Therapies for epilepsy prevention - focus on adenosine

预防癫痫的疗法——关注腺苷

• 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
• 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

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

项目摘要 预防癫痫及其进展（癫痫发生）仍然是癫痫研究的最终目标， 治疗发展。虽然这已经被NINDS癫痫研究确定为迫切需要 基准，仍然没有可用的治疗，干扰癫痫的过程。发展 治疗，以防止癫痫及其进展将是范式转变的方式癫痫，其中一个 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 利用现有的FDA- 批准的药物。我们的方法的基本原理是基于超过25年的研究适应不良 腺苷代谢的过程，驱动，并有助于，癫痫的过程，把一个 健康的大脑变成癫痫的大脑具体来说，大脑中与急性损伤相关的腺苷激增 通过腺苷A2 A活化增加的神经胶质活化和谷氨酸稳态失调 受体，其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A2 A 受体阻断剂伊司特福林或FDA批准的GLT-1激活剂头孢曲松是合理的治疗药物 干预措施，干扰癫痫级联发作期间的关键机制。延迟 癫痫级联反应是主要腺苷代谢的病理性过度表达， 腺苷激酶（ADK）导致癫痫脑中的慢性腺苷缺乏。我们已经表明 ADK的过表达，特别是在细胞核中表达的同种型（ADK-L）， 通过表观遗传机制（增加DNA甲基化）的癫痫过程。我们已经证明 治疗性腺苷增强有效地预防癫痫及其在4种不同啮齿动物中的进展 癫痫模型因此，ADK抑制剂和DNA甲基化阻断剂（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 一个药物发现项目，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由，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。本申请的核心目标 是确定和测试基于FDA的再利用的癫痫预防治疗策略， 批准的药物和靶向药物的组分的新型小分子化合物的用途。 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。 海人酸颞叶癫痫模型，并在创伤性脑损伤诱导的癫痫模型中得到验证。 创伤后癫痫我们的假设将在三个特定的目的：（1）靶向腺苷 受体依赖性癫痫预防机制（2）靶向腺苷受体非依赖性 癫痫预防机制（3）抗癫痫联合治疗的疗效试验