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.
Highlights
IntroductionAfter an ischemic attack, neuronal and non-neuronal cell deaths are induced by events such as energy failure, intracellular calcium overload, excitotoxicity and oxidative stress [1,2,3]
Cerebral ischemia is a neuronal disorder that causes high mortality and disability
Results extracellular Nicotinamide phosphoribosyltransferase (NAMPT) (eNAMPT) protein level increased in brain upon cerebral ischemia
Summary
After an ischemic attack, neuronal and non-neuronal cell deaths are induced by events such as energy failure, intracellular calcium overload, excitotoxicity and oxidative stress [1,2,3]. The release of pro-inflammatory factors triggers inflammation in peripheral and central systems and inflicts additional damage to the neuron [1,4]. As the brain-blood-barrier (BBB) breaks down, the interplay between central and peripheral inflammatory factors further aggravates the damage of an ischemic attack[5]. Nicotinamide phosphoribosyltransferase (NAMPT), known as pre-B cell enhancing factor (PBEF) [6] or visfatin [7], is located both intracellularly (iNAMPT) and extracellularly (eNAMPT)[8]. The iNAMPT is a key enzyme in the salvaging pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis. INAMPT is primarily expressed in neuron[10,15], and it has been shown that iNAMPT protects the neuron against ischemic injuries through the synthesis of NAD[10,15,16]
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