Prostanoid Receptors and Ischemic Brain Injury

描述（由申请人提供）： 环氧合酶-2（考克斯-2）是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，是治疗脑卒中的一个有前途的靶点。然而，最近的基础和临床研究结果表明，一些考克斯-2反应产物，如前列环素，具有有益的心血管作用。因此，为了开发考克斯-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，从而避免其它考克斯-2衍生试剂的有益作用。本申请的目的是鉴定导致缺血性脑损伤的特异性考克斯-2反应产物，并使用临床前方法鉴定其潜在的治疗价值。本研究将验证以下假设：（1）前列腺素类而非活性氧是引发脑损伤的主要考克斯-2反应产物;（2）前列腺素E2通过其EP 1受体参与缺血性脑损伤;（3）EP 1受体是考克斯-2在脑缺血后发挥毒性作用的效应器;（4）EP-1受体抑制剂的临床前保护作用特点提示其在脑卒中治疗中具有广阔的前景。实验将在小鼠中进行，其中脑缺血是通过大脑中动脉的短暂闭塞产生的。将使用药理学抑制剂、过表达抗氧化酶超氧化物歧化酶1的转基因小鼠或缺乏考克斯-2或EP 1受体的无效小鼠研究考克斯-2反应产物的作用。将通过组织学和行为标准评估缺血性脑损伤。分子、生物化学和神经解剖学技术将用于确定导致脑损伤的考克斯-2通路的反应产物。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，无论是单独使用还是与其他治疗方法联合使用，都可能对缺血性卒中患者有用。(End摘要）

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)