Therapeutic strategies targeting NAMPT against stroke.

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Presentation transcript:

Therapeutic strategies targeting NAMPT against stroke. Therapeutic strategies targeting NAMPT against stroke. There are two ways to maintain the cellular NAD level in mammals: the de novo pathway from tryptophan and the salvage pathway from NAM, NR and NA with different catalysing enzymes. NAMPT is the rate-limiting enzyme of NAD synthesis in the salvage pathway, thereby influencing NAD-dependent enzymes and regulating cellular metabolism, mitochondrial biogenesis and the adaptive response to inflammatory, oxidative, proteotoxic and genotoxic stresses. Accumulating in-vitro and in-vivo studies indicate that NAMPT is a therapeutic target against stroke from five potential therapeutic strategies: NAMPT overexpression, recombinant NAMPT, NAMPT activators, NAMPT enzymatic product NMN, NMN precursors NR and NAM. In ischaemic stroke, targeting NAMPT can confer neuroprotection via regulating mitochondrial biogenesis, activating SIRT1, inhibiting PARP1 activity and mimicking IPC. And, NAMPT related treatment exerts biological function in EPCs and NSCs to promote neovascularization and neurogenesis after ischaemic stroke. Remarkably, there is positive evidence of NAMPT in ICH, wherein NMN treatment can attenuate brain injury by activating Nrf2/HO-1 signalling pathway in the mouse model of cICH, and protect BBB integrity and attenuate brain infarction and haemorrhage in the mouse model of tPA-ICH, indicating NAMPT mediated neuroprotection in ICH. These preclinical evidences indicate targeting NAMPT can be a promising choice for developing novel and effective therapeutic interventions against stroke. BBB, blood–brain barrier; cICH, collagenase-induced intracerebral haemorrhage; EPCs, endothelial progenitor cells; IPC, ischaemic preconditioning; NA, nicotinic acid; NAD, nicotinamide adenine dinucleotide; NAM, nicotinamide; NAMN, nicotinic acid mononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NAPRT, nicotinic acid phosphoribosyltransferase; NMN, nicotinamide mononucleotide; NMNAT, nicotinamide mononucleotide adenylyltransferase; NR, nicotinamide riboside; NRK, nicotinamide ribose kinase; NSCs, neural stem cells; PARPs, poly-ADP-ribose polymerases; QAPRT, quinolinate phosphoribosyltransferase; SIRTs, sirtuins; tPA-ICH, tPA-induced cerebral infarction haemorrhagic transformation. Shu-Na Wang, and Chao-Yu Miao Stroke Vasc Neurol 2019;svn-2018-000199 © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.