Klotho alleviates NLRP3 inflammasome-mediated neuroinflammation in a temporal lobe epilepsy rat model by activating the Nrf2 signaling pathway

•Klotho was downregulated in the hippocampus of TLE rats.•Klotho attenuated cognitive impairment in TLE rats.•Klotho alleviated NLRP3 inflammasome-mediated neuroinflammation in TLE rats.•Klotho up-regulated activation of Nrf2 in the hippocampus of TLE rats.•Nrf2 inhibitor ML385 reversed klotho’s neu...

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Veröffentlicht in:Epilepsy & behavior 2022-03, Vol.128, p.108509-108509, Article 108509
Hauptverfasser: Xiang, Tao, Luo, Xiaodan, Ye, Lin, Huang, Hongmi, Wu, Yuan
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Sprache:eng
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Zusammenfassung:•Klotho was downregulated in the hippocampus of TLE rats.•Klotho attenuated cognitive impairment in TLE rats.•Klotho alleviated NLRP3 inflammasome-mediated neuroinflammation in TLE rats.•Klotho up-regulated activation of Nrf2 in the hippocampus of TLE rats.•Nrf2 inhibitor ML385 reversed klotho’s neuroprotective effects in TLE rats. 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.
ISSN:1525-5050
1525-5069
DOI:10.1016/j.yebeh.2021.108509