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

Abstract

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.

Ethyl Pyruvate Inhibits Peroxynitrite-induced DNA Damage and Hydroxyl Radical Generation: Implications for Neuroprotection

“…The mechanisms account for the neurocytotoxicity elicited by peroxynitrite are multiple, among them, induction of DNA strand breaks and the subsequent activation of poly (ADP-ribose) polymerase have been demonstrated to be critical events [11]. In this context, DNA single-stranded breakage initially trigged by endogenous or exogenous peroxynitrite may lead to cell death [12]. Moreover, studies have also demonstrated that some peroxynitrite-scavenging compounds are able to protect against peroxynitrite-mediated DNA strand breaks in target cells [13,14].…”

“…Although the antioxidant properties of EP appear to be responsible, at least partially, for its neuroprotective effects, it remains unclear whether the neuroprotective effects of EP may also occur through other mechanisms. Since peroxynitrite is involved in the pathogenesis of neurodegenerative diseases, and induction of DNA strand breaks is a critical initial lesion leading to cell death induced by peroxynitrite [11,12,22], in this study using uX-174 plasmid DNA as an in vitro system, we have investigated the effects of EP on peroxynitrite-induced DNA strand breaks. Our results demonstrate for the first time that EP at physiologically relevant concentrations inhibits peroxynitrite-mediated DNA strand breakage and hydroxyl radical formation in a concentration-dependent manner.…”

ADP-ribosyl-acceptor hydrolase 3 regulates poly (ADP-ribose) degradation and cell death during oxidative stress

“…In the cytoplasm, the process of AIF movement to the nucleus depends on its nuclear localization signal where it induces large-scale DNA fragmentation (10,13). The two death pathways that depend on PARP1 have been demonstrated in animal models of brain ischemia, myocardial injury, Parkinson's disease, and diabetes (14)(15)(16). Thus, because of its involvement in important biological processes, PAR metabolism is tightly controlled both spatially and temporally.…”

A General Sight about Linking PARP-1 and NFKB1 Variations to the Inflammatory Events

“…PARP-1 is involved in various cellular processes such as gene expression, amplification, malignant transformation, differentiation, division, DNA replication, mitochondrial function, DNA repair, chromatin replication, transcriptional regulation, cell death, and inflammatory response [16,17]. The human PARP-1 gene includes 23 exons spanning 43 kb and is located in 1q41-q43.…”