Therapies for epilepsy prevention - focus on adenosine

项目总结 预防癫痫及其进展(癫痫发生)仍然是癫痫研究和治疗的最终目标。 治疗的发展。尽管这已经被NINDS癫痫研究确定为迫切需要 根据基准，目前仍没有干扰癫痫形成过程的治疗方法。最新进展 一种预防癫痫的疗法及其进展将是癫痫的方式的范式转变，癫痫是 世界上最常见的神经系统疾病将得到治疗。此应用程序旨在测试新的 利用现有FDA在获得性癫痫啮齿动物模型中预防癫痫的介入治疗- 批准的药物。我们方法的理论基础是基于对适应不良的超过25年的研究。 腺苷代谢的过程，它推动并促进了致痫过程，使一种 健康的大脑变成了癫痫的大脑。具体地说，大脑中与急性损伤相关的腺苷激增驱动 腺苷A2a激活引起的神经胶质细胞激活和谷氨酸平衡失调 受体，与星形胶质细胞谷氨酸转运体GLT-1偶联。因此，使用FDA批准的A2A 受体阻滞剂依特拉布林或FDA批准的GLT-1激动剂头孢曲松是合理的治疗药物 干预在致痫级联反应发生过程中的关键机制。一个延迟的 致痫级联反应是主要腺苷代谢产物的病理性过度表达 腺苷激酶(ADK)酶导致癫痫脑中的慢性腺苷缺乏。我们已经展示了 ADK的过度表达，特别是在细胞核中表达的一种异构体(ADK-L)，推动了 通过表观遗传机制(DNA甲基化增加)的致痫过程。我们已经证明了 治疗性腺苷增强可有效预防4种不同啮齿类动物癫痫及其进展 癫痫发生的模型。因此，ADK抑制剂和DNA甲基化阻滞剂(例如FDA批准的药物- 5-氮胞苷)有望预防癫痫及其进展。为此，我们最近推出了 一项药物发现计划，产生了一种具有抗癫痫活性的候选ADK-L抑制剂(MRS-4203)。 总的来说，我们的初步数据提供了一个坚实的理论基础，即腺苷系统及其下游 介体提供了几种可能的抗癫痫治疗靶点。此应用程序的中心目标是 是识别和测试基于FDA重新用途的癫痫预防的治疗策略 已批准的药物和针对药物成分的新型小分子化合物的使用 腺苷能系统。我们的治疗方法将在小鼠海马区进行测试和优化 红藻氨酸颞叶癫痫模型及在创伤性脑损伤模型中的验证 创伤后癫痫。我们的假设有三个具体目标：(1)以腺苷为靶点 癫痫预防的受体依赖性机制(2)以腺苷受体非依赖性为靶点 癫痫的预防机制(3)抗癫痫联合治疗的疗效检验

PROJECT SUMMARY Preventing epilepsy and its progression (epileptogenesis) remains the ultimate goal for epilepsy research and therapy development. Although this has been identified as an urgent need by the NINDS Epilepsy Research Benchmarks, there is still no therapy available that interferes with the epileptogenic process. The development of a therapy to prevent epilepsy and its progression would be paradigm-shifting in the way epilepsy, one of the most frequent neurological conditions worldwide, would be treated. This application is designed to test new interventional therapies to prevent epilepsy in rodent models of acquired epilepsy utilizing existing FDA- approved drugs. The rationale for our approach is based on more than 25 years of research into maladaptive processes in adenosine metabolism, which drive, and contribute to, the epileptogenic process that turns a healthy brain into an epileptic brain. Specifically, an acute injury-associated adenosine surge in the brain drives glial activation and dysregulation of glutamate homeostasis through increased activation of adenosine A2A receptors, which couple to the astroglial glutamate transporter GLT-1. Hence, the use of the FDA approved A2A receptor blocker istradefylline, or the FDA approved GLT-1 activator ceftriaxone are rational therapeutic interventions to interfere with key mechanisms during the onset of the epileptogenic cascade. A delayed response of the epileptogenic cascade is pathological overexpression of the major adenosine metabolizing enzyme adenosine kinase (ADK) resulting in chronic adenosine deficiency in the epileptic brain. We have shown that overexpression of ADK, and specifically an isoform expressed in the cell nucleus (ADK-L), drives the epileptogenic process through an epigenetic mechanism (increased DNA methylation). We have shown that therapeutic adenosine augmentation effectively prevents epilepsy and its progression in 4 different rodent models of epileptogenesis. Hence ADK inhibitors and DNA methylation blockers (e.g. the FDA approved drug - 5-azacytidine) hold promise for the prevention of epilepsy and its progression. To this end we recently launched a drug discovery program, which yielded a candidate ADK-L inhibitor (MRS-4203) with antiepileptogenic activity. Collectively, our preliminary data provide a solid rationale that the adenosine system and its downstream mediators offer several possible antiepileptogenic therapeutic targets. The CENTRAL GOAL of this application is to identify and test therapeutic strategies for epilepsy prevention based on repurposing of FDA approved drugs and the use of novel small molecule compounds that target components of the adenosinergic system. Our therapeutic approaches will be tested and optimized in the mouse intrahippocampal kainic acid model of temporal lobe epilepsy and validated in a traumatic brain injury induced model of posttraumatic epilepsy. Our hypothesis will be addressed in three Specific Aims: (1) Targeting adenosine receptor dependent mechanisms for epilepsy prevention (2) Targeting adenosine receptor independent mechanisms for epilepsy prevention (3) Test therapeutic efficacy of antiepileptogenic combination therapies