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.
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