Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China.
Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China.
Neuropharmacology. 2018 Mar 15;131:377-388. doi: 10.1016/j.neuropharm.2018.01.012. Epub 2018 Jan 10.
The inflammatory response of glial cells contributes to neuronal damage or repair after brain ischemia/reperfusion insult. We previously demonstrated a protective role of TP53-induced glycolysis and apoptosis regulator (TIGAR) in ischemic neuronal injury through increasing the flow of pentose phosphate pathway (PPP). The present study investigated the possible role of TIGAR in ischemia/reperfusion-induced inflammatory response of astrocytes. Male ICR mice were subjected to middle cerebral artery occlusion for 2 h followed by 24 h reperfusion and cultured primary astrocytes were subjected to oxygen glucose deprivation for 9 h followed by 24 h reoxygenation (OGD/R). Adenoviral vectors were used to alter the levels of TIGAR protein in brain and in culture primary astrocytes. We showed that during the OGD/R insult the protein levels of TIGAR were rapidly increased in astrocytes. Overexpression of TIGAR mediated increased the viability, levels of NADPH and rGSH, and reduced intracellular reactive oxygen species (ROS) in cultured primary astrocytes. Overexpression of TIGAR not only significantly reduced infarct volume after stroke insult but also markedly reduced long-term mortality and improved recovery of neurological functions. Overexpression of TIGAR tempered OGD/R- or ischemia/reperfusion-induced the upregulation of inducible nitric oxide synthase (iNOS), cyclooxygenases COX2 and the release of pro-inflammatory cytokines interleukin 1 beta (IL-1β) and tumor necrosis factor-α (TNF-α), while TIGAR knockdown produced opposite effects on these parameters. Moreover, Overexpression of TIGAR suppressed OGD/R-induced degradation of IκBα and NF-κB nuclear translocation in cultured primary astrocytes. The present study elucidates a novel mechanism by which TIGAR protects neurons against ischemia/reperfusion injury.
星形胶质细胞的炎症反应有助于脑缺血/再灌注损伤后的神经元损伤或修复。我们之前通过增加戊糖磷酸途径 (PPP) 的流量证明了 TP53 诱导的糖酵解和凋亡调节剂 (TIGAR) 在缺血性神经元损伤中的保护作用。本研究探讨了 TIGAR 在缺血/再灌注诱导的星形胶质细胞炎症反应中的可能作用。雄性 ICR 小鼠接受大脑中动脉闭塞 2 小时，然后再灌注 24 小时，并培养原代星形胶质细胞进行 9 小时的氧葡萄糖剥夺，然后再进行 24 小时复氧 (OGD/R)。腺病毒载体用于改变大脑和培养原代星形胶质细胞中 TIGAR 蛋白的水平。我们表明，在 OGD/R 损伤期间，星形胶质细胞中的 TIGAR 蛋白水平迅速增加。TIGAR 的过表达介导了培养的原代星形胶质细胞活力、NADPH 和 rGSH 水平的增加，并减少了细胞内活性氧 (ROS)。TIGAR 的过表达不仅显著减少了中风损伤后的梗死体积，而且还显著降低了长期死亡率并改善了神经功能的恢复。TIGAR 的过表达缓和了 OGD/R 或缺血/再灌注诱导的诱导型一氧化氮合酶 (iNOS)、环氧化酶 COX2 的上调以及促炎细胞因子白细胞介素 1β (IL-1β) 和肿瘤坏死因子-α (TNF-α) 的释放，而 TIGAR 的敲低对这些参数产生了相反的影响。此外，TIGAR 的过表达抑制了 OGD/R 诱导的培养原代星形胶质细胞中 IκBα 的降解和 NF-κB 核易位。本研究阐明了 TIGAR 保护神经元免受缺血/再灌注损伤的新机制。
