Exploring reversible AChE inhibitors as a treatment for refractory epilepsies

项目总结 癫痫是一种常见的神经疾病，影响着全球5000万人。约30%的 癫痫患者有难治性(难治性)发作，因此是一个重大的临床挑战。 和负担。摘要颞叶癫痫(TLE)是人类难治性癫痫中最常见的一种类型。 颞叶癫痫(MTLE)是TLE最常见的形式。大约20%的MTLE患者失败 以实现充分的癫痫控制。MTLE的特征是自发性癫痫，海马区硬化， 和神经心理缺陷。目前，手术切除癫痫灶是最好的治疗方法。 治疗这种疾病的策略；然而，这种方法只在部分病例中使用。因此，有一个 需要开发能够有效缓解广泛临床特征的替代疗法 与MTLE相关，同时将不想要的副作用降至最低。 可逆乙酰胆碱酯酶抑制剂(RAChEIs)(如石杉碱甲和多奈哌齐)应用最为广泛 用于治疗痴呆症和阿尔茨海默氏症；然而，越来越多的证据表明，这 这类化合物可能在治疗癫痫方面具有治疗作用。我们小组最近发布的数据 证明石杉碱甲对诱发癫痫提供了强大和持续的保护作用 难治性脑病德雷特综合征(DS)小鼠模型。此外，我们 现在提供的初步数据表明：1)多奈哌齐也可以增强对诱发癫痫的抵抗力 在DS模型中，以及2)Hup A显著减少脑内自发性癫痫的发展。 海马海人酸(IH-KA)小鼠MTLE模型。基于这些观察，以及 RAChE还可以预防炎症和细胞死亡，并促进神经再生，我们假设 这类化合物在治疗MTLE方面将特别有效。我们将通过以下方式验证这一假设 评价和比较Hup A和多奈哌齐降低自发性癫痫发作频率和抑制癫痫发作的作用 严重程度(目标1)和改善行为异常和神经元丢失(目标2)的IH-KA小鼠模型 MTLE。这项研究也将对其他形式的难治性癫痫的治疗产生更广泛的影响。

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.