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

Abstract

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.

Molecular regulation of brain metabolism underlying circadian epilepsy

“…However, in contrast to this study, Rev‐erbα was found to be reduced in the epileptic foci from temporal neocortex samples of patients with temporal lobe epilepsy 36 . This study also demonstrated that Rev‐erbα was decreased in the hippocampus and temporal neocortex of mice treated with pilocarpine both in the acute status epilepticus and the chronic phase 36 . Thus, there is evidence implicating Rev‐erbα in different models of epilepsy, albeit with varying results.…”

“…Finally, in the aforementioned electroconvulsive study, Rev‐erbα showed the most significant change in its increase in gene oscillation pattern in line with an increase in steady‐state mRNA and protein levels in the frontal cortex of epileptic mice 26 . However, in contrast to this study, Rev‐erbα was found to be reduced in the epileptic foci from temporal neocortex samples of patients with temporal lobe epilepsy 36 . This study also demonstrated that Rev‐erbα was decreased in the hippocampus and temporal neocortex of mice treated with pilocarpine both in the acute status epilepticus and the chronic phase 36 .…”

“…Numerous studies with pilocarpine and kainate models of epilepsy show that the initial acute epileptogenic insult with these drugs caused acute changes in the circadian molecular system (such as increased Per1 and Rev‐erbα as well as reduced Rorα ) 32,36,37 . Interestingly, in these animal models, where initial epileptic insult resulted in kindling during the silent phase and generation of spontaneous epilepsy, some of these changes persisted during the silent phase (such as the reduced Rorα ), 37 some persisted throughout and up to the spontaneous epilepsy phase (such as the increased Rev‐erbα ), 36 and some returned to normal after the acute phase (such as the increased Per1 ) 25 . Thus, these changes in the circadian molecular system could either be an acute response to the epileptic insult or a change that contributes during the kindling process to the generation of a spontaneously epileptic network.…”

Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway

“…In addition to ERs, a PPAR β / δ agonist significantly reduces neuroinflammation after hypoxia–ischemia by inhibiting the expression of TXNIP and NLRP3 ( 134 ). Furthermore, temporal lobe epilepsy (TLE) is characterized by spontaneous recurrent seizures leading to neuroinflammation features such as astrocytosis associated with microglia activation and inflammatory cytokine production ( 156 ) ( Table 1 ). In the context of human and mouse TLE, the Rev-erb ligand, SR9009, prevents neuroinflammation by inhibiting NLRP3 mRNA and protein levels, reducing astrocytes and microglial activation and decreasing apoptosis, which then preserves neurons and provides neuroprotection ( 156 ).…”

IL-33 Alleviated Brain Damage via Anti-apoptosis, Endoplasmic Reticulum Stress, and Inflammation After Epilepsy

“…Previous studies showed seizure activity led to the production of inflammatory molecules including IL-1β and TNF-α ( He et al, 2020 ). In turn, IL-1β or TNF-α could contribute to the severity and relapse of seizures ( Yue et al, 2020 ). Moreover, inhibition of IL-1β or TNF-α expression may lead to prevention or delay of seizures and play a neuroprotective effect on a rat model of temporal lobe epilepsy ( Noe et al, 2013 ; Sitges et al, 2014 ).…”