Aim Nod‐like receptor protein 3 (NLRP3) inflammasome‐mediated inflammation has emerged as a contributor to epileptogenesis. Endoplasmic reticulum stress (ERS) plays an important role in epilepsy‐induced neurodegeneration. NLRP3 activation and ERS reactions share the same induction factors, suggesting that these processes may be interdependent. However, the correlation between NLRP3 and ERS in TLE has not been confirmed. Methods The expression patterns of NLRP3 inflammasome and ERS‐related markers in the temporal neocortices of TLE patients were investigated by western blotting, immunohistochemistry and immunofluorescent labelling. Correlations between the protein levels of NLRP3 and the expression of ERS‐related markers were assessed using Spearman’s rank correlation test. To observe the relationship between the NLRP3 inflammasome and ERS, inhibitors were used in a status epilepticus (SE) model. Results Our results show that NLRP3 inflammasome components and ERS‐related markers were upregulated in the temporal neocortices of TLE patients, and were mainly localized to neurons, astrocytes and microglia. We found a positive correlation between the protein levels of NLRP3 and the expression of ERS‐related markers in the temporal neocortices of 20 TLE patients. Furthermore, after blocking the NLRP3 inflammasome with MCC950, the expression of ERS‐related markers was markedly decreased in the hippocampi of SE mice. Moreover, TUDCA, a specific ERS inhibitor, also reduced the expression of NLRP3 components in the hippocampus under SE conditions. Conclusion Taken together, our data reveal the interdependence of the NLRP3 inflammasome and ERS in the epileptogenic zone of TLE patients and in the hippocampi of mice in the early post‐SE phase.

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Background: A hallmark of temporal lobe epilepsy (TLE) is brain inflammation accompanied by neuronal demise. Accumulating evidence demonstrates that Rev-Erbα is involved in regulating neuroinflammation and determining the fate of neurons. Therefore, we studied the expression and cellular distribution of Rev-Erbα in the epileptogenic zone of TLE and the effect of treatment with the Rev-Erbα specific agonist SR9009 in the pilocarpine model. Methods:The expression pattern of Rev-Erbα was investigated by western blotting, immunohistochemistry, and immunofluorescence labeling in patients with TLE. Next, the effects of SR9009 on neuroinflammation, neuronal apoptosis, and neuronal loss in the mouse hippocampus 7 days after status epilepticus (SE) were assessed by western blotting, immunofluorescence labeling staining, and TUNEL staining.Results: The western blotting, immunohistochemistry, and immunofluorescence labeling results revealed that Rev-Erbα was downregulated in the epileptogenic zone of TLE patients and mainly localized in neurons, astrocytes, and presumably microglia. Meanwhile, the expression of Rev-Erbα was decreased in the hippocampus and temporal neocortex of mice treated with pilocarpine in the early post-SE and chronic phases. Interestingly, the expression of Rev-Erbα in the normal hippocampus showed a 24-h rhythm; however, the rhythmicity was disturbed in the early phase after SE, and this disturbance was still present in epileptic animals. Our further findings revealed that treatment with SR9009 inhibited NLRP3 inflammasome activation, inflammatory cytokine (IL-1β, IL-18, IL-6, and TNFα) production, astrocytosis, microgliosis, and neuronal damage in the hippocampus after SE.Conclusions: Taken together, these results suggested that a decrease in Rev-Erbα in the epileptogenic zone may contribute to the process of TLE and that the activation of Rev-Erbα may have anti-inflammatory and neuroprotective effects.

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