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和阿尔茨海默病相关的正常神经功能丧失中发挥重要作用。环氧合酶是通过花生四烯酸代谢产生前列腺素的限速酶。COX-1在大多数神经细胞中有结构性表达，并被认为对基本功能有反应。另一方面，在包括缺氧、炎症和兴奋性毒性在内的各种脑损伤后，神经元中COX-2的表达和PG的产生显著增加。在啮齿动物缺血和兴奋毒性模型上的研究表明，COX-2酶活性促进神经元损伤，而给予特定的抑制剂减少神经元损伤。我们最近测试了选择性地在神经元中高表达COX-2的转基因小鼠，我们观察到这些转基因小鼠的脑梗塞面积增加；尽管在给予特定的COX-2抑制剂后，我们不能显示出显著的减少。流行病学研究表明，服用抗炎药的患者阿尔茨海默病的发病率降低，许多研究报告了AD大脑中COX-2的诱导。使用选择性COX-2抑制剂的临床试验已经设计；尽管到目前为止报道的结果还没有达到很高的期望。更好地了解PG受体是非常重要的，可以解释之前报道的几个差异和失败。PGs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，而另一些可能具有细胞保护作用。作为第一步，我们将专注于PGE2、PGD2和PGF2受体的敲除，因为我们知道这些PG似乎存在于大脑中更高的水平。利用体内研究和体外培养，我们建议在这四个相互关联的目标中确定PG受体在调节兴奋性毒性损伤中的作用。我们将确定1)脑内PG水平和受体分布的年龄相关性变化，2)特定PG受体在促进体内兴奋性毒性损伤中的作用，3)特定PG受体在促进β-淀粉样蛋白沉积中的作用，以及4)特定PG受体在神经细胞培养中促进或改善兴奋性毒性和β-淀粉样蛋白毒性的作用及其相关细胞机制的研究。

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.