Journal of Neurotrauma January 30, 2013 [ebub] Hasadsri L MD; Wang BH, MD;, PhD; Wang BH MD; Lee JV PhD; Erdman JW PhD;Llano DA MD, PhD; Wszalek T PhD; Sharrock MF BSc First author is from the Department of Neurosurgery, University of Illinois College ofMedicine. This article has 190 references KEY POINTS FROM THIS ARTICLE: 1) Traumatic Brain Injury (TBI) is a global public health epidemic. 2) In the US more than 3 million people sustain a TBI annually. 3) TBI may cause motor and sensory deficits and lead to severe cognitive,emotional, and psychosocial impairment, crippling vital areas of higher functioning. 4) TBI is the signature injury in wounded soldiers in Iraq and Afghanistan. 5) TBI may have a devastating impact on athletes playing contact sports. 6) There has been little progress in developing effective TBI interventions. 7) Nutritional intervention may provide a unique opportunity to enhance theneuronal repair process after TBI. 8) The two omega-3 fatty acids that are most promising for their neurorestorativecapacities in TBI are docosahexaenoic acid (DHA) and eicosapentaenoicacid (EPA). 9) Chronic repetitive sub-concussive head impacts may also result incumulative long-term deleterious effects. 10) Long-term health disorders associated with TBI include: A)) Post-traumatic stress disorder (PTSD) B)) Neurodegenerative diseases (Alzheimer’s disease or Parkinsonism) C)) Neurocognitive deficits D)) Psychosocial health problems (e.g., binge drinking, major depression,impairment of social functioning and ability to work, suicide) E)) Epilepsy F)) Pain G)) Other alterations in personality or behavior 11) Nutritional intervention, such as supplementation with n-3 (also known asomega-3) fatty acids, may be of therapeutic benefit in acute injury to the brain. 12) Omega-3 fatty acids have long been known to play a restorative role inseveral pathways implicated in traumatic insult to the brain. 13) Case studies show great benefit on the use of omega-3s in the acute phase ofsevere head injury. 14) N-3 polyunsaturated fatty acids (PUFAs) are uniquely protective againstdegeneration induced by TBI, and they improve behavioral and cognitive outcomesin patients with TBI. 15) The most important n-3 fatty acids for human health and nutrition aredocosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and alpha-linolenic acid(ALA). 16) Humans can convert a limited amount of ALA into EPA and DHA, butsynthesis of EPA and especially DHA from ALA is insufficient to supplant dietaryintake. [Important, especially for strict vegetarians] 17) DHA comprises more than 50% of brain neuronal membrane phospholipids. 18) Omega-3 fatty acids, especially DHA, are essential for maintaining membranefluidity. DHA is tremendously flexible allowing it to under go rapid interconversionsbetween multiple torsional states, and to readily undergo complex yet minimal energy-requiring conformational changes. [Fluidity] 19) During neuronal stress, both EPA and DHA are released from membranephospholipids and converted into compounds called resolvins, which resolveinflammatory processes, protect against oxidative stress, and maintain synapticintegrity. [Resolvins] 20) In the brain, omega-3s, especially DHA: A)) Increased the size of neurons B)) Increases the complexity of dendritic arboritizations C)) Increased the number of neurons D)) Increases serotonin and acetylcholine receptors E)) Improved attention, task performance, learning, and memory F)) Improves dopamine neurotransmission increases dopamine receptors, whichimproves motivational behavior and emotional functions 21) DHA is neuroprotective, and supplementation significantly amelioratessecondary mechanisms of injury and reduces the number of damaged axons. 22) Supplementation with n-3 fatty acids significantly decrease the productionof reactive oxygen species (ROS) and improve cognitive function. 23) DHA has an essential role in nervous system development and are requiredfor proper synaptogenesis, neural membrane synthesis, and the building offunctionally critical circuits within the brain. 24) DHA deficiency is associated with aging and neurodegenerative conditionssuch as Alzheimers disease, while DHA consumption has been shown to improveperformance on visuospatial learning and memory tasks in patients with age-relatedcognitive decline. 25) Dietary supplementation with omega-3 fatty acids improves functionalrecovery in subarachnoid hemorrhage and stroke. 26) Omega-3 fatty acids in the brain appear be neuroprotective in TBI becausethey protect against inflammation, apoptosis, and oxidative stress mechanisms. 27) TBI causes diffuse axonal destruction, demyelination, and neuronal cell death.This is followed by a secondary wave of disruption in the subsequent hours anddays due to inflammatory responses, excitotoxicity, and oxidative stress. 28) Omega-3 fatty acids mitigate the consequences of several key pathologicalpathways in TBI, such as mitochondrial malfunction, apoptotic cell death,glutamate-triggered excitotoxicity, and injury-induced oxidative stress andinflammation. 29) Omega-3 fatty acids may play a critical role in the restoration of cellularenergetics and repair of neuronal damage after TBI. 30) The production of pro-inflammatory prostaglandins is stimulated by andderived from the release of arachidonic acid (AA) secondary to disruption ofneuronal cell membranes. Arachidonic acid is rapidly converted into potentinflammatory mediators such as prostaglandins and leukotrienes. 31) DHA functions in a neuroprotective capacity, antagonizing the pro-deathsignaling pathways initially triggered by AA. 32) The release of the excitotoxic neurotransmitter glutamate is a destructiveevent following acute traumatic injury in the brain. Excess glutamate causesoveractivation of N-methyl d-aspartate (NMDA) and calcium-permeable AMPAreceptors, leading to a massive influx of Ca++ and the induction of bothprogrammed and necrotic cell death via calcium-dependent proteases. DHA: A)) Reduces glutamate excitotoxicity B)) Downregulates the expression of AMPA receptor subunits C)) Decreases Ca++ influx into the neuron 33) The most detrimental consequence of excess intracellular Ca++ is increasedoxidative stress, a key contributor to the pathophysiologic changes that occur afterTBI. 34) The influx of excess Ca++ into mitochondria increases ROS formation,damaging DNA and proteins, inducing programmed cell death. 35) ROS causes lipid peroxidation on a catastrophic scale, further disruptingneuronal membrane integrity and function. 36) The antioxidant defense mechanisms are relatively scarce in the human brain. 37) Traumatic disruptions in cerebral blood flow causes ATP energy depletion andcollapse of energy-dependent ion transport and active pumps, allowing intracellularCa++ overload. 38) Brain oxidative stress causes inflammation and additional microvasculardamage, secondary ischemia, and neuronal cell death. 39) The sex steroid progesterone reduces cerebral edema and has neuroprotective effects. 40) Multiple clinical trials have shown that high-dose fish oil consumption is safeeven in patients receiving other agents that may increase the risk of bleeding, suchas aspirin and warfarin. 41) DHA at doses up to 6g/d does not have deleterious effects on plateletaggregation or other clotting parameters in normal individuals, and fish oil does notaugment aspirin-induced inhibition of blood clotting. 42) It may be prudent to discontinue high-dose omega-3 supplementation in thesetting of an acute bleeding illness or in patients at high risk for hemorrhagicstroke. 43) PUFAs have high susceptibility to lipid peroxidation which may have apotential carcinogenic role.[This is why I advocate taking antioxidant co-factors] 44) High intake of fish may increase the risk of exposure to environmental toxinsand contaminants such as mercury and polychlorinated biphenyls; purified fish oilsare much safer. 45) Omega-3 fatty acids restore cellular energetics, reduce oxidative stress andinflammation, repair cellular damage, and mitigate the activation of apoptoticprocesses after TBI.