PG receptors--Controlling excitotoxicity in aging brain

PG受体——控制衰老大脑的兴奋性毒性

• 批准号: 6704692
• 负责人: Sylvain DORE
• 金额: $ 33.93万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6704692
• 关键词: aging; amyloid proteins; autoradiography; biological signal transduction; brain injury; calcium flux; cyclic AMP; cytotoxicity; gene mutation; genetically modified animals; glutamates; immunocytochemistry; inflammation; laboratory mouse; neuritic plaques; neuroprotectants; neurotoxicology; prostaglandin receptor; prostaglandins; protein localization; protein quantitation /detection; protein structure function; receptor binding; tissue /cell culture; western blottings

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.

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氏病中发挥重要作用。 COX 是通过花生四烯酸代谢产生 PG 的限速酶。 COX-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做出反应。另一方面，在各种脑损伤（包括缺氧、炎症和兴奋性毒性）后，神经元中 COX-2 的表达和 PG 的产生显着增加。啮齿动物缺血和兴奋性毒性模型的研究表明，COX-2 酶活性会促进神经元损伤，而施用特定抑制剂可减少神经元损伤。我们最近测试了在神经元中选择性过度表达 COX-2 的转基因小鼠，我们观察到这些转基因小鼠的梗塞面积增加；然而，在施用特定的 COX-2 抑制剂后，我们未能显示出显着的减少。流行病学研究表明，服用抗炎药物的患者阿尔茨海默病的发病率会降低，并且大量研究报告了 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；尽管如此，迄今为止报告的结果并没有满足人们的高期望。 更好地了解 PG 受体至关重要，并且可以解释之前报道的一些差异和失败。 PGs 在兴奋性毒性条件下促进神经元损伤的机制尚未明确。据报道，一些 PG 具有毒性，而另一些则可能具有细胞保护作用。第一步，我们将重点关注 PGE2、PGD2 和 PGF2 受体敲除，因为我们知道这些 PG 在大脑中似乎存在较高水平。利用体内研究和体外培养，我们提出这四个相互关联的目标来定义 PG 受体在调节兴奋性毒性损伤中的作用。我们将确定 1) 大脑中 PG 水平和受体分布与年龄相关的变化，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受体在促进或改善神经元细胞培养物中兴奋毒性和β-淀粉样蛋白毒性中的作用以及相关细胞机制的研究。