditions. The present study examined FFA concentrations in CSF
from 15 patients with traumatic brain injury (TBI) and compared the data with
values obtained from 73 contemporary controls. Concentrations of specific FFAs
from TBI patients, obtained within 48 h of the insult were significantly greater 
than those in the control group (arachidonic, docosahexaenoic and myristic,
P<0.001; oleic, palmitic, P<0.01; linoleic, P<0.05). Higher concentrations of
total polyunsaturated fatty acids (P<0.001) and of arachidonic, myristic and
palmitic acids measured individually in CSF (P<0.01) obtained 1 week after the
insult were associated with a worse outcome at the time of hospital discharge
using the Glasgow Outcome Scale. This preliminary investigation suggests that CSF
FFA concentrations may be useful as a predictive marker of outcome following TBI.

PMID: 12946571  [PubMed - indexed for MEDLINE]

75. Prostaglandins Leukot Essent Fatty Acids. 2003 Oct;69(4):253-9.

Potential role of dietary omega-3 essential fatty acids on some
oxidant/antioxidant parameters in rats' corpus striatum.

Sarsilmaz M, Songur A, Ozyurt H, Kuş I, Ozen OA, Ozyurt B, Söğüt S, Akyol O.

Department of Anatomy, Faculty of Medicine, Firat University, Dekanlik Binasi,
Elaziğ, Turkey. msarsilmaz@firat.edu.tr

Omega-3 (omega-3) is an essential fatty acid (EFA) found in large amounts in fish
oil. It contains eicosapentaenoic acid and docosahexaenoic acid (DHA). DHA is one
of the building structures of membrane phospholipids of brain and necessary for
continuity of neuronal functions. Evidences support the hypothesis that
schizophrenia may be the result of increased reactive oxygen species mediated
neuronal injury. Recent reports also suggest the protective effect of omega-3 EFA
against neuropsychiatric disorders including schizophrenia. This study proposed
to assess the changes in antioxidant enzyme and oxidant parameters in the corpus 
striatum (CS) of rats fed with omega-3 EFA diet (0.4g/kg/day) for 30 days. Eight 
control rats and nine rats fed with omega-3 were decapitated under ether
anesthesia, and CS was removed immediately. Thiobarbituric acid-reactive
substances (TBARS) and nitric oxide (NO) levels as well as total superoxide
dismutase (t-SOD) and xanthine oxidase (XO) enzyme activities in the CS were
measured. Rats treated with omega-3 EFA had significantly lower values of TBARS
(P<0.001), NO (P<0.002) and XO (P<0.005) whereas higher values of t-SOD enzyme
activity (P<0.002) than the control rats. These results indicate that omega-3 EFA
rich fish oil diet reduces some oxidant parameters in CS. This may be revealed by
means of reduced CS TBARS levels as an end product of lipid peroxidation of
membranes in treated rats. Additionally, reduced XO activity and NO levels may
support this notion. On the other hand, although the mechanism is not clear,
omega-3 EFA may indirectly enhance the activity of antioxidant enzyme t-SOD.
Taken together, this preliminary animal study provides strong support for a
therapeutic effect of omega-3 EFA supplemented to classical neuroleptic regimen
in the treatment of schizophrenic symptoms and tardive dyskinesia.

PMID: 12907135  [PubMed - indexed for MEDLINE]

76. J Biol Chem. 2003 Apr 25;278(17):14677-87. Epub 2003 Feb 17.

Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in
murine brain, human blood, and glial cells. Autacoids in anti-inflammation.

Hong S, Gronert K, Devchand PR, Moussignac RL, Serhan CN.

Center for Experimental Therapeutics and Reperfusion Injury, Department of
Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and
Harvard Medical School, Boston, Massachusetts 02115, USA.

