TIGAR overexpression alleviates intracerebral hemorrhage injury in mice by suppressing ATF4/NOX4/p22phox-mediated oxidative stress and inflammation.

Oxidative stress and inflammation play pivotal roles in the secondary brain injury following intracerebral hemorrhage (ICH). Our previous study on cerebral ischemia showed that TIGAR interacted directly with ATF4, thereby suppressing ATF4-mediated endoplasmic stress. In this study, we investigated whether TIGAR conferred protection against ICH by mitigating oxidative stress and inflammation and the regulatory mechanisms. ICH mouse model was established by microinjection of collagenase VII into the right striatum. Neurological dysfunction score was assessed at 24 h and 72 h post-ICH, and mice were sacrificed and the brains were collected at 72 h post-ICH. We found a significant elevation in TIGAR protein expression in the striatum of ICH mice with increased distribution of TIGAR protein among neurons, microglia and astrocytes. Deletion of TIGAR exacerbated neurological deficits and increased hematoma volume. Conversely, overexpression of TIGAR effectively mitigated neurological deficits, reduced hematoma volume and improved neuronal damage in ICH mice. We demonstrated that TIGAR overexpression significantly attenuated lipid peroxide 4-HNE as well as malondialdehyde content (a lipid oxidation product), while suppressing ROS production. In addition, TIGAR overexpression inhibited NLRP3 inflammasome expression along with caspase-1 cleavage. Moreover, TIGAR overexpression downregulated mRNA levels of inflammatory cytokines IL-1β and IL-6 while impeding microglial transformation into pro-inflammatory M1 phenotype. Intriguingly, TIGAR overexpression exerted inhibitory effects on the expression and activity of ATF4 and NOX4/p22phox involved in intracellular oxidative stress and inflammation regulation. In ICH mice, administration of NOX inhibitor GLX351322 (5 mg·kg