Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, 6th Shuangyong Road, Nanning, Guangxi, China; The First Affiliated Hospital, Department of Neurology, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, 6th Shuangyong Road, Nanning, Guangxi, China.
Epilepsy Behav. 2022 Mar;128:108509. doi: 10.1016/j.yebeh.2021.108509. Epub 2022 Jan 29.
Neuroinflammation not only contributes to epileptogenesis and neurodegeneration, but is also associated with cognitive impairment. Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation is positively correlated with progression of temporal lobe epilepsy (TLE) and cognitive impairment. Recent studies have shown that the anti-aging protein, klotho, exerts anti-neuroinflammation effects and enhances cognition in neurodegenerative disorders. In the present study, we investigated the role and underlying mechanism of klotho action in NLRP3 inflammasome-mediated neuroinflammation in a TLE model. Specifically, we first injected an adeno-associated viral (AAV)-mediated overexpression of klotho (AAV-KL) into the bilateral hippocampus of rats. After 3 weeks, rats were intraperitoneally injected with lithium-chloride pilocarpine (LiCl-Pilo) to generate a TLE model. Results showed that klotho was significantly downregulated six weeks after TLE, while AAV-mediated klotho overexpression substantially attenuated TLE-induced hippocampal neuronal injury and cognitive impairment. Interestingly, klotho overexpression significantly alleviated expression of NLRP3, IL-1β, and caspase-1 proteins, but up-regulated activation of nuclear factor erythroid 2-related factor 2 (Nrf2). However, treatment with Nrf2 inhibitor ML385 significantly reversed klotho's beneficial effects, including alleviated neuroinflammation, attenuated neuronal injury, and improved cognitive function. Taken together, these results indicated that klotho alleviated NLRP3 inflammasome-mediated neuroinflammation by activating the Nrf2 signaling pathway in the TLE rat model, suggesting that this the anti-aging protein could be a novel and promising therapeutic agent for managing TLE-associated cognitive impairment.
神经炎症不仅与癫痫发生和神经退行性变有关，还与认知障碍有关。Nod 样受体家族含 pyrin 结构域蛋白 3 (NLRP3) 炎性小体介导的神经炎症与颞叶癫痫 (TLE) 和认知障碍的进展呈正相关。最近的研究表明，抗衰老蛋白 klotho 发挥抗神经炎症作用，并增强神经退行性疾病中的认知功能。在本研究中，我们研究了 klotho 在 TLE 模型中 NLRP3 炎性小体介导的神经炎症中的作用及其潜在机制。具体而言，我们首先将腺相关病毒 (AAV) 介导的 klotho 过表达 (AAV-KL) 注射到大鼠双侧海马。3 周后，大鼠腹腔内注射氯化锂-匹罗卡品 (LiCl-Pilo) 生成 TLE 模型。结果表明，TLE 后 6 周 klotho 显著下调，而 AAV 介导的 klotho 过表达显著减轻 TLE 诱导的海马神经元损伤和认知障碍。有趣的是，klotho 过表达显著减轻 NLRP3、IL-1β 和 caspase-1 蛋白的表达，但上调核因子红细胞 2 相关因子 2 (Nrf2) 的激活。然而，Nrf2 抑制剂 ML385 的治疗显著逆转了 klotho 的有益作用，包括减轻神经炎症、减轻神经元损伤和改善认知功能。总之，这些结果表明，klotho 通过激活 TLE 大鼠模型中的 Nrf2 信号通路缓解 NLRP3 炎性小体介导的神经炎症，提示这种抗衰老蛋白可能成为治疗 TLE 相关认知障碍的一种新的有前途的治疗剂。
