PPARgamma, Epilepsy and Therapeutics

描述(由申请人提供)：大约30%的癫痫患者不能用目前的抗癫痫药物(ASD)实现足够的癫痫控制。这一难治性人群具有严重的癫痫表型，并面临癫痫猝死(SUDEP)的最大风险。因此，迫切需要进行详细的研究，确定具有潜在疾病改善效果的新的治疗靶点。研究表明，难治性癫痫的大脑慢性发炎，并伴有持续性线粒体功能障碍。最近的证据支持这一假设，即这两个因素都可以增加癫痫网络的兴奋性，并在一个病理周期中加剧癫痫发作的频率和严重程度。因此，有效的疾病修正干预措施很可能会中断这一循环。核转录因子过氧化体增殖物激活受体γ(PPARy)调节抗炎、抗氧化和线粒体途径的基因。对慢性癫痫小鼠的初步实验表明，抗癫痫效果令人印象深刻。我们假设(I)癫痫动物脑中PPARy的激活将具有改善疾病的作用，提供长期的益处，(Ii)确定PPARy的机制将揭示额外的治疗靶点。利用发育性癫痫小鼠模型，我们建议(1)阐明PPARy激活恢复正常兴奋性的细胞、突触和网络机制；(2)证明线粒体健康在癫痫脑内病理性突触活动中的重要贡献；(3)证明PPARy在癫痫脑内的炎症调节；以及(4)确定PPARy激活是否延长严重癫痫动物的寿命。这些拟议的研究跨越了体内和体外系统，结合了分子生物学、电生理学、显微镜、生物能量学和药理学的技术，将为癫痫发作、线粒体、炎症和体内平衡机制之间的相互作用提供洞察力。由于PPARy激动剂目前被用于II型糖尿病的临床治疗，这一结果将具有巨大的、立即的翻译潜力。PPARy正在接受研究，作为治疗多种其他神经系统疾病的药物，这些疾病的共同点是细胞死亡和炎症；因此，这项提案的结果将产生广泛的影响。

DESCRIPTION (provided by applicant): Approximately 30% of people with epilepsy do not achieve adequate seizure control with current anti-seizure drugs (ASDs). This medically refractory population has severe seizure phenotypes and is at greatest risk of sudden unexpected death in epilepsy (SUDEP). Therefore, there is an urgent need for detailed studies identifying new therapeutic targets with potential disease-modifying outcomes. Studies indicate that the refractory epileptic brain is chronically inflamed with persistent mitochondrial dysfunction. Recent evidence supports the hypothesis that both factors can increase the excitability of epileptic networks and exacerbate seizure frequency and severity in a pathological cycle. Thus, effective disease-modifying interventions will most likely interrupt this loop. The nuclear transcription factor peroxisome proliferator activated receptor gamma (PPARy) regulates genes in anti-inflammatory, anti-oxidant and mitochondrial pathways. Preliminary experiments in chronically epileptic mice indicate impressive anti-seizure efficacy. We hypothesize that (i) activation of brain PPARy in epileptic animals will have disease modifying effects that provide long-term benefits, and (ii) determining PPARy mechanisms will reveal additional therapeutic targets. Using a mouse model of developmental epilepsy, we propose to (1) elucidate the cellular, synaptic and network mechanisms by which PPARy activation restores normal excitability; (2) demonstrate the significant contribution of mitochondrial health in pathologic synaptic activity in epileptic brain; (3) demonstrate inflammatory regulation of PPARy in epileptic brain; and (4) determine whether PPARy activation extends the lifespan of severely epileptic animals. The proposed studies, spanning in vivo and in vitro systems using a combination of techniques in molecular biology, electrophysiology, microscopy, bioenergetics and pharmacology, will provide insight into the interplay of seizures, mitochondria, inflammation and homeostatic mechanisms. The results will have tremendous, immediate translational potential because PPARy agonists are currently used for clinical treatment of Type II Diabetes. PPARy is under investigation as treatment for a wide variety of other neurological diseases with cell death and inflammation as common denominators; therefore, the results of this proposal will have a broad impact.