Testing the effects of a selective calpain-2 inhibitor on spontaneous recurrent seizures in mouse models of epilepsy

测试选择性 calpain-2 抑制剂对小鼠癫痫模型自发性复发性癫痫发作的影响

• 批准号: 10696598
• 负责人: Michel Baudry
• 金额: $ 48.93万
• 依托单位: NEURAEGIS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696598
• 关键词: Acute; Address; Affect; Animals; Antiepileptic Agents; Antiepileptogenic; Appearance; Biotechnology; Brain; Brain Concussion; Brain Injuries; C57BL/6 Mouse; Calcium; Calpain; Chronic; Clinic; Data; Development; Disease; Dose; Drug resistance; Electroencephalography; Encephalitis; Epilepsy; Epileptogenesis; Event; Exhibits; Family; Formulation; Frequencies; Glial Fibrillary Acidic Protein; Hippocampus; Immunohistochemistry; Impaired cognition; Injections; Injury; Intranasal Administration; Intravenous; Kainic Acid; Knockout Mice; Laboratories; Lead; Learning; Location; Migraine; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Injury; Neurons; Pathologic; Patients; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Pilocarpine; Process; Property; Prosencephalon; Protein Isoforms; Rattus; Recurrence; Route; Seizures; Severities; Small Business Technology Transfer Research; Stains; Status Epilepticus; Stroke; Testing; Therapeutic; Traumatic Brain Injury; Video Recording; Wild Type Mouse; analog; astrogliosis; axonal degeneration; blood-brain barrier crossing; brain dysfunction; calpain inhibitor; clinical candidate; clinical development; compliance behavior; conditional knockout; conditioned fear; cost estimate; design; effectiveness evaluation; effectiveness testing; excitatory neuron; glial activation; glial cell development; inhibitor; mouse model; nervous system disorder; neuron loss; neuropathology; neuroprotection; novel; prevent; side effect; therapeutic target

Abstract Epilepsy is the most prevalent neurological diseases after migraines. Current antiepileptic drug treatments mainly attempt to reduce excitation or enhance inhibition in order to control seizures. Unfortunately, such therapeutics result in a number of undesirable side-effects, and demonstrate limited efficacy against drug- resistant cases of epilepsy. So far, no treatment has been developed as an anti-epileptogenic agent, in part because of the limited understanding of the processes involved in the development of epilepsy. It is generally accepted that up to 50% of all epileptic patients become epileptic as a result of a triggering initial injury such as status epilepticus, stroke or traumatic brain injury. This initial triggering injury has been postulated to activate a cascade of events leading to further seizures, increased brain damage and self-propagation. Calpains are a family of soluble calcium-dependent proteases, which have been implicated in epilepsy, since they are activated by seizures and participate in neuronal damage. Recent studies have also indicated that during early epileptogenesis, seizure occurrence, calpain activity and neuronal damage are correlated, and that treatment with a non-selective calpain inhibitor reduces the development of spontaneous recurrent seizures (SRS) in the pilocarpine model of epilepsy in rats. Our laboratory has demonstrated that calpain-1 and calpain-2, two of the major calpain isoforms in the brain, have opposite functions in the brain. We have also found that calpain-2 conditional knock-out mice with calpain-2 deletion in excitatory neurons from the forebrain show normal seizure activity following injections of repeated low doses of kainic acid (KA) but exhibit no brain inflammation, degeneration and cognitive impairment in hippocampus-dependent learning 7 days after seizures. Similar protective results were obtained when wild-type mice were treated daily and for seven days after seizures with a selective calpain-2 inhibitor. These results strongly support the hypothesis that calpain-2 might represent a potential therapeutic target to prevent various pathological consequences of seizures. This Phase I STTR is directed at first determining whether a selective calpain-2 inhibitor, NA-184, might prevent the appearance of SRSs or reduce their frequency in two mouse models of epilepsy, the repeated low doses of kainic acid (KA) or of pilocarpine models (Aim #1). In Aim # 2, we will test the effects of intranasal administration of NA-184 on KA- and pilocarpine-induced neuropathology, as intranasal delivery of a variety of anti-epileptic drugs is increasingly used in the clinic. In Phase II of this STTR, we will further pursue the development of intranasal delivery of NA- 184 as an anti-epileptic treatment. NeurAegis is a small biotech company focusing on the development of selective calpain-2 inhibitors for the treatment of acute neuronal injury, including traumatic brain injury and repeated concussions. This proposal is directed at expanding the potential applications of these calpain-2 inhibitors by determining whether they could also be developed as potential therapeutic treatment for epilepsy.

摘要 癫痫是继偏头痛之后最常见的神经系统疾病。目前的抗癫痫药物治疗 主要尝试减少兴奋或增强抑制以控制癫痫发作。可惜这样 治疗剂导致许多不希望的副作用，并显示出有限的抗药物- 抗癫痫病例。到目前为止，还没有开发出抗癫痫药物的治疗方法，部分原因是 因为对癫痫发展过程的了解有限。一般 接受高达50%的癫痫患者成为癫痫作为触发初始损伤的结果， 癫痫持续状态、中风或创伤性脑损伤。这种最初的触发性损伤被认为是激活了一种 一系列事件导致进一步的癫痫发作，增加脑损伤和自我传播。钙蛋白酶是一种 可溶性钙依赖性蛋白酶家族，与癫痫有关，因为它们被激活 参与神经元损伤。最近的研究还表明，在早期 癫痫发生、癫痫发作、钙蛋白酶活性和神经元损伤相关， 与非选择性钙蛋白酶抑制剂减少自发性复发性癫痫发作（SRS）的发展， 大鼠毛果芸香碱癫痫模型。我们的实验室已经证明，钙蛋白酶-1和钙蛋白酶-2，两个 大脑中主要的钙蛋白酶同种型在大脑中具有相反的功能。我们还发现钙蛋白酶-2 在前脑兴奋性神经元中具有钙蛋白酶-2缺失的条件性敲除小鼠显示正常癫痫发作 在重复注射低剂量红藻氨酸（KA）后的活性，但没有表现出脑炎症， 在癫痫发作后7天，海马依赖性学习的退化和认知障碍。类似 当野生型小鼠在癫痫发作后每天和连续7天用 选择性钙蛋白酶-2抑制剂。这些结果有力地支持了钙蛋白酶-2可能代表一种 潜在的治疗靶点，以防止癫痫发作的各种病理后果。第一阶段STTR是 旨在首先确定选择性钙蛋白酶-2抑制剂NA-184是否可以防止 在两种小鼠癫痫模型中，反复低剂量的海人酸（KA）或 毛果芸香碱模型（目标#1）。在目标#2中，我们将测试鼻内施用NA-184对KA-1的影响。 和毛果芸香碱诱导的神经病理学，因为各种抗癫痫药物的鼻内递送越来越多地被用于治疗癫痫。 在诊所使用。在本STTR的II期，我们将进一步开发NA-1的鼻内递送。 第184章抗癫痫药NeurAegis是一家小型生物技术公司，专注于开发 用于治疗急性神经元损伤包括创伤性脑损伤的选择性钙蛋白酶-2抑制剂 反复脑震荡该建议旨在扩大这些calpain-2的潜在应用 通过确定它们是否也可以被开发为癫痫的潜在治疗性治疗来确定抑制剂。