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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的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。不幸的是，这样的治疗会导致许多不良副作用，并且对药物的疗效有限难治性癫痫病例。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。一般是人们普遍认为，高达 50% 的癫痫患者是由于触发初始损伤（例如癫痫持续状态、中风或创伤性脑损伤。假设这种最初的触发伤害会激活导致进一步癫痫发作、脑损伤加剧和自我传播的一系列事件。钙蛋白酶是一种可溶性钙依赖性蛋白酶家族，由于它们被激活而与癫痫有关通过癫痫发作并参与神经元损伤。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是相关的，并且治疗使用非选择性钙蛋白酶抑制剂可以减少自发性复发性癫痫发作（SRS）的发生毛果芸香碱大鼠癫痫模型。我们的实验室已证明 calpain-1 和 calpain-2（其中的两种）大脑中主要的钙蛋白酶亚型在大脑中具有相反的功能。我们还发现 calpain-2 前脑兴奋性神经元中 calpain-2 缺失的条件性基因敲除小鼠表现出正常的癫痫发作重复注射低剂量红藻氨酸 (KA) 后活性增强，但未表现出脑部炎症，癫痫发作后 7 天海马依赖性学习的退化和认知障碍。相似的当野生型小鼠每天接受治疗并在癫痫发作后持续 7 天时，获得了保护性结果选择性 calpain-2 抑制剂。这些结果有力地支持了这样的假设：calpain-2 可能代表预防癫痫发作的各种病理后果的潜在治疗目标。第一阶段 STTR 是首先确定选择性钙蛋白酶 2 抑制剂 NA-184 是否可以预防在两种癫痫小鼠模型中重复使用低剂量红藻氨酸 (KA) 或降低其频率毛果芸香碱模型（目标#1）。在目标#2中，我们将测试鼻内施用NA-184对KA-的影响和毛果芸香碱诱发的神经病理学，随着各种抗癫痫药物的鼻内给药越来越多用于临床。在本 STTR 的第二阶段，我们将进一步开发 NA-鼻内递送 184作为抗癫痫治疗。 NeurAegis 是一家小型生物技术公司，专注于开发选择性钙蛋白酶 2 抑制剂用于治疗急性神经元损伤，包括创伤性脑损伤和反复脑震荡。该提案旨在扩大这些 calpain-2 的潜在应用通过确定它们是否也可以开发为癫痫的潜在治疗方法来确定抑制剂。