Prostanoid Receptors and Ischemic Brain Injury

环氧合酶-2(COX-2)是前列腺素合成的限速酶。 是缺血性脑损伤的主要致病因素，是治疗中风的良好靶点。 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，具有有益的心血管作用。因此，为了利用 COX-2通路的治疗潜力，涉及毒性的反应产物需要 有选择性地靶向，避免其他COX-2衍生剂的有益影响。的目标 这一应用是为了确定导致缺血的特定环氧合酶-2反应产物 并使用临床前方法来确定其潜在的治疗价值。这个 拟议的研究将检验以下假设：(1)前列腺素而不是活性氧 物种是启动损伤的主要COX-2反应产物；(2)前列腺素E2作用 通过其EP1受体参与缺血性脑损伤；(3)EP1受体是缺血性脑损伤的效应因子。 环氧合酶-2在脑缺血后的毒性作用；(4) EP1受体抑制剂的保护作用提示它们在治疗急性髓细胞白血病方面有希望 卒中。实验将在由短暂性脑缺血引起的小鼠身上进行。 大脑中动脉闭塞。将研究COX-2反应产物的作用 使用药物抑制剂，过量表达抗氧化酶的转基因小鼠 超氧化物歧化酶1，或缺乏COX-2或EP1受体的空白小鼠。缺血性脑损伤会 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 技术将被用来定义COX-2途径的反应产物，这些反应产物有助于 脑部受伤。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，无论是单独还是与其他治疗相结合，都可能是 对缺血性中风患者有用。

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.