Peroxisome proliferator-activated receptor gamma (PPAR?) is a nuclear receptor that controls the expression of several genes involved in lipid homeostasis, inflammation, cancer and diabetes. PPAR? is activated by synthetic drugs used for treating type II diabetes, as well as by polyunsaturated fatty acids and sorne of their oxidized derivatives.Recently, PPAR? has been recognized as a neuroprotective factor in the centralnervous system, since its agonists modulate inflammation and cell death inneurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, multiple sclerosis and brain ischemia.Previous studies in our laboratory have demonstrated that PPAR? has a directneuroprotective role in neurons, in addition to its anti-inflammatory action exerted on glia. In neurons, PPAR? protects against oxidative stress and amyloid-? peptide, and its neuronal deficiency is associated with an increase in damage susceptibility resultingfrom a down-regulation of target genes involved in cell protection, such as catalase, superoxide dismutase 1 and gluthation S-transferase. Despite the evidence that PPAR? and its agonists induce a cell survival program in neurons, little is known about theendogenous mechanism that regulates their activation under physiological andpathophysiological circumstances. PPAR? expression is upregulated after focal brain ischemia, particularly in neurons, suggesting that endogenous ligands are produced close to the damage site.Docosahexaenoic acid (DHA) is an n-3 fatty acid enriched in the nervous system, which accumulates in cellular membrane phospholipids and enhances plasma membrane fluidity, contributing to neuronal synaptic function. DHA is liberated from cellular membranes after damage and oxygenated to bioactive lipids vía the action of 15-lipoxygenase type 1, thus initiating pathways that include the production of D-series Resolvins and Neuroprotectins, which are potent inflammation and neuroprotectionmodulators. For example, DHA and Neuroprotectin D1 protect from A? peptide-induced death in human neural cells and upregulate the anti-apoptotic protein Bcl-2. DHA and NPD1 have been proposed to be PPAR? ligands. However, the mechanism by which DHA and NPD1 transduce their neuroprotective signaling in neurons is unknown.On this basis, the purpose of this work was to determine whether DHA signaling isactive during cytotoxic damage in neurons and whether DHA neuroprotective effects are dependent on lipid mediator production and PPAR?.The working hypothesis of this study postula tes that docosahexaenoic a cid is released during cytotoxic damage and protects against neuronal death via PPAR? induction and neuroprotective oxydized-derived lipid formation.To evaluate this hypothesis we studied PPARy-mediated DHA-inducedneuroprotection, PPAR? transcriptional activation and expression during excitotoxic neuronal damage, DHA release from neuronal membranes after injury and DHA-lipid mediator production in DHA-supplemented cortical neuron cultures.The results obtained showed the following: i) primary cortical neurons cultured under standard growing conditions presented a reduced content of DHA in membranes, probably caused by the absence of polyunsaturated fatty acids in the artificially neuronal growing medium. We observed that DHA levels can be efficiently restored to the physiological composition by exogenous DHA supplementation, without altering anyother polyunsaturated fatty acids; ii) DHA induced increased neuronal viability and conferred neuroprotection against glutamate-induced death; iii) although DHA was not detected as an unesterified form in cortical neurons and DHA-derived protectins and resolvins were not found in neurons after the DHA incubation, DHA induced neuroprotection through a mechanism that involves PPAR? activity and the induction of its neuroprotective target genes SOD-2, IDE and Bcl-2. PPAR? activation by DHA probably resulted from the formation of other natural activators, like 18-hydroxy-eicosapentaenoic acid (18-HEPE), which is a novel eicosapentaenoic acid-derivedmediator; iv) in cortical neurons, 18-HEPE was robustly increased due to DHAsupplementation and presented high transcriptional PPAR? induction ability. DHA induced 18-HEPE formation most probably resulted from DHA retroconversion to EPA(eicosapentaenoic acid), sine e neurons presented a transient in crease in the EPA levels after DHA incubation; v) 18-HEPE prevented neuronal cell death induced by glutamate exposure, suggesting that DHA might be mediating neuroprotection through this novelEPA-derived mediator generation.Our present data shows for first time a link between DHA and the PPAR? nuclearreceptor in neurons. Moreover, our findings provide novel evidence for the development of natural n-3-derived fatty acid PPAR? ligands, with increasing potential for therapeutic use in neurological pathologies including Alzheimer's disease, Parkinson's disease,stroke and also aging.PFCHA-BecasDoctor en Ciencias Biológicas Mención Biología Celular y Molecular159p.PFCHA-BecasTERMINADA