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 language | English |
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Pages (from-to) | 16-25 |
Number of pages | 10 |
Journal | Experimental Neurology |
Volume | 313 |
DOIs | |
State | Published - 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