PI3K/Akt/mTOR信号通路在AMPA受体拮抗剂吡仑帕奈改善癫痫共病的作用机制研究

Epilepsy comorbidity is an important clinical problem, and cognitive impairment is one of the most common comorbidities in epilepsy. Epilepsy itself and its underline etiology may cause it. However, many antiepileptic drugs have a cognitive side effect while treating epilepsy. The new anti-epileptic drug AMPA receptor antagonist perampanel has cognitive improvement in addition to anti-epilepsy. It is important to study the mechanism by which perampanel improves cognitive function in patients with epilepsy. We believe that perampanel may have other functions besides direct action on the AMPA receptor. Previous reports have found that perampanel exerts neuroprotective function in a rat stroke model by AKT. While the PI3K/AKT pathway activates mTOR, the role of the mTOR signaling pathway is widely demonstrated in learning and memory functions. Therefore, this study proposes a hypothesis that perampanel is likely to decrease PI3K/Akt/mTOR pathway activity. Improve cognitive ability in patients with epilepsy. This study intends to establish a rat model as a research object, and explore the possible mechanisms and effects of PI3K/Akt/mTOR signaling pathways in improving cognitive impairment of epilepsy from animal behavior, molecular biology, and electrophysiology. To better understand the mechanism of perampanel to improve cognitive function in patients with epilepsy, better choice of anti-epileptic drugs, and also help to develop anti-epileptic drugs with cognitive improvement in the future.

认知障碍是癫痫最为常见的共病之一。它可能是癫痫本身及其潜在病因引起。然而许多抗癫痫药物在治疗癫痫的同时有恶化认知的副作用。新型抗癫痫药物AMPA受体拮抗剂吡仑帕奈已经被证实在抗癫痫之外具有癫痫患者认知改善的作用，而其机制尚不明确。既往研究发现mTOR与学习及记忆密切相关，而癫痫合并认知障碍与PI3K/Akt/mTOR过度激活相关，在申请者的前期研究中发现吡仑帕奈能减少Akt的激活。因此本研究提出一个假说，吡仑帕奈很可能是通过抑制PI3K/Akt/mTOR的通路活性来提高癫痫患者的认知能力。在扎实的研究基础上，本研究拟以大鼠癫痫模型为研究对象，从癫痫发作情况、行为学、认知、分子生物学及电生理多个方面探索性研究其改善癫痫共病认知障碍的机制。从而为癫痫合并认知障碍的治疗提供新的靶点，新的思路。

癫痫患者常合并认知障碍，严重影响癫痫患者的生活质量，并且影响到患者的用药选择。现已知多种抗癫痫药物加重癫痫患者认知损害。.吡仑帕奈（Perampanel，PER）目前已经是一种常见的第三代抗癫痫药物，是第一种用于抗癫痫治疗的选择性非竞争性拮抗剂AMPA型谷氨酸受体拮抗剂。广泛的使用在临床场景中，在青少年和儿童的添加治疗中，吡仑帕奈没有表现出认知方面的负向作用。在部分动物的研究中，已经提示吡仑帕奈在抗癫痫之外，具有改善认知的作用。PI3K/Akt/mTOR的过度激活在癫痫发病及认知障碍的产生中起着关键作用。 最新的研究显示，AMPA受体拮抗剂能够影响到PI3K/Akt/mTOR通路。因而我们提出一个假说PER通过抑制PI3K/Akt/mTOR的通路的活性来提高癫痫患者的认知能力。.本研究在前人研究的基础上，进一步在癫痫小鼠模型上验证了吡仑帕奈治疗后小鼠记忆行为学有明显的改善，首次在小鼠离体脑切片电生理验证了使用吡仑帕奈后海马锥体神经元微小兴奋性突触后电流的改善，在WB分析中，提示吡仑帕奈治疗后p-MTOR降低，以及在添加了PI3K抑制剂后，小鼠的记忆行为学恶化，海马细胞凋亡水平增高，能够提示吡仑帕奈可能通过PI3K/AKT/mTOR通路发挥部分的认知改善机制。.上述研究结果多为首次报道。此项研究将有益于多种癫痫合并认知障碍患者（痴呆合并癫痫，脑炎脑病合并癫痫）的治疗选择，并有益于筛查新的抗癫痫药物同时改善认知的靶点。.