Nicotinamide: a jack of all trades (but master of none?)

Szabó, Csaba

doi:10.1007/s00134-003-1737-8

Cited by 17 publications

(13 citation statements)

References 29 publications

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“…The therapeutic window of opportunity was approximately 6 h in the transient model, which is similar the therapeutic window of nicotinamide, a PARP inhibitor of low potency. Nicotinamide has many additional actions, such as antioxidant effects and replenishment of cellular pyridine nucleotide pools (32), which makes direct comparisons difficult. The dose of nicotinamide was over 100 times higher than the dose of the PARP inhibitor used in the current study.…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose) polymerase inhibition protect neurons and the white matter and regulates the translocation of apoptosis-inducing factor in stroke

et al. 2004

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Abstract. Focal cerebral ischemia activates the nuclear protein poly(ADP-ribose) polymerase (PARP). Apoptosis-inducing factor (AIF) is a flavoprotein that is normally confined to the mitochondria, but translocates to the nucleus, as shown by in vitro models of neuronal injury. Using INO-1001, a novel potent inhibitor of PARP, we determined the role of PARP activation in the process of AIF translocation in a rat model of focal cerebral ischemia. The potency of INO-1001 as a PARP inhibitor and its cytoprotective potential in oxidantchallenged human neuronal SK-N-MC cells was first confirmed in vitro. PARP inhibition markedly reduced infarct size and improved neurological status in both transient and permanent models of MCA occlusion in Sprague-Dawley rats, with a therapeutic window of 6 h and 2 h in the transient and permanent ischemia models, respectively. The PARP inhibitor reduced the accumulation of poly(ADP-ribose) in the ischemic/ reperfused hemisphere and reduced the accumulation of APP in the white matter of the affected hemisphere, consistently with protection against neuronal necrosis and axonal damage, respectively. Immunohistochemical analysis showed the appearance of AIF labeling in neuronal nuclei of the border zone ischemic area in the striatum after stroke. Cytoplasmatic (axonal) AIF staining was significantly diminished in the necrotic core of the striatum, while it was somewhat enhanced at the borderline ischemic territories of the white matter. Inhibition of PARP with INO-1001 reshifted the location of the apoptotic marker to the axons in the ipsilateral striatum. Thus, PARP inhibition is neuroprotective and regulates the ischemic nuclear translocation of AIF in stroke. IntroductionFocal cerebral ischemia activates the nuclear protein poly(ADP-ribose) polymerase (PARP) by single DNA strand breaks, which leads to energy depletion and cell death and significantly contributes to the pathogenesis of stroke (overviewed in ref. 1).Apoptosis-inducing factor (AIF) is a flavoprotein that is normally confined to the mitochondrial intermembrane space, yet translocates to the nucleus, as shown in experimental models of neuronal injury in vitro. Deletion or inhibition of PARP protects against ischemic brain injury and prevents AIF translocation in vitro (2).Here, using INO-1001, a novel potent inhibitor of PARP (3,4), we determined the role of PARP activation in the process of AIF translocation in stroke in vivo. Materials and methodsIn vitro PARP activity and cytoprotection studies. The potency of the isoindolinone-based novel PARP inhibitor INO-1001 (3,4) was determined in vitro using purified PARP enzyme as previously described using a commercially available PARS inhibition assay kit (Trevigen, Gaithersburg, MD) (3). The potency of INO-1001 was compared with that of PJ34 (5,6), a phenanthridinone-based potent PARP inhibitor, and with 3-aminobenzamide, a prototypical benchmark PARP inhibitor. The assay was carried out in 96-well ELISA plates following manufacturer's instructions. Briefly, wells were coat...

