MLN4924 Exerts a Neuroprotective Effect against Oxidative Stress via Sirt1 in Spinal Cord Ischemia-Reperfusion Injury.

Sifei Yu,Lei Xie,Zhuochao Liu,Changwei Li,Yu Liang

doi:10.1155/2019/7283639

Abstract

Oxidative stress is a leading contributor to spinal cord ischemia-reperfusion (SCIR) injury. Recently, MLN4924, a potent and selective inhibitor of the NEDD8-activating enzyme, was shown to exert a neuroprotective effect against oxidative stress in vitro. However, it is unknown whether MLN4924 plays a protective role against SCIR injury. In the present study, we found that MLN4924 treatment significantly attenuated oxidative stress and neuronal cell death induced by H2O2 in SH-SY-5Y neural cells and during rat SCIR injury. Furthermore, MLN4924 administration restored neurological and motor functions in rats with SCIR injury. Mechanistically, we found that MLN4924 protects against H2O2- and SCIR injury-induced neurodegeneration by regulating sirtuin 1 (Sirt1) expression. Collectively, these findings demonstrate the neuroprotective role of MLN4924 against oxidative stress in SCIR injury via Sirt1.

Highlights

Spinal cord ischemia-reperfusion (SCIR) injury is a major complication of thoracoabdominal aortic surgery [1], which can result in debilitating paraplegia with a reported incidence of 3-18% [2]
In line with these reports, our previous studies revealed that the administration of adenine dinucleotide (NAD) or hydrogen sulfide effectively protected against SCIR injury by reducing oxidative stress-induced neuronal apoptosis [1, 9, 10]
We demonstrated the protective effect of NAD against SCIR injury via reductions in oxidative stressinduced neuronal apoptosis [9, 10]

Summary

Introduction

Spinal cord ischemia-reperfusion (SCIR) injury is a major complication of thoracoabdominal aortic surgery [1], which can result in debilitating paraplegia with a reported incidence of 3-18% [2]. The cellular and molecular mechanisms that cause I/R damage to the medulla spinalis are poorly understood, many studies have demonstrated that oxidative stress plays a crucial role in the pathogenesis of I/R injury [7, 8]. In line with these reports, our previous studies revealed that the administration of adenine dinucleotide (NAD) or hydrogen sulfide effectively protected against SCIR injury by reducing oxidative stress-induced neuronal apoptosis [1, 9, 10]. Pharmacological therapies targeting oxidative stress may be critical for limiting SCIR injury

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Conclusion