Abstract
BackgroundA 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.MethodsThe 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.ResultsThe 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 TNF-α) production, astrocytosis, microgliosis, and neuronal damage in the hippocampus after SE.ConclusionsTaken 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.
Highlights
A hallmark of temporal lobe epilepsy (TLE) is brain inflammation accompanied by neuronal demise
In experiment 2, we explored the effects of SR9009 on inflammatory reactions, glial proliferation, neuronal apoptosis, and neuronal loss in the hippocampus 7 days after pilocarpine induced-status epilepticus (SE) (Fig. 1c)
Based on previous reports [26, 27], we evaluated the density of neurons, astrocytes, and microglia in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus using a modified method
Summary
A hallmark of temporal lobe epilepsy (TLE) is brain inflammation accompanied by neuronal demise. Temporal lobe epilepsy (TLE) is the most common epileptic syndrome in adults. Spontaneous recurrent seizures are characteristic of patients and animals with TLE [1, 2]. These recurrent seizures trigger a series of cellular and molecular events, which lead to the progression of epilepsy. Known critical events include astrocytosis accompanied by the activation of brain microglia and the production of inflammatory cytokines [3,4,5,6]. Subsequent neuronal apoptosis and damage gradually lead to the pathological sequelae of specific epileptogenic foci [5, 7]. It is profitable to actively explore the underlying molecular mechanisms of these critical events
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