Decreased expression of Rev-Erbα in the epileptic foci of temporal lobe epilepsy and activation of Rev-Erbα have anti-inflammatory and neuroprotective effects in the pilocarpine model

Background A hallmark of temporal lobe epilepsy (TLE) is brain inflammation accompanied by neuronal demise. Accumulating evidence demonstrates that Rev-Erb alpha is involved in regulating neuroinflammation and determining the fate of neurons. Therefore, we studied the expression and cellular distribution of Rev-Erb alpha in the epileptogenic zone of TLE and the effect of treatment with the Rev-Erb alpha specific agonist SR9009 in the pilocarpine model. Methods The expression pattern of Rev-Erb alpha 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-Erb alpha was downregulated in the epileptogenic zone of TLE patients and mainly localized in neurons, astrocytes, and presumably microglia. Meanwhile, the expression of Rev-Erb alpha 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-Erb alpha 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-1 beta, IL-18, IL-6, and TNF-alpha) production, astrocytosis, microgliosis, and neuronal damage in the hippocampus after SE. Conclusions Taken together, these results suggested that a decrease in Rev-Erb alpha in the epileptogenic zone may contribute to the process of TLE and that the activation of Rev-Erb alpha may have anti-inflammatory and neuroprotective effects.