Sirt1 Regulates Oxidative Stress in Oxygen-Glucose Deprived Hippocampal Neurons

Lina Shi,Xiuyong Cheng,Yan Wang,Jing Zhang,Qingfei Hao,Haoming Chen

doi:10.3389/fped.2020.00455

Abstract

Oxidative stress is an important mechanism of neonatal hypoxic-ischemic brain damage. Sirtuin1 (Sirt1) is a deacetylase that depends on NAD+, which has an important role in antioxidant metabolism. Furthermore, peroxisome proliferator-activated receptor γ-co-activator 1α (PGC-1α) is a key regulator of mitochondrial oxidative stress, which is regulated by Sirt1. Here, we investigated the role of Sirt1 in the pathogenesis of brain injuries after modulating its activity in primary cultured hippocampal neurons. Our study shows that the expression of Sirt1 was downregulated after oxygen-glucose deprivation. Activation of Sirt1 with resveratrol improved cell's resistance to oxidative stress, whereas inhibition of Sirt1 with EX527 significantly reduced cell viability after cellular oxidative stress. Our study also shows that activation of Sirt1 with resveratrol exerts its antioxidant effect by regulating the expression of PGC-1α. In contrast, application of EX527 decreased the expression of PGC-1α. In summary, these results confirmed that Sirt1 is a potent protective factor for neurons subjected to oxidative stress, and the protective effect of Sirt1 is attributed to its regulation of PGC-1α.

Highlights

Therapeutic hypothermia has been widely applied, 40–50% of Hypoxic ischemic encephalopathy (HIE) neonates still have some neurodevelopmental problems [1]
Despite the fact that therapeutic hypothermia is an effective treatment in hypoxic ischemia, neonatal brain injury is still one of the main reasons for morbidity and mortality in children [25]
Sirt1 is a member of the sirtuin family, which is a crucial epigenetic regulator involved in many biological and pathological processes including metabolism, genomic stability maintenance, immune responses, and others [32, 33]

Summary

Introduction

Therapeutic hypothermia has been widely applied, 40–50% of Hypoxic ischemic encephalopathy (HIE) neonates still have some neurodevelopmental problems [1]. Hypoxic ischemia (HI) involves multiple mechanisms, but the detailed pathogenesis is still unclear. Studies aiming to reducing morbidity and mortality of neonates with brain injuries are still needed. Oxidative stress is one of the most important mechanisms of perinatal HI. The production of reactive oxygen species (ROS) rapidly accumulates and leads to mitochondrial dysfunction and delayed neuronal death. Oxidative stress-mediated mitochondrial damage has been shown to be involved in apoptosis

Methods

Results

Conclusion