GPR120 调节 NLRP3 炎性小体介导的癫痫发作和神经炎症。
GPR120 modulates epileptic seizure and neuroinflammation mediated by NLRP3 inflammasome.
机构信息
Institute of Neuroscience, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, China.
Department of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
出版信息
J Neuroinflammation. 2022 May 27;19(1):121. doi: 10.1186/s12974-022-02482-2.
BACKGROUND
The complex pathophysiology of epilepsy hampers the development of effective treatments. Although more than ten kinds of anti-seizures drugs (ASDs) have good effects on seizure control worldwide, about 30% of patients still display pharmacoresistance against ASDs. Neuroinflammation seems to play a crucial role in disease progression. G protein-coupled receptor 120 (GPR120) has been shown to negatively regulate inflammation and apoptosis. However, the role of GPR120 in epilepsy remains unclear. In this study, we aimed to explore the mechanism of GPR120 in epilepsy.
METHODS
Male adult C57BL/6 mice were intracranially injected with kainic acid (KA) to establish epilepsy model, and the adeno associated virus (AAV) was administered intracranially at 3 weeks before KA injection. VX765 was administered by intragastric administration at 30 min before KA induced and an equal dose administrated twice a day (10 a.m. and 4 p.m.) lasting 7 days until the mice were killed. Western blot analysis, immunofluorescence staining, video monitoring of seizure, LFP recording, Nissl staining were performed.
RESULTS
GPR120 was increased in both the hippocampus and cortex in the KA-induced model with temporal lobe epilepsy (TLE), and both were most highly expressed at 7 days after KA injection. Overexpression of GPR120 significantly alleviated epileptic activity, reduced neuronal death after status epilepticus (SE), downregulated the expression of IL-1β, IL-6, IL-18, and pyrin domain-containing protein 3 (NLRP3) inflammasome, whereas knockdown GPR120 showed the opposite effect. The effects of GPR120 knockdown were reversed by VX765 inhibition cysteinyl aspartate specific proteinase-1 (Caspase-1).
CONCLUSION
GPR120 modulates epileptic seizure activity and affects neuronal survival in KA-induced mouse model of temporal lobe epilepsy. Furthermore, GPR120 regulated neuroinflammation in epileptic animals through NLRP3/Caspase-1/IL-1β signaling pathway.
背景
癫痫的复杂病理生理学阻碍了有效治疗方法的发展。尽管全世界有十多种抗癫痫药物（ASD）对控制癫痫发作有很好的效果，但仍有约 30%的患者对 ASD 表现出耐药性。神经炎症似乎在疾病进展中起着至关重要的作用。G 蛋白偶联受体 120（GPR120）已被证明可负调节炎症和细胞凋亡。然而，GPR120 在癫痫中的作用尚不清楚。在这项研究中，我们旨在探讨 GPR120 在癫痫中的作用机制。
方法
雄性成年 C57BL/6 小鼠通过脑内注射海人酸（KA）建立癫痫模型，并在 KA 注射前 3 周脑内注射腺相关病毒（AAV）。在 KA 诱导前 30 分钟通过灌胃给予 VX765，并且每天两次（上午 10 点和下午 4 点）给予相同剂量，持续 7 天，直至处死小鼠。进行 Western blot 分析、免疫荧光染色、癫痫发作视频监测、LFP 记录、尼氏染色。
结果
KA 诱导的颞叶癫痫（TLE）模型中海马和皮质中 GPR120 增加，并且在 KA 注射后 7 天表达最高。GPR120 的过表达显著减轻癫痫活动，减少癫痫持续状态（SE）后神经元死亡，下调白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、白细胞介素-18（IL-18）和富含吡啶结构域的蛋白 3（NLRP3）炎性小体的表达，而 GPR120 的敲低则显示出相反的效果。GPR120 敲低的作用通过 VX765 抑制半胱天冬氨酸特异性蛋白酶-1（Caspase-1）而逆转。
结论
GPR120 调节 KA 诱导的颞叶癫痫小鼠模型中的癫痫发作活动，并影响神经元存活。此外，GPR120 通过 NLRP3/Caspase-1/IL-1β 信号通路调节癫痫动物的神经炎症。
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