Docosahexaenoic acid (DHA, C22:6) is highly enriched in brain, synapses, and
retina and is a major omega-3 fatty acid. Deficiencies in this essential fatty
acid are reportedly associated with neuronal function, cancer, and inflammation. 
Here, using new lipidomic analyses employing high performance liquid
chromatography coupled with a photodiode-array detector and a tandem mass
spectrometer, a novel series of endogenous mediators was identified in blood,
leukocytes, brain, and glial cells as 17S-hydroxy-containing docosanoids denoted 
as docosatrienes (the main bioactive member of the series was
10,17S-docosatriene) and 17S series resolvins. These novel mediators were
biosynthesized via epoxide-containing intermediates and proved potent (pico- to
nanomolar range) regulators of both leukocytes reducing infiltration in vivo and 
glial cells blocking their cytokine production. These results indicate that DHA
is the precursor to potent protective mediators generated via enzymatic
oxygenations to novel docosatrienes and 17S series resolvins that each regulate
events of interest in inflammation and resolution.

PMID: 12590139  [PubMed - indexed for MEDLINE]

77. Lipids. 2003 Apr;38(4):303-15.

The potential role for arachidonic and docosahexaenoic acids in protection
against some central nervous system injuries in preterm infants.

Crawford MA, Golfetto I, Ghebremeskel K, Min Y, Moodley T, Poston L, Phylactos A,
Cunnane S, Schmidt W.

Institute of Brain Chemistry and Human Nutrition, The London Metropolitan
University, North Campus, London N7 8DB, United Kingdom.
michael@macrawf.demon.co.uk

The risk of central nervous, visual, and auditory damage increases from 2/1000
live births in the normal birthweight to > 200/1000 as birthweight falls below
1500 g. Such babies are most likely to be born preterm. Advances in infant care
have led to increasing numbers of very-low-birthweight, preterm infants surviving
to school age with moderate to severe brain damage. Steroids are one of the
current treatments, but they cause significant, long-term problems. The evidence 
reported here suggests an additional approach to protecting the very preterm
infant by supporting neurovascular membrane integrity. The complications of
preterm, very-low-birthweight babies include bronchopulmonary dysplasia,
retinopathy of prematurity, intraventricular hemorrhage, periventricular
leukomalacia, and necrotizing enterocolitis, all of which have a vascular
component. Arachidonic acid (AA) and DHA are essential, structural, and
functional constituents of cell membranes. They are especially required for the
growth and function of the brain and vascular systems, which are the primary
biofocus of human fetal growth. Molecular dynamics and experimental evidence
suggest that DHA could be the ligand for the retinoid X receptor (RXR) in neural 
tissue. RXR activation is an obligatory step in signaling to the nucleus and in
the regulation of gene expression. Very preterm babies are born with minimal fat 
stores and suboptimal circulating levels of these nutrients. Postnatally, they
lose the biomagnification of the proportions of AA and DHA by the placenta for
the fetus. No current nutritional management repairs these deficits. The
placental biomagnification profile highlights AA rather than DHA. The resultant
fetal FA profile closely resembles that of the vascular endothelium and not the
brain. Without this nourishment, cell membrane abnormalities would be predicted. 
We present a scientific rationale for a common pathogenic process in the
complications of prematurity.

PMID: 12848275  [PubMed - indexed for MEDLINE]

78. Neuroscience. 2003;119(4):999-1012.

Neuroprotective effect of developmental docosahexaenoic acid supplement against
excitotoxic brain damage in infant rats.

Högyes E, Nyakas C, Kiliaan A, Farkas T, Penke B, Luiten PG.

Department of Animal Physiology, University of Groningen, Kerklaan 30, POB 14,
9750 AA, Haren, The Netherlands.

