Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, China.
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, China.
Eur J Pharmacol. 2024 Oct 15;981:176903. doi: 10.1016/j.ejphar.2024.176903. Epub 2024 Aug 16.
Epilepsy is a prevalent disorder of the central nervous system. Approximately, one-third of patients show resistance to pharmacological interventions. The pathogenesis of epilepsy is complex, and neuronal apoptosis plays a critical role. Aberrantly reactive astrocytes, induced by cytokine release from activated microglia, may lead to neuronal apoptosis. This study investigated the role of glucagon-like peptide 1 receptor (GLP1R) in microglial activation in epilepsy and its impact on astrocyte-mediated neurotoxicity.
We used human hippocampal tissue from patients with temporal lobe epilepsy and a pilocarpine-induced epileptic mouse model to assess neurobiological changes in epilepsy. BV2 microglial cells and primary astrocytes were used to evaluate cytokine release and astrocyte activation in vitro. The involvement of GLP1R was explored using the GLP1R agonist, Exendin-4 (Ex-4).
Our findings indicated that reduced GLP1R expression in hippocampal microglia in both epileptic mouse models and human patients, correlated with increased cytokine release and astrocyte activation. Ex-4 treatment restored microglial homeostasis, decreased cytokine secretion, and reduced astrocyte activation, particularly of the A1 phenotype. These changes were associated with a reduction in neuronal apoptosis. In addition, Ex-4 treatment significantly decreased the frequency and duration of seizures in epileptic mice.
This study highlights the crucial role of microglial GLP1R in epilepsy pathophysiology. GLP1R downregulation contributes to microglial- and astrocyte-mediated neurotoxicity, exacerbating neuronal death and seizures. Activation of GLP1R with Ex-4 has emerged as a promising therapeutic strategy to reduce neuroinflammation, protect neuronal cells, and control seizures in epilepsy. This study provides a foundation for developing novel antiepileptic therapies targeting microglial GLP1R, with the potential to improve outcomes in patients with epilepsy.
癫痫是一种常见的中枢神经系统疾病。大约三分之一的患者对药物干预表现出耐药性。癫痫的发病机制复杂，神经元凋亡起着关键作用。细胞因子从活化的小胶质细胞释放后诱导的异常反应性星形胶质细胞可能导致神经元凋亡。本研究探讨了胰高血糖素样肽 1 受体（GLP1R）在癫痫中小胶质细胞激活中的作用及其对星形胶质细胞介导的神经毒性的影响。
我们使用来自颞叶癫痫患者的人脑海马组织和匹鲁卡品诱导的癫痫小鼠模型来评估癫痫中的神经生物学变化。BV2 小胶质细胞和原代星形胶质细胞用于评估体外细胞因子释放和星形胶质细胞激活。使用 GLP1R 激动剂 Exendin-4（Ex-4）探索 GLP1R 的参与。
我们的研究结果表明，在两种癫痫小鼠模型和人类患者的海马小胶质细胞中，GLP1R 表达减少与细胞因子释放和星形胶质细胞激活增加相关。Ex-4 处理恢复了小胶质细胞的内稳态，减少了细胞因子的分泌，并减少了星形胶质细胞的激活，特别是 A1 表型。这些变化与神经元凋亡的减少有关。此外，Ex-4 处理显著减少了癫痫小鼠的癫痫发作频率和持续时间。
本研究强调了微胶质 GLP1R 在癫痫发病机制中的关键作用。GLP1R 的下调导致小胶质细胞和星形胶质细胞介导的神经毒性，加剧神经元死亡和癫痫发作。用 Ex-4 激活 GLP1R 已成为一种有前途的治疗策略，可减少神经炎症、保护神经元细胞并控制癫痫发作。本研究为开发针对微胶质 GLP1R 的新型抗癫痫治疗方法提供了基础，有可能改善癫痫患者的预后。
