NAMPT inhibitor and metabolite protect mouse brain from cryoinjury through distinct mechanisms. (16th April 2015)

• Record Type: Journal Article
• Authors: Zhang, X.-Q.; Lu, J.-T.; Jiang, W.-X.; Lu, Y.-B.; Wu, M.; Wei, E.-Q.; Zhang, W.-P.; Tang, C.
• Is Part Of: Neuroscience. Volume 291(2015)
• Page Start: 230
• Page End: 240
• Publication Date: 2015-04-16
• Subjects: ANOVA analysis of variance -- NAD nicotinamide adenine dinucleotide -- NAMPT nicotinamide phosphoribosyltransferase -- NMN nicotinamide mononucleotide; NAMPT -- FK866 -- NMN -- NAD -- cryoinjury -- brain injury; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2015.02.007
• Languages: English
• ISSNs: 0306-4522

Abstract

Graphical abstract: Highlights: NAMPT metabolite NMN increases the NAD level in the mouse brain. NMN alleviates cryoinjury-induced brain injury. NAMPT inhibitor FK866 decreases the NAD level in the mouse brain. FK866 inhibits neuroinflammation and alleviates cryoinjury-induced brain injury. 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.