Dynamic-related protein 1 inhibitor eases epileptic seizures and can regulate equilibrative nucleoside transporter 1 expression

Zhong Luo,Yongsu Zheng,Xuejiao Zhou,Shirong Tang,Jing Wang,Zucai Xu,Fei Tian

doi:10.1186/s12883-020-01921-y

Abstract

BackgroundDynamic-related protein 1 (Drp1) is a key protein involved in the regulation of mitochondrial fission, and it could affect the dynamic balance of mitochondria and appears to be protective against neuronal injury in epileptic seizures. Equilibrative nucleoside transporter 1 (ENT1) is expressed and functional in the mitochondrial membrane that equilibrates adenosine concentration across membranes. Whether Drp1 participates in the pathogenesis of epileptic seizures via regulating function of ENT1 remains unclear.MethodsIn the present study, we used pilocarpine to induce status epilepticus (SE) in rats, and we used mitochondrial division inhibitor 1 (Mdivi-1), a selective inhibitor to Drp1, to suppress mitochondrial fission in pilocarpine-induced SE model. Mdivi-1administered by intraperitoneal injection before SE induction, and the latency to firstepileptic seizure and the number of epileptic seizures was thereafter observed. The distribution of Drp1 was detected by immunofluorescence, and the expression patterns of Drp1 and ENT1 were detected by Western blot. Furthermore, the mitochondrial ultrastructure of neurons in the hippocampal CA1 region was observed by transmission electron microscopy.ResultsWe found that Drp1 was expressed mainly in neurons and Drp1 expression was significantly upregulated in the hippocampal and temporal neocortex tissues at 6 h and 24 h after induction of SE. Mitochondrial fission inhibitor 1 attenuated epileptic seizures after induction of SE, reduced mitochondrial damage and ENT1 expression.ConclusionsThese data indicate that Drp1 is upregulated in hippocampus and temporal neocortex after pilocarpine-induced SE and the inhibition of Drp1 may lead to potential therapeutic target for SE by regulating ENT1 after pilocarpine-induced SE.

Highlights

Dynamic-related protein 1 (Drp1) is a key protein involved in the regulation of mitochondrial fission, and it could affect the dynamic balance of mitochondria and appears to be protective against neuronal injury in epileptic seizures
We aimed to investigate the alteration of mitochondrial division after Status epilepticus (SE), and we evaluated the role of Drp1 against mitochondrial damage and Equilibrative nucleoside transporter 1 (ENT1) expression
Effects of status epilepticus on Drp1 expression in brain tissues To clearly determine Drp1 expression alterations in response to SE, we used the pilocarpine-induced SE model

Summary

Introduction

Dynamic-related protein 1 (Drp1) is a key protein involved in the regulation of mitochondrial fission, and it could affect the dynamic balance of mitochondria and appears to be protective against neuronal injury in epileptic seizures. Mitochondria are virtually ubiquitous in the cytoplasm and play a vital role in cell metabolism, being involved in processes such as adenosine triphosphate (ATP) generation, which provides energy for cell activities, antioxidant stress, calcium homeostasis, and the synthesis of neurotransmitters in specific neuron types [2]. Epileptic seizure can induce glutamate overexposure, overactivation of NMDA, and AMPA/KA receptors, increasing Ca2+ influx into neurons [3]. This Ca2+ can be taken up by mitochondria and lead to mitochondrial calcium overload [4] and oxidative stress, damaging the mitochondria and neurons in kainic acid (KA), pilocarpine, and pentylenetetrazole (PTZ) treatment models [5]. Zhang et al demonstrated that succinate accumulation plays a vital role in mitochondrial ROS production, oxidative stress, mitoSOX levels, and seizure phenotypes in the KA-induced SE rat model [9]

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