Analysis of COX-2 as a therapeutic target in acquired epilepsy (epileptogenesis)

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DESCRIPTION (provided by applicant): Epilepsy is a chronic debilitating neurological disease that according to the National Institutes of Health affects more than 50 million people worldwide. After the landmark "Curing Epilepsy: Focus on the Future" Conference, in March 2000, NINDS developed a newly invigorated research agenda for epilepsy. One major feature is to support research that would "create and implement new therapies aimed at the prevention of epilepsy in patients at risk", which means those persons who acquire the epileptic condition following injury to the nervous system. Although there are numerous drugs available to effectively treat established epilepsy (i.e. anti-epileptic drugs), drugs that prevent epilepsy development (i.e. anti- epileptogenic drugs) remain to be identified. Data from studies examining the role of cyclooxygenase-2 (COX-2) in the acquisition of epilepsy (i.e. epileptogenesis) have been equivocal. Kindling, an animal model of epileptogenesis, was only modestly affected by pharmacological inhibition or genetic deletion of COX-2. While this could suggest that COX-2 contributes only partially to the process of epileptogenesis, it could also be due to suboptimal pharmacological properties of the drugs used and/or developmental abnormalities in the COX-2 deficient mice (i.e., COX-1 compensation) that could confound interpretation of the kindling studies. Thus, the goal of the research to be supported by this two year R21 proposal is to 1) determine unequivocally the contribution of cyclooxygenase-2 in epileptogenesis, 2) identify a novel candidate anti-epileptogenic therapeutic, and 3) assess the potential role of arachidonic acid shunting to the therapeutic potential of a candidate inhibitor. Epilepsy is a chronic debilitating neurological disease that affects tens of millions worldwide. After the landmark "Curing Epilepsy: Focus on the Future" Conference, in March 2000, NINDS developed a newly invigorated research agenda for epilepsy. One major feature is to support research that would "create and implement new therapies aimed at the prevention of epilepsy in patients at risk", that is those persons who acquire the epileptic condition following injury to the nervous system. Although there are numerous drugs available to effectively treat established epilepsy (i.e. anti-epileptic drugs), drugs that prevent epilepsy development (i.e. anti-epileptogenic drugs) remain to be identified.