title: A TIGAR-regulated metabolic pathway is critical for protection of brain ischemia.
abstract: TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits glycolysis and increases the flow of pentose phosphate pathway (PPP), which generates NADPH and pentose. We hypothesized that TIGAR plays a neuroprotective role in brain ischemia as neurons do not rely on glycolysis but are vulnerable to oxidative stress. We found that TIGAR was highly expressed in brain neurons and was rapidly upregulated in response to ischemia/reperfusion insult in a TP53-independent manner. Overexpression of TIGAR in normal mice with lentivirus reduced ischemic neuronal injury, whereas lentivirus-mediated TIGAR knockdown aggravated it. In cultured primary neurons, increasing TIGAR expression reduced oxygen and glucose deprivation (OGD)/reoxygenation-induced injury, whereas decreasing its expression worsened the injury. The glucose 6-phosphate dehydrogenase was upregulated in mouse and cellular models of stroke, and its upregulation was further enhanced by overexpression of TIGAR. Supplementation of NADPH also reduced ischemia/reperfusion brain injury and alleviated TIGAR knockdown-induced aggravation of ischemic injury. In animal and cellular stroke models, ischemia/reperfusion increased mitochondrial localization of TIGAR. OGD/reoxygenation-induced elevation of ROS, reduction of GSH, dysfunction of mitochondria, and activation of caspase-3 were rescued by overexpression of TIGAR or supplementation of NADPH, while knockdown of TIGAR aggravated these changes. Together, our results show that TIGAR protects ischemic brain injury via enhancing PPP flux and preserving mitochondria function, and thus may be a valuable therapeutic target for ischemic brain injury.
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University School of Pharmaceutical Science; Suzhou 215123, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University School of Pharmaceutical Science; Suzhou 215123, China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University School of Pharmaceutical Science; Suzhou 215123, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University School of Pharmaceutical Science; Suzhou 215123, China.
authors.forename: Jin-hua
authors.initials: JH
authors.lastname: Gu
authors.affiliation: The Second People's Hospital of Nantong, Nantong 226002, China.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Ge
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University School of Pharmaceutical Science; Suzhou 215123, China.
authors.forename: Jieyu
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University School of Pharmaceutical Science; Suzhou 215123, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Han
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University School of Pharmaceutical Science; Suzhou 215123, China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Qin
authors.affiliation: Department of Radiology, Affiliated Hospital of Guilin Medical College, Guilin 541001, China, and.
authors.forename: Zhi-Peng
authors.initials: ZP
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, Tongji University School of Medicine, Shanghai 200092, China qinzhenhong@suda.edu.cn dingyuqiang@gmail.com.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University School of Pharmaceutical Science; Suzhou 215123, China, qinzhenhong@suda.edu.cn dingyuqiang@gmail.com.
authors.forename: Zheng-Hong
authors.initials: ZH
authors.lastname: Qin
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D002478:Cells, Cultured; D008297:Male; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases; D011506:Proteins / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D018696:Neuroprotective Agents; D011506:Proteins; D010744:Phosphoric Monoester Hydrolases; C554952:TIGAR protein, mouse
keywords: NADPH; TIGAR; glucose 6-phosphate dehydrogenase; ischemia/reperfusion; mitochondria; pentose phosphate pathway