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Focal ischemic stroke (FIS) results from the lack of blood flow in a particular region of the brain and accounts for about 80% of all human strokes. Although tremendous efforts have been made in translational research, the treatment strategies are still limited. Tissue plasminogen activator is the only FDA-approved drug currently available for acute stroke treatment, but it is only effective within a narrow therapeutic window that is within a few hours after the onset of a stroke. Thus exploring novel molecular pathways that can reduce neuronal death and improve stroke outcomes will allow us to identify potential targets for stroke therapy. Neurons are highly metabolically active cells and especially susceptible to an ischemic insult. Energy depletion triggers rapid necrotic neuronal death in the ischemic core as well as more delayed apoptosis in the penumbral region after an FIS. Thus it is conceivable that rescue or compensation for energy metabolism in the neurons is an important neuronal and brain protective strategy in FIS. Recently, we found that pre-B-cell colony-enhancing factor (PBEF), also known as nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage pathway of mammalian nicotinamide adenine dinucleotide (NAD) biosynthesis through converting nicotinamide (NAM) to nicotinamide mononucleotide (NMN) (Canto et al., 2015) (Figure 1A, B), is mainly expressed in neurons in the mouse brain under physiological conditions (Figure 1C, D) (Zhang et al., 2010). NAD is an essential coenzyme in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation in the mitochondria and glycolysis in the cytoplasm. The major cellular functions of NAD and its reduced form NADH include modulating cellular energy homeostasis. NAD is also a substrate of some NAD-consuming enzymes such as sirtuins (Sirt1-7), poly(ADP-Ribose) polymerases (PARP) and CD38 (Canto et al., 2015). We also found for the first time that heterozygous knockout of PBEF increases brain infarction in a mouse model of photothrombosis (PT)-induced FIS (Zhang et al., 2010). Furthermore, we demonstrated that the enzymatic activity of NAD synthesis is required for the neuroprotective effect of PBEF after glutamate and oxygen-glucose deprivation (OGD) in primary cultured cortical neurons since the overexpression of wide-type (WT) PBEF, but not mutants lacking enzymatic activity, can reduce neuronal death (Bi et al., 2012). Ischemia causes the depletion of NAD levels and the supplementation of NAD can protect against neuronal death in ischemia (Wang et al., 2014; Zhang et al., 2010; Bi et al., 2012). NAD is also highly correlated with mitochondrial biogenesis (Wang et al., 2014). To further study the mechanism of PBEF in the neuronal protection in ischemia, we focused our investigation on whether the neuroprotective effect of PBEF is through regulating mitochondrial function and biogenesis. We initially overexpressed WT and PBEF mutants H247A and H247E by DNA transfection and determined their effect on mitochondrial membrane potential (MMP) depolarization after excitotoxic glutamate stimulation using live cell fluorescent imaging (Bi et al., 2012). We found that neurons transfected with WT PBEF exhibited a much slower fluorescence decrease than non-transfected neurons or neurons transfected with EGFP alone; furthermore, neurons transfected with H247A and H247E mutants had the comparable rates of MMP depolarization with neurons expressing EGFP alone or non-transfected neurons (Bi et al., 2012). The results indicate that the overexpression of PBEF renders neurons more resistant to excitotoxicity-induced MMP collapse. Ischemic stroke leads to translocation of arterial input function (AIF) from mitochondria to the nucleus. AIF release from mitochondria induces peripheral chromatin condensation, large-scale DNA fragmentation and eventually caspase-independent intrinsic apoptotic cell death (Hong et al., 2004). Next, we tested whether PBEF could inhibit AIF translocation after glutamate stimulation. We found that neurons overexpressing WT PBEF exhibited a dramatic reduction of AIF translocation rate as compared with neurons overexpressing the mutant H247A PBEF after glutamate excitotoxicity (Wang et al., 2016). Thus the enzymatic activity of PBEF for NAD synthesis is required to inhibit glutamate-induced AIF translocation. Ischemia triggers intrinsic apoptosis of both caspase-3 independent pathway associated with AIF translocation and caspase-3 dependent pathway with cytochrome C release from the mitochondria. Using viral transduction approach, we found that the overexpression of PBEF can reduce cleaved caspase-3 levels after OGD, indicating that in addition to AIF translocation-involved caspase-3 independent pathway, a caspase-dependent apoptotic signaling pathway also contributes to the neuroprotective effect of PBEF in ischemia (Wang et al., 2016). Mitochondrial morphology including length, size and shape is controlled by balanced fission and fusion processes in the neurons. Under normal conditions, new mitochondria are produced through the orchestrated action of transcriptional factors and co-activators. The balance is disrupted in injured neurons, thus causing morphological damage associated with mitochondrial dysfunction. Mitochondrial fragmentation is an early event that occurs before the release of mitochondria-dependent apoptotic proteins and is the key mechanism in glutamate excitotoxicity and AIF translocation-mediated cell death. We investigated the effect of PBEF on glutamate-induced mitochondrial fragmentation, which has been widely detected during excitotoxicity-induced

Pre-B-cell colony-enhancing factor as a target for protecting against apoptotic neuronal death and mitochondrial damage in ischemia