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.

Extracellular Visfatin has Nicotinamide Phosphoribosyltransferase Enzymatic Activity and is Neuroprotective Against Ischemic Injury

“…Thus, the NAMPT enzymatic activity is required for the neuroprotection of extracellular visfatin. When this manuscript was prepared, a recent report showed that cerebral ischemic injury in cultured neural cells was exacerbated by extracellular visfatin . In that paper, extracellular visfatin did not affect the cell viability of cultured neuron cells under normal or OGD conditions.…”

Fasting‐ and ghrelin‐induced food intake is regulated by NAMPT in the hypothalamus

“…In most of these studies, FK866 was administered in mice intraperitoneally without any effect on body weight and food intake despite observable decreases in NMN or NAD + in the whole brain . Studies that utilized FK866 centrally in rodents focused more on the benefits of NAMPT inhibition on neuronal injury and neuroinflammation during ischaemia without reporting effects on food intake . Our data show that central inhibition of NAMPT with FK866 decreases cumulative food intake and abolishes ghrelin‐induced feeding.…”

Physiological and pathophysiological roles of NAMPT and NAD metabolism

“…89 Whether eNAMPT exhibits pro-inflammatory or antiinflammatory activity is still the subject of debate. 21,[58][59][60]90,91 However, several studies have reported pro-inflammatory effects of eNAMPT on different cell types, which include induction of inducible nitric oxide synthase, 92 activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2), 66 nuclear factor NF-κB activation 92,93 and production of cytokines such as TNF-α, IL-6, IL-1β, 93,94 transforming growth factor β 95 and monocyte chemoattractant protein 1. 96 Production of inflammatory cytokines and NAMPT expression in adipocytes, thus, seem to be regulated by a positive feedback activation loop.…”