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

Abstract

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.