Cyclooxygenase 2 and Ischemic Neuronal Injury

说明(申请人提供)：环氧合酶是一种催化花生四烯酸产生前列腺素的酶，长期以来一直被认为通过其血管和炎症作用在加重脑缺血造成的损伤中发挥作用。最近发现，该酶的诱导型亚型环氧合酶2(COX2)在神经元中高水平表达。我们假设，神经元内的COX2活动本身促进了缺氧/缺血后的细胞死亡。拟议的实验旨在测试COX2活性是否通过氧化应激、前列腺素(包括环戊烯酮前列腺素)的产生，或两者兼而有之而加剧缺氧损伤。 提出了以下具体目标： 1.检测COX2活性是否通过过氧化物酶活性产生氧化应激而加重缺氧损伤。 2.检测COX2活性是否通过环氧合酶活性产生前列腺素而加重缺氧损伤。 3.检测15-脱氧-β-(12，14)-前列腺素J2或其他前列腺素是否通过激活PPARγ受体而激活PPARγ受体，从而加重缺氧性神经元死亡。 COX2活性与中风和神经退行性疾病的发病机制有关，包括阿茨海默病和肌萎缩侧索硬化症。目前的研究将解决COX2活性可以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.