TIGAR alleviates oxidative stress in brain with extended ischemia via a pentose phosphate pathway-independent manner
Mengru Liu,
Xinyu Zhou,
Yue Li,
Shijia Ma,
Ling Pan,
Xingxian Zhang,
Wanqing Zheng,
Zhanxun Wu,
Ke Wang,
Anil Ahsan,
Jiaying Wu,
Lei Jiang,
Yangyang Lu,
Weiwei Hu,
Zhenghong Qin,
Zhong Chen,
Xiangnan Zhang
Affiliations
Mengru Liu
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China
Xinyu Zhou
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China
Yue Li
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China
Shijia Ma
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China
Ling Pan
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China
Xingxian Zhang
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China
Wanqing Zheng
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China
Zhanxun Wu
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China
Ke Wang
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China
Anil Ahsan
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China
Jiaying Wu
The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003, Hangzhou, China
Lei Jiang
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China
Yangyang Lu
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China
Weiwei Hu
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China
Zhenghong Qin
Department of Pharmacology, Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China
Zhong Chen
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China; Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China; Corresponding author. Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China.
Xiangnan Zhang
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China; Jinhua Institute of Zhejiang University, 321299, Jinhua, China; Corresponding author. Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, 310058, Hangzhou, China.
TP53-induced glycolysis and apoptosis regulator (TIGAR) alleviates oxidative stress and protects against ischemic neuronal injury by shifting glucose metabolism into the pentose phosphate pathway (PPP). However, the brain alters glucose metabolism from PPP to glycolysis during prolonged ischemia. It is still unknown whether and how TIGAR exerts the antioxidant activity and neuroprotection in prolonged ischemic brains. Here, we determined the significant upregulation of TIGAR that was proportional to the duration of ischemia. However, TIGAR failed to upregulate the NADPH level but still alleviated oxidative stress in neuronal cells with prolonged oxygen glucose-deprivation (OGD). Furthermore, inhibiting PPP activity, either by the expression of mutant TIGAR (which lacks enzymatic activity) or by silencing Glucose 6-phosphate dehydrogenase, still retained antioxidant effects and neuroprotection of TIGAR with prolonged OGD. Intriguingly, TIGAR-induced autophagy alleviated oxidative stress, contributing to neuron survival. Further experiments indicated that TIGAR-induced autophagy neutralized oxidative stress by activating Nrf2, which was cancelled by ML385 or Nrf2 knockdown. Remarkably, either Atg7 deletion or Nrf2 silencing abolished the neuroprotection of TIGAR in mice with prolonged ischemia. Taken together, we found a PPP-independent pathway in which TIGAR alleviates oxidative stress. TIGAR induces autophagy and, thus, activates Nrf2, offering sustainable antioxidant defense in brains with extended ischemia. This previously unexplored mechanism of TIGAR may serve as a critical compensation for antioxidant activity caused by the lack of glucose in ischemic stroke.