Long-chain polyunsaturated fatty acid (LC-PUFA) composition of neural membranes
is a key factor for brain development, in chemical communication of neurons and
probably also their survival in response to injury. Viability of cholinergic
neurons was tested during brain development following dietary supplementation of 
fish oil LC-PUFAs (docosahexaenoic acid [DHA], eicosapentaenoic acid, arachidonic
acid) in the food of mother rats. Excitotoxic injury was introduced by
N-methyl-D,L-aspartate (NMDA) injection into the cholinergic nucleus basalis
magnocellularis of 14-day-old rats. The degree of loss of cholinergic cell
bodies, and the extend of axonal and dendritic disintegration were measured
following immunocytochemical staining of cell bodies and dendrites for choline
acetyltransferase and p75 low-affinity neurotrophin receptor and by histochemical
staining of acetylcholinesterase-positive fibres in the parietal neocortex. The
impact of different feeding regimens on fatty acid composition of neural membrane
phospholipids was also assayed at 12 days of age. Supplementation of LC-PUFAs
resulted in a resistance against NMDA-induced excitotoxic degeneration of
cholinergic neurones in the infant rats. More cholinergic cells survived, the
dendritic involution of surviving neurons in the penumbra region decreased, and
the degeneration of axons at the superficial layers of parietal neocortex also
attenuated after supplementing LC-PUFAs. A marked increment in DHA content in all
types of phospholipids was obtained in the forebrain neuronal membrane fraction
of supplemented rats. It is concluded that fish oil LC-PUFAs, first of all DHA,
is responsible for the neuroprotective action on developing cholinergic neurons
against glutamate cytotoxicity.

PMID: 12831859  [PubMed - indexed for MEDLINE]

79. J Neurochem. 2002 Nov;83(3):515-24.

Systemic fatty acid responses to transient focal cerebral ischemia: influence of 
neuroprotectant therapy with human albumin.

Rodriguez de Turco EB, Belayev L, Liu Y, Busto R, Parkins N, Bazan NG, Ginsberg
MD.

Neuroscience Center of Excellence, Louisiana State University Health Sciences
Center, School of Medicine, New Orleans, Louisiana, USA.

Human albumin therapy is highly neuroprotective in focal cerebral ischemia.
Because albumin is the main carrier of free fatty acids (FFA) in plasma, we
investigated the content and composition of plasma FFA in jugular vein (JV),
femoral artery (FA) and femoral vein (FV) of rats given intravenous human albumin
(1.25 g/kg) or saline vehicle (5 mL/kg) 1 h after a 2 h middle cerebral artery
occlusion (MCAo) or sham surgery. Arachidonic acid was the only FFA significantly
increased by MCAo in all plasma samples prior to albumin administration,
remaining at the same level regardless of subsequent treatments. Albumin
treatment induced in both MCAo- and sham-groups a 1.7-fold increase in total
plasma FFA (mainly 16:0, 18:1, 18:2n-6) during 90-min reperfusion. MCAo
selectively stimulated the albumin-mediated mobilization of n-3 polyunsaturated
fatty acids (PUFA), with an early increase in 22:5n-3 and 22:6n-3 in the FA prior
to detectable changes in the JV. In the MCAo-albumin group, the lower level of
FFA in JV as compared with FA and FV suggests an albumin-mediated systemic
mobilization and supply of FFA to the brain, which may favor the replenishment of
PUFA lost from cellular membranes during ischemia and/or to serve as an
alternative source of energy, thus contributing to albumin neuroprotection.

PMID: 12390513  [PubMed - indexed for MEDLINE]

80. J Exp Med. 2002 Oct 21;196(8):1025-37.

Resolvins: a family of bioactive products of omega-3 fatty acid transformation
circuits initiated by aspirin treatment that counter proinflammation signals.

Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick G, Moussignac RL.

