Nogo-A aggravates oxidative damage in oligodendrocytes

摘要

Nogo-A is considered one of the most important inhibitors of myelin-associated axonal regeneration in the central nervous system.It is mainly expressed by oligodendrocytes.Although previous studies have found regulatory roles for Nogo-A in neurite outgrowth inhibition,neuronal homeostasis,precursor migration,plasticity,and neurodegeneration,its functions in the process of oxidative injury are largely uncharacterized.In this study,oligodendrocytes were extracted from the cerebral cortex of newborn Sprague-Dawley rats.We used hydrogen peroxide(H2O2)to induce an in vitro oligodendrocyte oxidative damage model and found that endogenously expressed Nogo-A is significantly upregulated in oligodendrocytes.After recombinant virus Ad-ZsGreen-rat Nogo-A infection of oligodendrocytes,Nogo-A expression was increased,and the infected oligodendrocytes were more susceptible to acute oxidative insults and exhibited a markedly elevated rate of cell death.Furthermore,knockdown of Nogo-A expression in oligodendrocytes by Ad-ZsGreen-shRNA-Nogo-A almost completely protected against oxidative stress induced by exogenous H2O2.Intervention with a Nogo-66 antibody,a LINGO1 blocker,or Y27632,an inhibitor in the Nogo-66-NgR/p75/LINGO-1-RhoA-ROCK pathway,did not affect the death of oligodendrocytes.Ad-ZsGreen-shRNA-Nogo-A also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and inhibited BCL2 expression in oligodendrocytes.In conclusion,Nogo-A aggravated reactive oxygen species damage in oligodendrocytes,and phosphorylated extracellular signal-regulated kinase 1/2 and BCL2 might be involved in this process.This study was approved by the Ethics Committee of Peking University People’s Hospital,China(approval No.2018PHC081)on December 18,2018.