Neural Regeneration Research ›› 2021, Vol. 16 ›› Issue (6): 1037-1043.doi: 10.4103/1673-5374.300453

Previous Articles     Next Articles

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

Lan-Lan Tan1, #, Xiao-Lu Jiang1, #, Li-Xiao Xu2, Gen Li2, Chen-Xi Feng2, Xin Ding1, Bin Sun1, Zheng-Hong Qin3, Zu-Bin Zhang3, *, Xing Feng1, *, Mei Li2, *#br#   

  1. 1 Department of Neonatology, Children’s Hospital of Soochow University, Suzhou, Jiangsu Province, China;  2 Department of Pediatrics Research Institute, Children’s Hospital of Soochow University, Suzhou, Jiangsu Province, China;  3 Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu Province, China 
  • Online:2021-06-15 Published:2020-12-31
  • Contact: Mei Li, PhD, meili_edu@163.com; Xing Feng, PhD, xing_feng66@suda.edu.cn; Zu-Bin Zhang, PhD, zubinzhang.2008@163.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 81872845 (to ML), 81771625 (to XF); the Natural Science Foundation of Jiangsu Province of China, No. BK20180207 (to ML); Jiangsu Provincial Medical Youth Talent of China, No. QNRC2016762(to ML); the Pediatric Clinical Center of Suzhou City of China, No. Szzx201504 (to XF); Postgraduate Research & Practice Innovation Program of Jiangsu Province of China, No. KYCX19_1998 (to LLT); Jiangsu Government Scholarship for Overseas Studies of China, No. JS-2017-127 (to ML); and the Fifth Batch of Gusu Health Talent Plan of China (to ML).

PDF

406

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. 

Key words: hypoxic-ischemic brain damage, in vitro, in vivo, microglia, NADPH, pyroptosis, ROS, TIGAR