Silencing MicroRNA-134 Alleviates Hippocampal Damage and Occurrence of Spontaneous Seizures After Intraventricular Kainic Acid-Induced Status Epilepticus in Rats.

Xiaoying Gao,Ying Cui,Jiahang Sun,Dawei Meng,Xin Gu,Yan Zhao,Mian Guo,Lianyue Guan,Sihua Qi,Xichun Wang,Feixiang Sun

doi:10.3389/fncel.2019.00145

Abstract

Epilepsy is a disorder of abnormal brain activity typified by spontaneous and recurrent seizures. MicroRNAs (miRNAs) are short non-coding RNAs, critical for the post-transcriptional regulation of gene expression. MiRNA dysregulation has previously been implicated in the induction of epilepsy. In this study, we examined the effect of silencing miR-134 against status epilepticus (SE). Our results showed that level of miR-134 was significantly up-regulated in rat brain after Kainic acid (KA)-induced SE. TUNEL staining showed that silencing miR-134 alleviated seizure-induced neuronal apoptosis in the CA3 subfield of the hippocampus. Western blot showed that a miR-134 antagonist suppressed lesion-induced endoplasmic reticulum (ER) stress and apoptosis related expression of CHOP, Bim and Cytochrome C, while facilitated the expression of CREB at 24 h post KA-induced lesion in the hippocampus. Consistently, silencing miR-134 significantly diminished loss of CA3 pyramidal neurons using Nissl staining as well as reducing aberrant mossy fiber sprouting (MFS) in a rat epileptic model. In addition, the results of EEG and behavior analyses showed seizures were alleviated by miR-134 antagonist in our experimental models. These results suggest that silencing miR-134 modulates the epileptic phenotype by upregulating its target gene, CREB. This in turn attenuates oxidative and ER stress, inhibits apoptosis, and decreases MFS long term. This indicates that silencing miR-134 might be a promising intervention for the treatment of epilepsy.

Highlights

Epilepsy is a common, chronic neurologic disorder characterized by recurrent spontaneous seizure, which affects an estimated 50 million people globally
MiR-134 levels were relatively decreased in the status epilepticus (SE)+ant-134 group (Figure 1A). 24 h after 0.12 nmol of miR-134 antagonist was injected into the rat ventricle, there was a significant decrease of miR-134
This study demonstrates that inhibition of miR-134 effectively protects hippocampal neurons from status epilepticus-induced neuronal death in an animal model of epilepsy

Summary

Introduction

Chronic neurologic disorder characterized by recurrent spontaneous seizure, which affects an estimated 50 million people globally. A large number of studies using clinical neuroimaging in conjunction with experiments in model systems have indicated that seizures may cause neuronal death under certain circumstances (Ben-Ari, 1985; Henshall and Simon, 2005), our current understanding of the mechanistic processes underlying seizure-related cell death remains poorly understood. Recent studies have shown that oxidative stress, defined as a disruption of pro-oxidant/antioxidant balance, is potentially toxic for neuronal cells and increases the production of reactive oxygen species (ROS) and redox (Uttara et al, 2009). The aberrant ROS levels and redox balance can result in endoplasmic reticulum (ER) dysfunction, ER stress, and the unfolded protein response, which play a fundamental role in the pathogenesis of epilepsy. CREB exerts profound neuroprotective actions against various insults, including ischemia, traumatic injury, and neuro-degeneration

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Conclusion