Exploring reversible AChE inhibitors as a treatment for refractory epilepsies

探索可逆的 AChE 抑制剂治疗难治性癫痫

• 批准号: 9764633
• 负责人: Andrew P Escayg
• 金额: $ 42.54万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764633
• 关键词: Acetylcholinesterase Inhibitors; Ache; Affect; Alzheimer' s Disease; Behavioral; Behavioral Paradigm; Cell Death; Cells; Clinical; Data; Dementia; Development; Disease; Early Intervention; Electroencephalography; Encephalopathies; Epilepsy; Epileptogenesis; Excision; Exhibits; Focal Seizure; Frequencies; Generations; Hippocampus (Brain); Histology; Hour; Human; Impairment; Implant; Inflammation; Intervention; Kainic Acid; Learning; Modeling; Mus; Neurons; Neuropsychology; Operative Surgical Procedures; Patient observation; Patients; Pharmaceutical Preparations; Procedures; Process; Publishing; Recurrence; Refractory; Resistance; Seizures; Severities; Temporal Lobe Epilepsy; Testing; Therapeutic; alternative treatment; base; cohort; donepezil; dravet syndrome; experimental study; granule cell; hippocampal sclerosis; huperzine A; inhibitor/antagonist; mossy fiber; mouse model; nervous system disorder; neurogenesis; neuron loss; osmotic minipump; prevent; protective effect; side effect; therapy development; translational study; treatment strategy

PROJECT SUMMARY Epilepsy is a common neurological disorder that affects 50 million people worldwide. Approximately 30% of epileptic patients have treatment resistant (refractory) seizures, thereby presenting a major clinical challenge and burden. Temporal lobe epilepsy (TLE) is the most common form of refractory human epilepsy, and mesial temporal lobe epilepsy (MTLE) is the most common form of TLE. Approximately 20% of patients with MTLE fail to achieve adequate seizure control. MTLE is characterized by spontaneous seizures, hippocampal sclerosis, and neuropsychological deficits. At present, surgical resection of the epilepsy focus is the best treatment strategy for this disorder; however, this procedure is only used in a subset of cases. Consequently, there is a need to develop alternative treatments that can effectively mitigate the broad spectrum of clinical features associated with MTLE, while minimizing unwanted side effects. Reversible acetylcholinesterase inhibitors (rAChEIs) (e.g., Huperzine A and donepezil) are most widely used in the treatment of dementia and Alzheimer's disease; however, there is increasing evidence that this class of compounds might be therapeutic in the treatment of epilepsy. Recently published data from our group demonstrated that the Huperzine A provides robust and sustained protection against induced seizures in a mouse model of the catastrophic, treatment-resistant encephalopathy Dravet syndrome (DS). In addition, we now provide preliminary data demonstrating 1) that donepezil can also increase resistance to induced seizures in the DS model, and 2) that Hup A dramatically reduces spontaneous seizure development in the intra- hippocampal kainic acid (IH-KA) mouse model of MTLE. Based on these observations, and the ability of rAChEIs to also protect against inflammation and cell death, and promote neurogenesis, we hypothesize that this class of compounds will be particularly efficacious in the treatment of MTLE. We will test this hypothesis by evaluating and comparing the ability of Hup A and donepezil to reduce spontaneous seizure frequency and severity (Aim 1) and ameliorate behavioral abnormalities and neuron loss (Aim 2) in the IH-KA mouse model of MTLE. This study will also have broader implications for the treatment of other forms of refractory epilepsy.

项目摘要 癫痫是一种常见的神经系统疾病，影响了全球5000万人。大约30％ 癫痫患者具有耐药性（难治性）癫痫发作，从而提出了重大的临床挑战 和负担。颞叶癫痫（TLE）是难治性人癫痫的最常见形式 颞叶癫痫（mtle）是最常见的TLE形式。大约20％的MTLE患者失败 实现足够的癫痫发作。 mtle的特征是自发癫痫发作，海马硬化， 和神经心理学缺陷。目前，癫痫焦点的手术切除是最好的治疗方法 这种疾病的策略；但是，此过程仅在一部分情况下使用。因此，有一个 需要开发可以有效减轻广泛临床特征的替代治疗 与MTLE相关，同时最大程度地减少不需要的副作用。 可逆的乙酰胆碱酯酶抑制剂（Racheis）（例如Huperzine A和Donepezil）是最广泛的 用于治疗痴呆症和阿尔茨海默氏病；但是，有越来越多的证据表明这 一类化合物在治疗癫痫的治疗中可能具有治疗性。最近发布了我们小组的数据 证明Huperzine A为A提供了强大而持续的保护，以防止A 灾难性，耐药性脑病Dravet综合征（DS）的小鼠模型。另外，我们 现在提供初步数据，证明1）多奈代兹也可以增加对诱发癫痫发作的耐药性 在DS模型中，2）大大减少了在内部内的自发癫痫发育 Mtle的海马海藻酸（IH-KA）小鼠模型。基于这些观察以及 Racheis还可以防止炎症和细胞死亡，并促进神经发生，我们假设 这类化合物在治疗MTLE方面将特别有效。我们将通过 评估和比较HUP A和多奈锡的能力降低自发癫痫发作频率和 严重程度（AIM 1）和改善行为异常和神经元丧失（AIM 2）在IH-KA小鼠模型中 姆特。这项研究还将对治疗其他形式的难治性癫痫的治疗具有更广泛的影响。