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Therapies for epilepsy prevention - focus on adenosine

预防癫痫的疗法——关注腺苷

基本信息

批准号：
10655634
负责人：
Detlev Boison
金额：
$ 43.22万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10655634
关键词：
ADORA2A gene Acute Address Adenosine Adenosine Kinase Affect Antibiotics Antiepileptogenic Applications Grants Azacitidine Benchmarking Brain Ceftriaxone Cell Nucleus Chronic Clinical Combined Modality Therapy Cytoplasm DNA Methylation Data Development Disease Dose Drug Utilization Enzymes Epigenetic Process Epilepsy Epileptogenesis Event FDA approved Foundations Future Genetic Glutamate Transporter Glutamates Goals Homeostasis Hour Impairment Injury Kainic Acid Knowledge Link Measures Mediating Mediator Metabolism Modeling Mus National Institute of Neurological Disorders and Stroke Neurologic Nuclear Outcome Pathologic Pharmaceutical Preparations Pharmacotherapy Play Post-Traumatic Epilepsy Prevention strategy Prevention therapy Process Protein Isoforms Purinergic P1 Receptors Rattus Research Rodent Model Role Seizures Severities Signal Pathway Solid Status Epilepticus System Temporal Lobe Epilepsy Testing Therapeutic Therapeutic Intervention Time Traumatic Brain Injury Treatment Efficacy Work acquired epilepsy adenosine receptor activation astrogliosis clinical development clinical translation comparative efficacy design drug discovery experimental study extracellular glial activation inhibitor innovation kinase inhibitor neuronal excitability novel overexpression pharmacologic prevent preventable epilepsy programs receptor research and development response small molecule therapeutic evaluation therapeutic target therapy development uptake

项目摘要

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

项目概要预防癫痫及其进展（癫痫发生）仍然是癫痫研究和治疗的最终目标疗法的发展。尽管这已被 NINDS 癫痫研究确定为迫切需要基准来看，仍然没有可干扰癫痫发生过程的治疗方法。发展历程预防癫痫及其进展的疗法将彻底改变癫痫的治疗方式，而癫痫是一种常见的疾病。世界上最常见的神经系统疾病将得到治疗。该应用程序旨在测试新的利用现有 FDA- 的介入疗法在获得性癫痫啮齿动物模型中预防癫痫批准的药物。我们的方法的基本原理是基于超过 25 年的适应不良研究腺苷代谢过程，驱动并促成癫痫过程，从而使癫痫发作健康的大脑变成了癫痫的大脑。具体来说，大脑中与急性损伤相关的腺苷激增通过增加腺苷 A2A 的激活来激活神经胶质细胞并调节谷氨酸稳态受体，与星形胶质细胞谷氨酸转运蛋白 GLT-1 偶联。因此，使用 FDA 批准的 A2A 受体阻滞剂伊曲茶碱或 FDA 批准的 GLT-1 激活剂头孢曲松是合理的治疗方法在致癫痫级联反应发生期间干扰关键机制的干预措施。一个延迟的致癫痫级联的反应是主要腺苷代谢的病理性过度表达腺苷激酶（ADK）导致癫痫脑中慢性腺苷缺乏。我们已经展示了 ADK 的过度表达，特别是细胞核中表达的亚型 (ADK-L)，驱动通过表观遗传机制（DNA 甲基化增加）导致癫痫的过程。我们已经证明治疗性腺苷增强可有效预防 4 种不同啮齿动物的癫痫及其进展癫痫发生模型。因此 ADK 抑制剂和 DNA 甲基化阻滞剂（例如 FDA 批准的药物 - 5-氮杂胞苷）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由，即腺苷系统及其下游介质提供了几种可能的抗癫痫治疗靶点。该应用程序的中心目标是根据 FDA 的重新利用来确定和测试预防癫痫的治疗策略批准的药物和针对该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内进行测试和优化颞叶癫痫的红藻氨酸模型，并在创伤性脑损伤诱发的模型中得到验证外伤后癫痫。我们的假设将通过三个具体目标来解决：（1）靶向腺苷癫痫预防的受体依赖性机制（2）靶向腺苷受体非依赖性癫痫预防机制（3）测试抗癫痫联合疗法的疗效