The long-term goal of this research program is to elucidate the role of the prostanoid-synthesizing enzyme cyclooxygenase-2 (COX-2) in ischemic brain injury. Studies during the previous funding period have provided evidence that COX-2 is one of the factors by which the inflammatory process involving the ischemic brain (post-ischemic inflammation) contributes to the late progression of focal cerebral ischemic damage. These findings have indicated that COX-2 participates in the late stages of ischemic brain injury. Other evidence however suggests additional mechanisms by which COX-2 could contribute to ischemic brain injury. In particular, COX-2-derived prostanoids are potent constrictors of cerebral blood vessels and participate in pathogenic processes linked to the activation of glutamate receptors. Considering that cerebral blood flow and activation of glutamate receptors play a critical role in the initiation of ischemic damage, these data raise the possibility that COX-2 could also be involved in early events of the ischemic cascade. Therefore, in this renewal application we will continue to pursue our long-term goal by testing the hypothesis that COX-2, in addition to its role in post-ischemic inflammation, is also involved in the mechanisms initiating ischemic brain injury. As a starting point, we will focus on the role of COX-2 in critical hemodynamic changes that occur during ischemia-reperfusion and in glutamate receptor-mediated cytotoxicity. In the proposed experiment, we will use molecular and biochemical approaches, as well as methods to assess hemodynamic, histological, and neurological outcome after cerebral ischemia. Focal cerebral ischemia will be produced by transient occlusion of the middle cerebral artery in mice. The brain damage resulting from focal microinjection of N-methyl-D-aspartate or kainate in neocortex will also be investigated. The role of COX-2 will be examined using both pharmacological inhibition of COX-2, and COX-2-deficient mice. The role of COX-2 derived reactive oxygen species will be examined using mice over expressing the antioxidant superoxide dismutase. While the proposed studies will expand our understanding of the involvement of COX-2 in ischemic brain injury, they will also provide the rational basis for new neuroprotective strategies for human stroke.
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