Center for Experimental Therapeutics and Reperfusion Injury, Department of
Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital
and Harvard Medical School, Boston, MA 02115, USA. cnserhan@zeus.bwh.harvard.edu

Aspirin (ASA) is unique among current therapies because it acetylates
cyclooxygenase (COX)-2 enabling the biosynthesis of R-containing precursors of
endogenous antiinflammatory mediators. Here, we report that lipidomic analysis of
exudates obtained in the resolution phase from mice treated with ASA and
docosahexaenoic acid (DHA) (C22:6) produce a novel family of bioactive
17R-hydroxy-containing di- and tri-hydroxy-docosanoids termed resolvins. Murine
brain treated with aspirin produced endogenous 17R-hydroxydocosahexaenoic acid as
did human microglial cells. Human COX-2 converted DHA to 13-hydroxy-DHA that
switched with ASA to 17R-HDHA that also proved a major route in hypoxic
endothelial cells. Human neutrophils transformed COX-2-ASA-derived
17R-hydroxy-DHA into two sets of novel di- and trihydroxy products; one initiated
via oxygenation at carbon 7 and the other at carbon 4. These compounds inhibited 
(IC(50) approximately 50 pM) microglial cell cytokine expression and in vivo
dermal inflammation and peritonitis at ng doses, reducing 40-80% leukocytic
exudates. These results indicate that exudates, vascular, leukocytes and neural
cells treated with aspirin convert DHA to novel 17R-hydroxy series of docosanoids
that are potent regulators. These biosynthetic pathways utilize omega-3 DHA and
EPA during multicellular events in resolution to produce a family of protective
compounds, i.e., resolvins, that enhance proresolution status.

PMCID: PMC2194036
PMID: 12391014  [PubMed - indexed for MEDLINE]

81. Crit Care Clin. 1997 Jan;13(1):39-49.

Nutritional management of the critically ill neurologic patient.

Twyman D.

Commercial Development Department, Nutrasweet Kelco Company, Deerfield, Illinois,
USA.

To summarize, the event of severe neurologic injury results in significant
metabolic changes. These changes cause increased requirements for protein and
nonprotein calories, micronutrients, and small bowel feedings or TPN. Early
feeding has been shown to improve survival. Therefore, every effort should be
made to provide aggressive nutritional support within the first 72 hours after
injury. Specific guidelines are as follows: Provide full-strength, full-rate
feedings within 72 hours. Provide enteral nutrients via nasojejunal or
percutaneous endoscopic jejunostomy feeding tube if access is available; attempt 
gastric feedings if not. Provide TPN within 48 hours if enteral access is not
available and begin enteral feeding as soon as possible. Provide 2 to 2.3 g
protein/kg/d if renal function is normal. Provide 40% to 70% above basal needs as
total calories, with 30% to 40% of calories as lipid to minimize hyperglycemia.
Provide protein as small peptides to improve tolerance, absorption, utilization, 
and gut integrity. Provide a lipid source with 50% to 70% medium-chain
triglycerides and an omega-6 to omega-3 ratio of 2:1 to 8:1 to minimize negative 
effects of omega-6 fatty acids and provide an easily absorbed and utilized source
of lipid.

PMID: 9012575  [PubMed - indexed for MEDLINE]

82. Neurology. 1993 Jun;43(6):1227-32.

Effects of fish oil supplementation on acute ischemic brain injury in the rat.

Lai ML, Hsu CY, Liu TH, He YY, Xu J, Navidi M, Sun G, Hogan EL.

Department of Neurology, Medical University of South Carolina, Charleston.

We studied the effects of long-term fish oil (FO) dietary supplementation on
brain edema, polymorphonuclear neutrophil (PMN) infiltration, and infarct size in
a rat stroke model. Rats were given regular rat chow with or without FO
supplement (20% of total calories) for 7 weeks. Body weight did not differ
between the two groups. In the FO group, an increase in eicosapentaenoic acid and
a decrease in arachidonic acid content in hepatic phospholipids were significant 
in the phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine but 
not in the phosphoinositol fraction. Platelet activity reflected by serum
thromboxane B2 levels was reduced in the FO group. Postischemic brain edema and
PMN infiltration were not different between the two groups. The infarct volume
was significantly greater in the FO group (controls: 96 +/- 7 mm3, n = 49; FO
group: 124 +/- 6 mm3, n = 53; p = 0.0036). The greater ischemic brain injury in
the FO-supplemented animals is probably related to the intraischemic
hyperglycemia, which was worse in the FO group than in the control group
(controls: 265 +/- 19 mg/dl, n = 14; FO group: 340 +/- 18 mg/dl, n = 16; p =
0.0079).

