Effects of Mdivi-1 on Neural Mitochondrial Dysfunction and Mitochondria-Mediated Apoptosis in Ischemia-Reperfusion Injury After Stroke: A Systematic Review of Preclinical Studies.

Nguyen Thanh Nhu,Qing Li,Shu-Yun Xiao,Jian Xu,Shin-Da Lee,Yijie Liu

doi:10.3389/fnmol.2021.778569

Abstract

This systematic review sought to determine the effects of Mitochondrial division inhibitor-1 (Mdivi-1) on neural mitochondrial dysfunction and neural mitochondria-mediated apoptosis in ischemia/reperfusion (I/R) injury after ischemic stroke. Pubmed, Web of Science, and EMBASE databases were searched through July 2021. The studies published in English language that mentioned the effects of Mdivi-1 on neural mitochondrial dysfunction and neural mitochondria-mediated apoptosis in I/R-induced brain injury were included. The CAMARADES checklist (for in vivo studies) and the TOXRTOOL checklist (for in vitro studies) were used for study quality evaluation. Twelve studies were included (median CAMARADES score = 6; TOXRTOOL scores ranging from 16 to 18). All studies investigated neural mitochondrial functions, providing that Mdivi-1 attenuated the mitochondrial membrane potential dissipation, ATP depletion, and complexes I-V abnormalities; enhanced mitochondrial biogenesis, as well as inactivated mitochondrial fission and mitophagy in I/R-induced brain injury. Ten studies analyzed neural mitochondria-mediated apoptosis, showing that Mdivi-1 decreased the levels of mitochondria-mediated proapoptotic factors (AIF, Bax, cytochrome c, caspase-9, and caspase-3) and enhanced the level of antiapoptotic factor (Bcl-2) against I/R-induced brain injury. The findings suggest that Mdivi-1 can protect neural mitochondrial functions, thereby attenuating neural mitochondria-mediated apoptosis in I/R-induced brain injury. Our review supports Mdivi-1 as a potential therapeutic compound to reduce brain damage in ischemic stroke (PROSPERO protocol registration ID: CRD42020205808).Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42020205808].

Highlights

Ischemic stroke is one of the most common diseases, causing a considerable number of deaths and disabilities globally (RoyO’Reilly and McCullough, 2018)
Our systematic review summarized the current evidence from both in vivo and in vitro studies to evaluate the therapeutic effects of Mdivi-1 on neural mitochondrial functions and neural mitochondria-related apoptosis in ischemia and reperfusion (I/R) injury after ischemic stroke
From the included studies with several ischemic stroke models, our review suggests that Mdivi-1 treatment might attenuate neural mitochondrial respiratory deficiency as well as neural mitochondrial quality-control dysregulation and reduce neural mitochondria-mediated apoptosis

Summary

Introduction

Ischemic stroke is one of the most common diseases, causing a considerable number of deaths and disabilities globally (RoyO’Reilly and McCullough, 2018). Neural mitochondrial dysfunction, characterized by neural mitochondrial respiratory deficiency and neural mitochondrial quality-control dysregulation, is considered the primary mechanism in I/R-induced brain injury (Andrabi et al, 2020; He et al, 2020; Carinci et al, 2021). Neural mitochondrial quality-control dysregulation in I/R injury is exhibited by abnormal changes in mitochondrial biogenesis, dynamic (fusion/fission), and mitophagy (Anzell et al, 2018; Yang et al, 2018; He et al, 2020). Research has suggested that changes in neural mitophagy (autophagy of neural mitochondria) are varied after ischemic stroke, playing both positive and negative roles in the brain under I/R injury (Anzell et al, 2018)

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