Prostanoid Receptors and Ischemic Brain Injury

环氧合酶-2（考克斯-2）是前列腺素类合成的限速酶，已成为前列腺素类合成的一个重要途径。 是缺血性脑损伤的主要致病因素，是脑卒中有前途的治疗靶点。 然而，最近的基础和临床发现表明，一些考克斯-2反应产物， 例如前列环素，具有有益的心血管作用。因此，为了利用 考克斯-2途径的治疗潜力，涉及毒性的反应产物需要 选择性靶向，避免其它考克斯-2衍生剂的有益作用。的目标 本申请旨在鉴定导致缺血性疾病的特异性考克斯-2反应产物， 脑损伤，并使用临床前方法来确定其潜在的治疗价值。的 拟进行的研究将检验以下假设：（1）前列腺素而不是活性氧 前列腺素E2是启动损伤的主要考克斯-2反应产物 EP 1受体通过其受体参与缺血性脑损伤;（3）EP 1受体是缺血性脑损伤的效应器。 考克斯-2在缺血后脑组织中的毒性作用;（4）COX-2的临床前特征; EP 1受体抑制剂的保护作用表明，它们在治疗 中风实验将在小鼠中进行，其中脑缺血是由短暂的 大脑中动脉闭塞将研究考克斯-2反应产物的作用 使用药理学抑制剂，过度表达抗氧化酶的转基因小鼠 超氧化物歧化酶1，或缺乏考克斯-2或EP 1受体的无效小鼠。缺血性脑损伤将是 通过组织学和行为学标准进行评估。分子生物化学和神经解剖学 技术将被用来定义考克斯-2途径的反应产物， 脑损伤该应用程序满足RFA HL-05-004的要求，因为它探索了 新的治疗方法，无论是单独或与其他治疗组合， 可用于缺血性中风患者。

Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostanoid synthesis, has emerged as a major pathogenic factor in ischemic brain injury and is a promising therapeutic target for stroke. However, recent basic and clinical findings have suggested that some COX-2 reaction products, such as prostacyclin, have beneficial cardiovascular effects. Therefore, in order to exploit the therapeutic potential of the COX-2 pathway, the reaction products involved in the toxicity need to be selectively targeted, sparing the beneficial effects of other COX-2 derived agents. The goals of this application are to identify the specific COX-2 reaction products that contribute to ischemic brain injury and to use preclinical approaches to identify their potential therapeutic value. The proposed studies will test the following hypotheses: (1) Prostanoids rather than reactive oxygen species are the main COX-2 reaction products initiating the injury; (2) Prostaglandin E2 acting through its EP1 receptor contributes to ischemic brain injury; (3) EP1 receptors are the effectors of the toxicity exerted by COX-2 in the post-ischemic brain; (4) the preclinical characteristics of the protective effect of EP1 receptor inhibitors suggest that they have promise in the treatment of stroke. Experiments will be conducted in mice in which cerebral ischemia is produced by transient occlusion of the middle cerebral artery. The role of COX-2 reaction products will be investigated using pharmacological inhibitors, transgenic mice overexpressing the antioxidant enzyme superoxide dismutase 1, or null mice lacking COX-2 or EP1 receptors. Ischemic brain injury will be assessed by histological and behavioral criteria. Molecular, biochemical and neuroanatomical techniques will be used to define the reaction products of the COX-2 pathway that contribute to brain injury. The application fulfills the requirements of the RFA HL-05-004 because it explores novel therapeutic approaches that, either alone or in combination with other treatments, could be useful in patients with ischemic stroke.