title: NAMPT inhibitor and metabolite protect mouse brain from cryoinjury through distinct mechanisms.
abstract: Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD). In the brain, NAMPT is primarily expressed in neurons and can prevent neuronal degeneration. NAMPT is also highly expressed in inflammatory cells, and is responsible for their activation. Since inflammation following traumatic brain injury enhances neuronal damage, we assessed the effects of nicotinamide mononucleotide (NMN), the direct NAMPT metabolite, and FK866, a potent NAMPT inhibitor, on brain injury in a cryoinjury mouse model. Twenty-four hours after brain cryoinjury, the density of neuron and the level of NAD decreased. Both NMN and FK866 alleviated the neuronal loss and decreased the lesion volume. NMN prevented the cryoinjury-induced decrease of NAD level, and FK866 decreased it further. On day 14 after cryoinjury, further neuronal loss occurred, astrocytes and Iba1-positive macrophage/microglia activated, and the NAD level increased. At this time-point, NAMPT expression was strongly induced in Iba1-positive macrophages/microglia in the lesion core. NMN and FK866 also alleviated the neuronal loss and decreased the lesion volume. In addition, FK866 significantly attenuated the activation of astrocytes and Iba1-positive macrophages/microglia, and decreased the NAD, while NMN had no such effects. Taken together, both FK866 and NMN attenuate traumatic brain injury. However, FK866 acts via the inhibition of the NAMPT activity in inflammatory cells resulting in the inhibition of inflammation, whereas NMN is effective via replenishing NAD.
authors: Department of Pharmacology, Zhejiang University School of Medicine, 866 Yu-Hang-Tang Road, Hangzhou, Zhejiang 310058, China.
authors: X-Q
authors: XQ
authors: Zhang
authors: Department of Pharmacology, Zhejiang University School of Medicine, 866 Yu-Hang-Tang Road, Hangzhou, Zhejiang 310058, China.
authors: J-T
authors: JT
authors: Lu
authors: CAS Key Laboratory of Magnetic Resonance in Biological Systems, National Center of Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics and Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, Hubei Province 430071, China.
authors: W-X
authors: WX
authors: Jiang
authors: Department of Pharmacology, Zhejiang University School of Medicine, 866 Yu-Hang-Tang Road, Hangzhou, Zhejiang 310058, China.
authors: Y-B
authors: YB
authors: Lu
authors: Department of Cardiothoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, China.
authors: M
authors: M
authors: Wu
authors: Department of Pharmacology, Zhejiang University School of Medicine, 866 Yu-Hang-Tang Road, Hangzhou, Zhejiang 310058, China.
authors: E-Q
authors: EQ
authors: Wei
authors: Department of Pharmacology, Zhejiang University School of Medicine, 866 Yu-Hang-Tang Road, Hangzhou, Zhejiang 310058, China. Electronic address: weiping601@zju.edu.cn.
authors: W-P
authors: WP
authors: Zhang
authors: CAS Key Laboratory of Magnetic Resonance in Biological Systems, National Center of Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics and Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, Hubei Province 430071, China.
authors: C
authors: C
authors: Tang
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000208:Acute Disease; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002452:Cell Count; D002908:Chronic Disease; D003080:Cold Temperature; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009243:NAD / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009537:Nicotinamide Mononucleotide / Q000494:pharmacology*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*
chemical_list: D000178:Acrylamides; C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D016207:Cytokines; D008840:Microfilament Proteins; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D018696:Neuroprotective Agents; D010880:Piperidines; D009243:NAD; D009537:Nicotinamide Mononucleotide; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse
keywords: FK866; NAD; NAMPT; NMN; brain injury; cryoinjury