MiR-96 attenuates status epilepticus-induced brain injury by directly targeting Atg7 and Atg16L1

Jing Gan,Qianyun Cai,Rong Luo,Yi Qu,Chaomin Wan,Dezhi Mu,Fengyan Zhao

doi:10.1038/s41598-017-10619-0

Abstract

Status epilepticus (SE) can cause brain damage and lead to neural dysfunction. Developing novel targets for SE therapy and diagnosis is important and necessary. Previously, we found several differentially expressed microRNAs (miRNAs) in the developing hippocampus following SE, including the autophagy-related miR-96. In the present study, we employed immunofluorescence staining and Western blot analysis to assess the expression of autophagy-related 7 (Atg7) and Atg16L1 and the status of autophagosome formation in the hippocampus of immature rats with SE. Additional in vivo intervention was also performed to investigate the potential therapeutic function of miR-96 in developing rats with SE. We found that Atg7 and Atg16L1 were up-regulated in the neurons after SE, together with an increase in autophagosome formation. Meanwhile, overexpression of miR-96 significantly prevented brain damage in SE rats by inhibiting Atg7 and Atg16L1 expression and autophagosome formation in the hippocampus. Furthermore, Rapamycin negated miR-96 mediated brain injury attenuation through inducing autophagosome formation. Our study indicates that miR-96 might be a potential target for therapy of pediatric SE.

Highlights

Epilepsy is a chronic neurological disorder characterized by recurrent unprovoked seizures, often resulting from abnormal and highly synchronous neuronal discharges within the brain[1]
We investigated the potential of autophagy-related miRNAs as diagnosis and treatment target markers for Status epilepticus (SE) in immature rats
We showed that autophagosome were found in neurons after SE, together with increasing expression of Atg[7] and Atg16L1

Summary

Introduction

Epilepsy is a chronic neurological disorder characterized by recurrent unprovoked seizures, often resulting from abnormal and highly synchronous neuronal discharges within the brain[1]. Autophagy has been proposed as a therapeutic target for the treatment of neurological diseases. Previous studies have indicated that the central nervous system (CNS) expresses the richest diversity of miRNAs among all human tissues[22], and that miRNAs could be used as diagnosis and treatment targets for neural damage. By miRNA array and differential analysis, 29 up-regulated and 20 down-regulated miRNAs were identified in developing rat hippocampi[23] Targets of these deregulated miRNAs were analysed using the miRWalk database, showing that the identified autophagy signalling pathway was involved in the molecular mechanisms underlying epileptogenesis. We further investigated the potential autophagy-related miR-96, which we propose can be used as a diagnostic and therapeutic target for SE in immature rats. Our study suggests that miR-96 acquires its protective role during the development of SE, thereby supporting its role as a novel therapeutic target for SE

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Results

Conclusion