Inflammation and its consequences are suggested to play an important role in the loss of normal neuronal functions associated with aging and in Alzheimer's disease. COX is the rate-limiting enzyme for the production of the PGs through metabolism of the arachidonic acid. COX-1 is constitutively expressed in most neuronal cells and has been suggested to respond to basal functions. On the other hand, COX-2 expression and PG production increase markedly in neurons following a variety of brain insults including hypoxia, inflammation and excitotoxicity. Studies in rodent ischemic and excitotoxic models show that COX-2 enzymatic activity promotes neuronal injury and the administration of specific inhibitors reduces neuronal damage. We have recently tested transgenic mice overexpressing COX-2 selectively in neurons and, we observed an increased infarct size in these transgenic mice; although, we were not able to show significant reduction after administration of a specific COX-2 inhibitor. Epidemiological studies have suggested a reduction in the incidence of Alzheimer's disease in patients who were taking anti-inflammatory drugs, and numerous studies reporting the induction of COX-2 in AD brains. Clinical trials using selective COX-2 inhibitors clinical trials have been designed; although, the results reported so far have not satisfied the high expectations. A better understanding of the PG receptors is of utmost importance and could explain several of the discrepancies and failures previously reported. Mechanisms by which PGs promote neuronal injury in excitotoxic conditions have not yet been defined. Some PGs have been reported to be toxic while others may be cytoprotective. As a first step, we will concentrate on the PGE2, PGD2, and PGF2 receptor knockouts, knowing that these PGs appear to be present at higher levels in the brain. Using in vivo studies as well as in vitro cultures, we propose in these four interconnected aims to define the role of PG receptors in regulating excitotoxic damage. We will determine 1) age-related changes in PG levels and receptor distribution in the brain, 2) the role of specific PG receptors in promoting excitotoxic injury in vivo, 3) the role of specific PG receptor in promoting beta-amyloid deposits, and 4) the role of specific PG receptor in promoting or ameliorating excitotoxic and beta-amyloid toxicity in neuronal cell cultures and investigation of the associated cellular mechanism.
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