Antagomirs Targeting MiroRNA-134 Attenuates Epilepsy in Rats through Regulation of Oxidative Stress, Mitochondrial Functions and Autophagy.

Jiahang Sun,Chuanlu Jiang,Xin Gu,Mian Guo,Hongwen Yan,Xiaoying Gao,Xichun Wang,Yongri Zheng,Dawei Meng,Yang Xu,Xiaodong Shao

doi:10.3389/fphar.2017.00524

Abstract

The effects of the existing anti-epileptic drugs are unsatisfactory to almost one third of epileptic patients. MiR-134 antagomirs prevent pilocarpine-induced status epilepticus. In this study, a lithium chloride-pilocarpine-induced status epilepticus model was established and treated with intracerebroventricular injection of antagomirs targeting miR-134 (Ant-134). The Ant-134 treatment significantly improved the performance of rats in Morris water maze tests, inhibited mossy fiber sprouting in the dentate gyrus, and increased the survival neurons in the hippocampal CA1 region. Silencing of miR-134 remarkably decreased malonaldehyde and 4-hydroxynonenal levels and increased superoxide dismutase activity in the hippocampus. The Ant-134 treatment also significantly increased the production of ATP and the activities of mitochondrial respiratory enzyme complexes and significantly decreased the reactive oxygen species generation in the hippocampus compared with the status epilepticus rats. Finally, the Ant-134 treatment remarkably downregulated the hippocampal expressions of autophagy-associated proteins Atg5, beclin-1 and light chain 3B. In conclusion, Ant-134 attenuates epilepsy via inhibiting oxidative stress, improving mitochondrial functions and regulating autophagy in the hippocampus.

Highlights

Epilepsy is a serious chronic neurological disorder characterized by chronic and spontaneous seizures, and subjected more than 65 million people worldwide into both physical distress and psychological stress (Moshe et al, 2015)
We first detected the mRNA expression of miR-134 in hippocampal tissues of status epilepticus (SE) rats at day 3 after LiClpilocarpine injection. like previous studies (Jimenez-Mateos et al, 2012, 2015), real-time quantitative PCR analysis showed the hippocampal miR-134 level was significantly increased in the LiCl-pilocarpine-induced SE rats (Figure 1A)
A dense band was observed in the SE rats, indicating the occurrence of aberrant mossy fibers sprouting (MFS) in the hippocampus, which is consistent with previous studies on various epilepsia models (Sharma et al, 2007; Kuo et al, 2008; Baluchnejadmojarad and Roghani, 2013)

Summary

Introduction

Epilepsy is a serious chronic neurological disorder characterized by chronic and spontaneous seizures, and subjected more than 65 million people worldwide into both physical distress and psychological stress (Moshe et al, 2015). Epilepsy has been extensively treated by anti-epileptic drugs, the effects are unsatisfactory to almost one-third of epileptic patients. It is urgent to investigate novel treating targets and develop novel anti-epileptic drugs. Mitochondria are important subcellular organelles involved in several key cell functions, and are usually known as energy producers for their roles in generating the majority of adenosine triphosphate (ATP). Excessive ROS generation is more important than abnormal energy supply (Jacobson et al, 2005). A key factor in the pathogenesis of epilepsy, would injure the mitochondrial respiratory chain and induce excessive ROS production. The accumulation of ROS can depress the activities of mitochondrial respiratory enzyme complexes and result in cell death in the epileptic area (Frantseva et al, 2000).

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