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

描述（由申请人提供）：癫痫是一种慢性衰弱性神经系统疾病，根据美国国立卫生研究院的数据，全球有超过5000万人患有癫痫。2000年3月，在具有里程碑意义的“治愈癫痫：关注未来”会议之后，NINDS制定了一项新的癫痫研究议程。其中一个主要特点是支持“创造和实施旨在预防高危患者癫痫的新疗法”的研究，高危患者指的是那些在神经系统受伤后患癫痫的人。虽然有许多药物可用于有效治疗已确诊的癫痫（即抗癫痫药物），但预防癫痫发展的药物（即抗癫痫药物）仍有待鉴定。研究环氧合酶-2（考克斯-2）在癫痫发生（即癫痫发生）中的作用的数据不明确。点燃，癫痫发生的动物模型，仅受到药物抑制或考克斯-2基因缺失的适度影响。虽然这可能表明考克斯-2仅部分参与癫痫发生过程，但这也可能是由于所用药物的次优药理学性质和/或考克斯-2缺陷小鼠的发育异常（即，考克斯-1补偿），这可能混淆点燃研究的解释。因此，这项为期两年的R21提案支持的研究目标是：1）明确确定环氧合酶-2在癫痫发生中的作用，2）确定一种新的候选抗癫痫治疗药物，3）评估花生四烯酸分流到候选抑制剂治疗潜力的潜在作用。癫痫是一种慢性神经衰弱性疾病，影响着全世界数千万人。2000年3月，在具有里程碑意义的“治愈癫痫：关注未来”会议之后，NINDS制定了一项新的癫痫研究议程。其中一个主要特点是支持“创造和实施旨在预防高危患者癫痫的新疗法”的研究，高危患者是指那些因神经系统损伤而患癫痫的人。虽然有许多药物可用于有效治疗已确诊的癫痫（即抗癫痫药物），但预防癫痫发展的药物（即抗癫痫药物）仍有待确定。

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.