TP53-induced glycolysis and apoptosis regulator alleviates hypoxia/ischemia-induced microglial pyroptosis and ischemic brain damage.

ABSTRACT: Our previous studies have demonstrated that TP53-induced glycolysis and apoptosis regulator (TIGAR) can protect neurons after cerebral ischemia/reperfusion. However, the role of TIGAR in neonatal hypoxic-ischemic brain damage (HIBD) remains unknown. In the present study, 7-day-old Sprague-Dawley rat models of HIBD were established by permanent occlusion of the left common carotid artery followed by 2-hour hypoxia. At 6 days before induction of HIBD, a lentiviral vector containing short hairpin RNA of either TIGAR or gasdermin D (LV-sh_TIGAR or LV-sh_GSDMD) was injected into the left lateral ventricle and striatum. Highly aggressively proliferating immortalized (HAPI) microglial cell models of in vitro HIBD were established by 2-hour oxygen/glucose deprivation followed by 24-hour reoxygenation. Three days before in vitro HIBD induction, HAPI microglial cells were transfected with LV-sh_TIGAR or LV-sh_GSDMD. Our results showed that TIGAR expression was increased in the neonatal rat cortex after HIBD and in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation. Lentivirus-mediated TIGAR knockdown in rats markedly worsened pyroptosis and brain damage after hypoxia/ischemia in vivo and in vitro. Application of exogenous nicotinamide adenine dinucleotide phosphate (NADPH) increased the NADPH level and the glutathione/oxidized glutathione ratio and decreased reactive oxygen species levels in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation. Additionally, exogenous NADPH blocked the effects of TIGAR knockdown in neonatal HIBD in vivo and in vitro. These findings show that TIGAR can inhibit microglial pyroptosis and play a protective role in neonatal HIBD. The study was approved by the Animal Ethics Committee of Soochow University of China (approval No. 2017LW003) in 2017.

SUBMITTER: Tan LL 

PROVIDER: S-EPMC8224121 | biostudies-literature |

REPOSITORIES: biostudies-literature