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Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose) polymerase inhibition protect neurons and the white matter and regulates the translocation of apoptosis-inducing factor in stroke

et al. 2004

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“…Additional approaches to prevent PARP activation include oxidant and free radical scavenging, which prevents the generation of DNA strand breaks and hence the activation of PARP [99,102].…”

Section: Upstream Processes Related To Parp Activation In Stroke and mentioning

confidence: 99%

Poly (ADP-Ribose) Polymerase Inhibitors as Potential Therapeutic Agents in Stroke and Neurotrauma

2005

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Poly (ADP-ribose) polymerase-1 (PARP-1) is a DNA-binding protein that is primarily activated by nicks in the DNA molecule. It regulates the activity of various enzymes - including itself- that are involved in the control of DNA metabolism. Upon binding to DNA breaks, activated PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins including histones, transcription factors and PARP itself. Poly(ADP-ribosylation) contributes to DNA repair and to the maintenance of genomic stability. Evidence obtained with pharmacological PARP inhibitors of various structural classes, as well as animals lacking the PARP-1 enzyme indicate that PARP plays an important role in cerebral ischemia/reperfusion, stroke and neurotrauma. Overactivation of PARP consumes NAD+ and ATP culminating in cell dysfunction and necrosis. PARP activation can also act as a signal that initiates cell death programs, for instance through AIF (apoptosis inducing factor) translocation. PARP has also been shown to associate with and regulate the function of several transcription factors. Of special interest is the enhancement by PARP of NF-kappaB-mediated transcription, which plays a central role in the expression of inflammatory cytokines, chemokines, adhesion molecules and inflammatory mediators. Via this mechanism, PARP is involved in the up-regulation of numerous pro-inflammatory genes that play a pathogenetic role in the later stage of stroke and neurotrauma. Here we review the roles of PARP in DNA damage signaling and cell death, and summarize the pathogenetic role of PARP in stroke and neurotrauma.

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“…Cellular targets of NAM include protein kinase B, forkhead transcription factors, poly(ADP-ribose) polymerase, and cysteine proteases (37). Suppression of the nuclear enzyme poly(ADP-ribose) polymerase is thought to be potentially important (38,39), as it contributes to tissue injury by depletion of NAD + and by upregulation of inflammatory cytokines and chemokines (40,41). More recently, NAM has been shown to induce granulocytosis in human subjects by activation of C/EBPα and G-CSF (42).…”

Section: Introductionmentioning

confidence: 99%

C/EBPε mediates nicotinamide-enhanced clearance of Staphylococcus aureus in mice

Kyme

Thoennissen²,

Tseng³

et al. 2012

J. Clin. Invest.

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The myeloid-specific transcription factor, CCAAT/enhancer-binding protein ε (C/EBPε) is a critical mediator of myelopoiesis. Mutation of this gene is responsible for neutrophil-specific granule deficiency in humans, a condition that confers susceptibility to Staphylococcus aureus infection. We found that C/EBPε-deficient mice are severely affected by infection with S. aureus, and C/EBPε deficiency in neutrophils contributes to the infectious phenotype. Conversely, exposure to the epigenetic modulator nicotinamide (vitamin B3) increased expression of C/EBPε in WT myeloid cells. Further, nicotinamide increased the activity of C/EBPε and select downstream antimicrobial targets, particularly in neutrophils. In a systemic murine infection model as well as in murine and human peripheral blood, nicotinamide enhanced killing of S. aureus by up to 1,000 fold but had no effect when administered to either C/EBPε-deficient mice or mice depleted of neutrophils. Nicotinamide was efficacious in both prophylactic and therapeutic settings. Our findings suggest that C/EBPε is an important target to boost killing of bacteria by the innate immune system.

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Nicotinamide: a jack of all trades (but master of none?)

Cited by 17 publications

References 29 publications

Poly(ADP-ribose) polymerase inhibition protect neurons and the white matter and regulates the translocation of apoptosis-inducing factor in stroke

Poly(ADP-ribose) polymerase inhibition protect neurons and the white matter and regulates the translocation of apoptosis-inducing factor in stroke

Poly (ADP-Ribose) Polymerase Inhibitors as Potential Therapeutic Agents in Stroke and Neurotrauma

C/EBPε mediates nicotinamide-enhanced clearance of Staphylococcus aureus in mice

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