Prostanoid Receptors and Ischemic Brain Injury

描述(由申请人提供)： 环氧合酶-2(COX-2)是一种前列腺素合成的限速酶，已成为缺血性脑损伤的主要致病因素，有望成为卒中的治疗靶点。然而，最近的基础和临床研究结果表明，一些COX-2反应产物，如前列环素，具有有益的心血管效应。因此，为了开发COX-2途径的治疗潜力，需要选择性地靶向参与毒性的反应产物，避免其他COX-2衍生剂的有益作用。这项应用的目标是确定导致缺血性脑损伤的特定COX-2反应产物，并使用临床前方法来确定其潜在的治疗价值。拟议的研究将检验下列假设：(1)引发损伤的主要COX-2反应产物是前列腺素而不是活性氧；(2)前列腺素E2通过其EP1受体参与缺血性脑损伤；(3)EP1受体是COX-2在缺血后脑内毒性的效应者；(4)EP1受体抑制剂的临床前保护作用的特点表明它们在卒中的治疗中有希望。实验将在大脑中动脉短暂闭塞造成脑缺血的小鼠身上进行。COX-2反应产物的作用将使用药物抑制剂、过度表达抗氧化酶超氧化物歧化酶1的转基因小鼠或缺乏COX-2或EP1受体的空白小鼠来研究。缺血性脑损伤将通过组织学和行为学标准进行评估。分子、生化和神经解剖学技术将用于确定导致脑损伤的COX-2途径的反应产物。该应用程序符合RFA HL-05-004的要求，因为它探索了新的治疗方法，无论是单独使用还是与其他治疗方法结合使用，都可能对缺血性中风患者有用。(摘要结束)

DESCRIPTION (provided by applicant): 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. (End of Abstract)