PMID: 8170570  [PubMed - indexed for MEDLINE]

83. Thromb Res. 1992 Dec 1;68(4-5):383-91.

The effect of dietary n-3 fatty acids on in vivo platelet aggregation in the
cerebral microcirculation.

Heizer ML, McKinney JS, Ellis EF.

Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia 
Commonwealth University, Richmond 23298.

Diets enriched in n-3 fish oil have been suggested to decrease coronary artery
disease in part through their ability to decrease cyclooxygenase-dependent
platelet aggregation. However little is known concerning the effect of n-3 fatty 
acids on in vivo platelet aggregation. The purpose of these experiments was to
determine whether dietary n-3 fatty acids affect the rate at which platelet
aggregation occurs in cerebral arterioles. Fish oil (200 mg eicosapentaenoic acid
+ 143 mg docosahexaenoic acid/kg), corn oil or water was given daily by gavage to
mice (n = 30) for six weeks and then in vivo platelet aggregation was induced by 
the light plus dye method, which injuries the endothelium. Two additional groups 
of mice were acutely treated with saline or indomethacin (0.5 mg/kg, ip), with
the latter serving as a positive control for therapeutic inhibition of platelet
aggregation. Serum thromboxane B2 was analyzed by RIA. All fed groups gained
weight equally. Serum thromboxane B2 was decreased by 40% in the fish oil group
(p = 0.05 vs. corn oil, p = 0.07 vs. water). The mean (+/- SE) time to first
aggregate in pial arterioles was 101 +/- 6, 91 +/- 6 and 101 +/- 9 seconds in the
fish corn oil and water groups, respectively. Indomethacin significantly
increased the time to first arteriolar aggregate by 35% (p < 0.002) and caused an
80% reduction in serum thromboxane. These studies show dietary fish oil produces 
a moderate reduction in serum TxB2 level and does not affect arteriolar platelet 
aggregation whereas indomethacin produces a drastic TxB2 reduction and
significantly slows platelet aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 1290166  [PubMed - indexed for MEDLINE]

84. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2903-7.

Membrane docosahexaenoate is supplied to the developing brain and retina by the
liver.

Scott BL, Bazan NG.

Louisiana State University School of Medicine, Louisiana State University Eye
Center, New Orleans 70112.

Docosahexaenoic acid [22:6 omega 3; 22:6(4, 7, 10, 13, 16, 19)] is concentrated
in phospholipids of cellular membranes from brain and retina. Although linolenic 
acid [18:3 omega 3; 18:3(9, 12, 15)] is the major omega 3 fatty acid of mouse
dams' milk, 22:6 is the prevalent omega 3 fatty acid in serum and tissues.
Intraperitoneal injection of [1-14C]18:3 into 3-day-old mouse pups resulted in
liver and serum lipid labeling that was initially high, followed by a rapid
decline. In contrast, labeling of brain and retinal lipids were initially low and
increased with time. Labeled 22:6 first appeared in liver 2 hr after injection
and later in brain and retina. We suggest that 22:6 synthesized from 18:3 by the 
liver is secreted into the bloodstream in lipoproteins, taken up by brain and
retina, and incorporated into cell membranes. We hypothesize that the 22:6
requirements of membranes (e.g., during synaptogenesis, photoreceptor membrane
biogenesis, or repair after ischemic injury or neurodegenerative disorders) are
met by a signal that is sent by the appropriate tissues to the liver to evoke the
secretion of 22:6-containing lipoproteins.

PMCID: PMC287028
PMID: 2523075  [PubMed - indexed for MEDLINE]