title: Cerebral ischemia is exacerbated by extracellular nicotinamide phosphoribosyltransferase via a non-enzymatic mechanism.
abstract: Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) in neuron has been known as a protective factor against cerebral ischemia through its enzymatic activity, but the role of central extracellular NAMPT (eNAMPT) is not clear. Here we show that eNAMPT protein level was elevated in the ischemic rat brain after middle-cerebral-artery occlusion (MCAO) and reperfusion, which can be traced to at least in part from blood circulation. Administration of recombinant NAMPT protein exacerbated MCAO-induced neuronal injury in rat brain, while exacerbated oxygen-glucose-deprivation (OGD) induced neuronal injury only in neuron-glial mixed culture, but not in neuron culture. In the mixed culture, NAMPT protein promoted TNF-α release in a time- and concentration-dependent fashion, while TNF-α neutralizing antibody protected OGD-induced, NAMPT-enhanced neuronal injury. Importantly, H247A mutant of NAMPT with essentially no enzymatic activity exerted similar effects on ischemic neuronal injury and TNF-α release as the wild type protein. Thus, eNAMPT is an injurious and inflammatory factor in cerebral ischemia and aggravates ischemic neuronal injury by triggering TNF-α release from glia cells, via a mechanism not related to NAMPT enzymatic activity.
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China ; Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Xia-Yan
authors.initials: XY
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Center for Magnetic, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xing
authors.affiliation: State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Center for Magnetic, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Qiao-Juan
authors.initials: QJ
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Yun-Bi
authors.initials: YB
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Er-Qing
authors.initials: EQ
authors.lastname: Wei
authors.affiliation: Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Center for Magnetic, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Tang
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000201:enzymology; D002545:Brain Ischemia / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D005110:Extracellular Space / Q000201:enzymology*; D005947:Glucose / Q000378:metabolism; D008297:Male; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D054409:Nicotinamide Phosphoribosyltransferase; D005947:Glucose; D010100:Oxygen