The effect of metformin treatment on endoplasmic reticulum (ER) stress induced by status epilepticus (SE) via the PERK-eIF2α-CHOP pathway.

Jing Chen,Jiao Jiang,Xiao Yang,Zhong-Nan Shi,Xian-Yu Liu,Hu Guo,Guo Zheng,Xiao-Yu Wang

doi:10.17305/bjbms.2017.2044

Abstract

Status epilepticus (SE) is defined as continuous seizure activity lasting more than 5 minutes. It results in neuronal cell death, mediated by endoplasmic reticulum (ER) stress response. Previously, metformin demonstrated neuroprotective effects in primary cortical neurons. In this study, we analyzed the effect of metformin on ER stress via the pro-apoptotic protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α)-C/EBP homologous protein (CHOP) pathway. SE was induced in rats by pentylenetetrazole. Following SE, the rats were treated with salubrinal, GSK2656157, or metformin. In a control group (normal saline) SE was not induced. CHOP, eIF2α, and PERK expression was determined by Western blot; apoptosis was analyzed by TUNEL assay. CHOP expression was significantly increased at 6 and 24 hours following SE. At both time points, eIF2α and PERK levels were also increased. At 6 hours, CHOP expression was significantly reduced in salubrinal, GSK2656157 and metformin groups versus SE group. eIF2α and PERK levels were decreased in metformin compared to SE group. eIF2α expression was markedly decreased in salubrinal versus SE group, while PERK expression was markedly reduced in GSK2656157 versus SE group. At 6 and 24 hours, the apoptosis rate was significantly increased in SE versus control group, while it was significantly reduced in salubrinal, GSK2656157, and metformin groups compared to SE group. The apoptosis rate also decreased in salubrinal group at 24 hours, although not to the extent observed in metformin group. Overall, CHOP expression and apoptosis induced by SE in rats were reduced with metformin. Further studies are required to evaluate the clinical relevance of metformin for patients with SE.

Highlights

Status epilepticus (SE) is a serious neurological disorder resulting from continuous clinical and/or electrographic seizure activity lasting ≥5 minutes, or from recurrent seizure activity without returning to the baseline [1]
EIF2α and protein kinase RNA-like endoplasmic reticulum kinase (PERK) levels were increased with SE at both time points
At 6 hours, CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP) expression was significantly reduced in SE + Sal, SE + GSK, and SE + Met groups compared to SE group, not to the levels observed in control group

Summary

Introduction

Status epilepticus (SE) is a serious neurological disorder resulting from continuous clinical and/or electrographic seizure activity lasting ≥5 minutes, or from recurrent seizure activity without returning to the baseline [1]. Studies in the U.S have reported the incidence rates of SE in children (60 years) of 156/100,000/ year and 86/100,000/year, respectively [2,3]. The incidence rate of a first episode of SE in Asia is 42/100,000/ year [4,5,6]. The mortality rate of SE is 26% in adults, and it increases to 50% in patients >80 years old [1]. Neuronal cell death due to continuous seizure activity can result in Submitted: 15 March 2017/Accepted: 27 May 2017 irreversible neuronal injury [7]. Rapid diagnosis and management of SE are very important

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