GCN2 reduces inflammation by p-eIF2α/ATF4 pathway after intracerebral hemorrhage in mice

Zhengyang Lu, Zhong Wang, Lingyan Yu, Yan Ding, Yang Xu, Ningbo Xu, Runnan Li, Jiping Tang, Gang Chen, John H. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Intracerebral hemorrhage (ICH) is a common and severe neurological disorder, which is associated with high rates of mortality and morbidity. This study aimed to evaluate whether general control non-derepressible-2 (GCN2) stimulation ameliorated neuroinflammation after ICH. Male CD-1 mice were subjected to experimental ICH by infusion of bacterial collagenase. Post-ictus assessment included neurobehavioral tests, brain edema measurement, quantification of neutrophil infiltration and microglia activation, and measurement of TNF-α and IL-1β expression at 24 h after ICH. Furthermore, we tested the long-term neurological improvement by GCN2 at 21 days after ICH. Our results showed that GCN2 improved neurological function and reduced brain edema at 24 and 72 h following experimental ICH in CD-1 mice in contrast to the vehicle administration alone. GCN2 was also found to decrease levels of IL-1β and TNF-α and inhibit neutrophil infiltration activation. In addititon, GCN2 also alleviated long-term neurological impairment after ICH. However, inhibition of eIF2α or ATF4 abolished the protective effects of GCN2, indicating eIF2α/ATF4 signaling pathway as the downstream mediator of GCN2.

Original languageEnglish
Pages (from-to)16-25
Number of pages10
JournalExperimental Neurology
Volume313
DOIs
StatePublished - Mar 2019

ASJC Scopus Subject Areas

  • Neurology
  • Developmental Neuroscience

Keywords

  • Early brain injury
  • General control non-derepressible-2
  • Inflammation
  • Inflammsome
  • Intracerebral hemorrhage
  • Up-Regulation/drug effects
  • Anti-Inflammatory Agents/pharmacology
  • Male
  • Signal Transduction/drug effects
  • Activating Transcription Factor 4/biosynthesis
  • Cerebral Hemorrhage/complications
  • Behavior, Animal
  • Brain Edema/etiology
  • Eukaryotic Initiation Factor-2/biosynthesis
  • Animals
  • Inflammation/etiology
  • Neutrophil Infiltration/drug effects
  • Mice
  • Maze Learning/drug effects
  • Inflammasomes/drug effects
  • Cytokines/biosynthesis
  • Protein Serine-Threonine Kinases/pharmacology

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