Hypoxic-ischemic brain injury (HI) is the major cause of permanent neurological handicap in children. Omega- 3 (n-3) fatty acids (FA), especially eicosapentaenoic (EPA) and docosahexaenoic acids (DHA), have emerged as major elements for cell membrane structure+-function. n-3 FA beneficially alter outcomes of hypoxic-ischemic brain injury in rodents. The investigators' laboratories are demonstrating that acute injectio of intravenous triglyceride (TG) emulsions enriched in DHA and EPA markedly protect rodent brains against HI injury after HI in neonatal mice. Emulsions with TG containing only DHA (triDHA) showed major neuroprotective effects, and this was not shared by emulsions containing only triEPA or n-6 TG. The neuroprotection shown by triDHA occurred when injected even at 2hr after reperfusion. Neuroprotection was associated with 1) increased brain content of neuroprotectin D1 (NPD1), 2) increased DHA in cerebral mitochondria, and 3) attenuation of mitochondrial membrane permeabilization after HI. Our overall hypothesis is that triDHA changes mitochondrial FA composition and preserves mitochondrial function after HI by limiting Ca2+ induced membrane permeabilization, a central mechanism of cell death after ischemia. A key component of our hypothesis is that beneficial effects of triDHA relate to decreasing reactive oxygen species (ROS) surges in mitochondria, limiting mitochondrial self-oxidation, thereby preserving mitochondrial membrane integrity. These hypotheses will be tested under three Specific Aims.
Aim 1 will characterize how n-3 TG and their catabolites are delivered to neonatal brain after acute injection following HI injury and determine optimal dosages and FA specificity for maximum neuroprotection and compare this with hypothermia treatment. We anticipate that after injection triDHA is first taken up by liver and after repackaging into TG or FA, and/or partially catabolized to NPD1 to reach brain to promote neuroprotection.
In Aim 2 we will determine whether n- 3 TG treatment after HI modifies mitochondrial FA composition and how this alleviates secondary mitochondrial dysfunction in reperfusion. We expect these experiments will confirm a major role for DHA in protecting mitochondria by decreasing mitochondrial generation of ROS, a major factor for injury to mitochondria and cells.
Aim 3 will determine whether DHA-associated neuroprotection relates to increased production of NPD1 through its anti-apoptotic effects. The focus will be on the role of NPD1 interacting with mitochondria to prevent permeabilization of outer mitochondrial membranes and whether this involves translocation of anti-apoptotic pathways.
Cardiovascular disease, stroke, and myocardial infarction are currently the leading cause of death in the USA and in societies that are transitioning to Western style life habits. Our planned studies have direct relevance to treating morbidity and mortality associated with one major cause of cardiovascular disease in humans, stroke. Our studies will use acute injections of triglyceride emulsions rich in omega-3 (n-3) fatty acids to decrease brain death after exposure to low oxygen levels and arterial blockages. Our studies will uncover mechanisms underlying the potential benefits of acute treatment with n-3 triglycerides by delineating the effects of these bioactive n-3 compounds have in protecting mitochondrial function in brain and characterize pathways that are beneficial to brain survival after acute injur induced by oxygen deprivation.
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