EP2 antagonists as novel anti-epileptogenic agents

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Epilepsy is associated with significant mortality and morbidity, with an estimated annual cost of $15 billion to the USA. About 150,000 new cases of epilepsy are diagnosed in the United States each year. The anti-seizure drugs, which blunt seizures in epilepsy patients, do not prevent the development of epilepsy. Posttraumatic epilepsy (PTE) arises in patients due to traumatic brain injury (TBI). The incidence of epilepsy in adults after a penetrating TBI is about 50%. Thus, it is very important to identify novel adjunct therapeutic agents which can be administered along with anti-seizure drugs to delay the progression and prevent the development of PTE and other types of epilepsy. Induction of COX-2 and PGE2 were found in the brain of patients and rodent models after TBI and seizures. Recently, we have shown that COX-2 deletion restricted to forebrain neurons is beneficial in pilocaprine induced model of status epilepticus (SE). A selective antagonist of PGE2 receptor EP2 recapitulated many features of conditional COX-2 deletion in SE model by blunting several proinflammatory mediators, gliosis and neurodegeneration, suggesting that most of the COX-2 proinflammatory effects are mediated through EP2 receptor in a brain injury model. Thus, we hypothesized that targeting EP2 receptor, downstream of COX-2, will be a superior strategy for the development of anti-epileptogenic therapy. In this study, we propose to test a proof-of-concept whether targeting EP2 receptor with small molecule antagonist will be anti-epileptogenic in rat rostral parasagittal fluid percussion injury (rpFPI) model of posttraumatic epilepsy.