PG receptors in controling excitotoxicity in aging brain

描述（由申请人提供）：炎症及其后果被认为在与衰老相关的正常神经元功能丧失和阿尔茨海默病中起重要作用。考克斯是花生四烯酸代谢产生前列腺素的限速酶。考克斯-1在大多数神经元细胞中组成型表达，并被认为对基础功能有反应。另一方面，在各种脑损伤包括缺氧、炎症和兴奋毒性后，神经元中考克斯-2表达和PG产生显著增加。在啮齿动物缺血和兴奋性毒性模型中的研究表明，考克斯-2酶活性促进神经元损伤，并且施用特异性抑制剂减少神经元损伤。我们最近测试了在神经元中选择性过表达考克斯-2的转基因小鼠，我们观察到这些转基因小鼠的梗死面积增加;尽管我们在给予特异性考克斯-2抑制剂后不能显示出显著减少。流行病学研究表明服用抗炎药的患者中阿尔茨海默病的发病率降低，并且许多研究报告了AD脑中考克斯-2的诱导。已经设计了使用选择性考克斯-2抑制剂的临床试验;尽管，迄今为止报道的结果没有满足高期望。 更好地了解PG受体是至关重要的，可以解释以前报道的几个差异和失败。PG在兴奋性毒性条件下促进神经元损伤的机制尚未确定。据报道，一些PG是有毒的，而另一些可能是细胞保护性的。作为第一步，我们将专注于PGE 2，PGD 2和PGF 2受体敲除，知道这些PG似乎在大脑中以更高的水平存在。使用在体内的研究以及在体外培养，我们建议在这四个相互关联的目的，以确定PG受体在调节兴奋性毒性损伤的作用。我们将确定1）大脑中PG水平和受体分布的年龄相关变化，2）特异性PG受体在体内促进兴奋性毒性损伤中的作用，3）特异性PG受体在促进β-淀粉样蛋白沉积中的作用，以及4）特异性PG受体在促进或改善神经元细胞培养物中的兴奋性毒性和β-淀粉样蛋白毒性中的作用，并研究相关的细胞机制。

DESCRIPTION (provided by applicant): 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.