JAK2/STAT3 involves oxidative stress-induced cell injury in N2a cells and a rat MCAO model

Int J Neurosci. 2020 Nov;130(11):1142-1150. doi: 10.1080/00207454.2020.1730829. Epub 2020 Feb 24.

Abstract

Purpose: In this study, we sought to test the hypothesis that oxidative stress injury in ischemic brains and H2O2-treated mouse neuroblastoma Neuro-2a cells (N2a) was related to STAT3 activation.Materials and methods: Rat middle cerebral artery occlusion (MCAO) model and H2O2-treated mouse neuroblastoma Neuro-2a cells (N2a) were used to investigate the relationship between oxidative stress injury and STAT3 activation.Results: 8-Hydroxy-2'-deoxyguanosine (8-OHdG) content and STAT3 protein phosphorylation level were significantly increased after cerebral ischemia-reperfusion. H2O2 treatment inhibited the cell viability, induced the apoptosis, and further raised pSTAT3 protein level in N2a cells. Moreover, the addition of AG490, the protein inhibitor of JAK2, significantly alleviated cerebral ischemic damage in vivo and H2O2-induced injury in vitro, and JAK2 siRNA also alleviated H2O2-induced injury in N2a cell.Conclusions: JAK2/STAT3 pathway may play a crucial role in mediating reactive oxidative species (ROS)-induced cell injury in rat middle cerebral artery occlusion (MCAO) model and N2a cells. ROS scavenging and down-regulation of STAT3 activation might be a candidate design of therapeutic strategies against oxidative stress-related neurological diseases.

Keywords: AG490; H2O2; Middle cerebral artery occlusion (MCAO); mouse neuroblastoma Neuro-2a (N2a) cells; signal transducer and activator of transcription 3 (STAT3).

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine / metabolism
  • Animals
  • Apoptosis* / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology*
  • Hydrogen Peroxide / pharmacology*
  • Infarction, Middle Cerebral Artery / metabolism*
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 2 / drug effects
  • Janus Kinase 2 / metabolism*
  • Mice
  • Neuroblastoma*
  • Oxidants / pharmacology*
  • Oxidative Stress* / drug effects
  • Rats
  • Reperfusion Injury / metabolism*
  • STAT3 Transcription Factor / drug effects
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction* / drug effects
  • Tyrphostins / pharmacology

Substances

  • Enzyme Inhibitors
  • Oxidants
  • STAT3 Transcription Factor
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • 8-Hydroxy-2'-Deoxyguanosine
  • Hydrogen Peroxide
  • Janus Kinase 2