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Objective: Mesial temporal lobe epilepsy (MTLE) is the most common type of refractory epilepsy. It is often associated with hippocampal sclerosis, which is histopathologically characterized by selective neuron loss, mossy fiber sprouting, and synapse reconstruction, and is the primary cause of refractory epilepsy. Its mechanism has not been fully elucidated. Substantial evidence now supports that inflammatory pathways are activated in epilepsy foci. We have confirmed that the interleukin-1β (IL-1β) level is involved in the epileptogenesis of MTLE, and we further investigated how it works in its chronicity in this study. Methods: The MTLE model was induced by pilocarpine, and Western blot and co-immunoprecipitation were used to detect proteins related to the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway in the hippocampi of MTLE rats and MTLE children. Meanwhile, primary hippocampal neurons were cultured and transfected by lentivirus, and the same methods were used to test the related protein expression; fluorescent dye FM4-64 was used to measure synaptic vesicle endocytosis (SVE) of neurons. Results: We revealed that mTOR is continuously activated in the rat MTLE model and children with MTLE, and it correlated with the IL-1β level. We further proved that IL-1β activates neurons via the PI3K/Akt/mTOR signaling pathway, accompanied by the upregulation of MAP2 and the enhancement of SVE in hippocampal neurons. Conclusion: Our findings suggest that IL-1β can activate mTOR, followed by activated neurons, which is critical in the pathogenesis of MTLE chronicity. These findings contribute to the understanding of the pathogenesis of MTLE, and targeting inflammation modulators in MTLE may provide new pathways for therapy of refractory epilepsy. [ABSTRACT FROM AUTHOR]

Purpose: Increasing evidence indicates that neuroinflammation plays a critical role in the pathogenesis of mesial temporal lobe epilepsy (MTLE). The aim of this study was to investigate the dynamic expression of interleukin (IL)-1β as a proinflammatory cytokine and microRNA (miR)-146a as a posttranscriptional inflammation-associated microRNA (miRNA) in the hippocampi of an immature rat model and children with MTLE. Methods: To study the expression of IL-1β and miR-146a, we performed a reverse transcription polymerase chain reaction, Western blot, and real-time quantitative PCR on the hippocampi of immature rats at 11 days of age. Expression was monitored in the acute, latent, and chronic stages of disease (2 h and 3 and 8 weeks after induction of lithium-pilocarpine status epilepticus, respectively), and in control hippocampal tissues corresponding to the same timeframes. Similar expression methods were applied to hippocampi obtained from children with MTLE and normal controls. Key Findings: The expression of IL-1β and miR-146a in both children and immature rats with MTLE differs according to the stage of MTLE development. Both IL-1β and miR-146a are significantly up-regulated, but in opposite ways: IL-1β expression is highest in the acute stage, when expression of miR-146a is at its lowest level; miR-146a expression is highest in the latent stage, when IL-1β expression is at its lowest level. Both IL-1β and miR-146a are up-regulated in the chronic stage, but not as much as in the other stages. Significance: Our study is the first to focus on the expression of miR-146a in the immature rat model of lithium-pilocarpine MTLE and in children with MTLE. We have detected that the expression of proinflammatory cytokine IL-1β and posttranscriptional inflammation-associated miR-146a is variable depending on the disease stage. Furthermore, both IL-1β and miR-146a are up-regulated in immature rats and children with MTLE. Our findings elucidate the role of inflammation in the pathogenesis of MTLE in the immature rat model and children. Therefore, modulation of the IL-1β-miR-146a axis may be a novel therapeutic target in the treatment of MTLE. [ABSTRACT FROM AUTHOR]

Although the pathogenesis and epileptogenesis of mesial temporal lobe epilepsy (MTLE) have been studied for years, many questions remain. The ubiquitin–proteasome system (UPS) is one factor that might regulate ion channels, inflammation and neuron excitability. Nedd4-2 is an E3 ubiquitin ligase linked with ion channels and synaptic vesicle recycling. Here, we explore the role of the UPS and its E3 ligase Nedd4-2 in the pathogenesis of MTLE. Our western blot results revealed that ubiquitin and Nedd4-2 were expressed differentially in different stages of MTLE. Co-immunoprecipitation and double immunostaining results indicated that Nedd4-2 was the substrate protein of ubiquitin both in vivo and in vitro. Inhibition of the UPS aggravated the epileptogenesis of MTLE, causing early and frequent spontaneous seizures, more obvious neuron loss and aberrant mossy fiber sprouting. Inhibition of ubiquitin also enhanced the activation of Nedd4-2, and switched ion channel α-ENaC downstream. Our study is the first to report that the UPS participates in the pathogenesis of MTLE, inhibition of UPS could aggravate the epileptogenesis, and that Nedd4-2 is a critical E3 ligase involved in this process. [ABSTRACT FROM AUTHOR]