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

• Published in: Neural regeneration research Vol. 16; no. 6; pp. 1037 - 1043
• Main Authors: Tan, Lan-Lan, Jiang, Xiao-Lu, Xu, Li-Xiao, Li, Gen, Feng, Chen-Xi, Ding, Xin, Sun, Bin, Qin, Zheng-Hong, Zhang, Zu-Bin, Feng, Xing, Li, Mei
• Format: Journal Article
• Language: English
• Published: Mumbai Wolters Kluwer India Pvt. Ltd 01.06.2021; Medknow Publications and Media Pvt. Ltd; Medknow Publications & Media Pvt. Ltd; Department of Neonatology, Children's Hospital of Soochow University, Suzhou, Jiangsu Province, China%Department of Pediatrics Research Institute, Children's Hospital of Soochow University, Suzhou, Jiangsu Province, China%Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu Province, China; Wolters Kluwer - Medknow; Wolters Kluwer Medknow Publications
• Subjects: Apoptosis; Brain damage; Cerebral ischemia; Complications and side effects; Development and progression; Genetic aspects; Glucose; Glycolysis; Health aspects; Hypoxia; hypoxic-ischemic brain damage; in vitro; in vivo; microglia; nadph; pyroptosis; ros; tigar; Ischemia; Microglia; Physiological aspects; Reactive oxygen species; Tumor proteins; China; hypoxic-ischemic brain damage; NADPH; pyroptosis; TIGAR; in vitro; ROS; in vivo; microglia
• ISSN: 1673-5374; 1876-7958
• DOI: 10.4103/1673-5374.300453

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.