Cyclooxygenase 2 and Ischemic Neuronal Injury

描述（由申请人提供）：环氧合酶是一种催化花生四烯酸生成异甘草素的酶，长期以来一直被认为通过其血管和炎症效应在加重脑缺血所致损伤中发挥作用。最近，人们已经发现，诱导异构体的酶，环氧合酶2（COX 2），在神经元内的高水平表达。我们推测，COX 2活性在神经元本身促进缺氧/缺血后的细胞死亡。所提出的实验旨在测试COX 2活性是否加剧氧化应激引起的缺氧损伤、包括环戊烯酮类胡萝卜素的胡萝卜素的产生或两者。 建议的具体目标如下： 1.测试COX 2活性是否通过过氧化物酶活性产生氧化应激而加剧缺氧损伤。 2.测试COX 2活性是否通过环氧合酶活性产生洋地黄素而加剧缺氧损伤。 3.测试15-deoxy-delta（12，14）-PGJ 2或其他洋地黄素是否激活PPARgamma受体结合并通过激活PPARgamma受体加剧缺氧神经元死亡。 COX 2活性与中风和神经退行性疾病的发病机制有关，包括阿茨海默氏病和肌萎缩侧索硬化症。目前的研究将解决COX 2活性直接损伤神经元的机制，从而可能导致中风和神经退行性疾病的新治疗策略。

DESCRIPTION (provided by applicant): Cyclooxygenase, the enzyme that catalyzes the production of prostaglandins from arachidonic acid, has long been thought to play a role in exacerbating injury due to cerebral ischemia via its vascular and inflammatory effects. Recently it has been found that the inducible isoform of the enzyme, cyclooxygenase 2 (COX2), is expressed in high levels within neurons. We hypothesize that COX2 activity within the neuron itself promotes cell death after hypoxia/ischemia. The proposed experiments are designed to test whether COX2 activity exacerbates anoxic injury by oxidative stress, production of prostaglandins including the cyclopentenone prostaglandins, or both. The following specific aims are proposed: 1. Test whether COX2 activity exacerbates anoxic injury through production of oxidative stress via peroxidase activity. 2. Test whether COX2 activity exacerbates anoxic injury through production of prostaglandins via cyclooxygenase activity. 3. Test whether 15-deoxy-delta(12,14) -PGJ2 or other prostaglandins activate PPARgamma receptor binding and exacerbate anoxic neuronal death via activation of the PPARgamma receptor. COX2 activity has been implicated in the pathogenesis of stroke and neurodegenerative diseases, including Atzheimer's disease and amyotrophic lateral sclerosis. The current studies will address the mechanisms by which COX2 activity can directly injure neurons and thus could lead to new therapeutic strategies for stroke and neurodegenerative diseases.