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

Komjáti, Katalin; Besson, Valérie; Szabó, Csaba

doi:10.2174/1568007053544138

Cited by 50 publications

(31 citation statements)

References 160 publications

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“…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].…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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Ethyl pyruvate (EP) has recently been reported to afford protection against neurodegenerative disorders. However, the mechanism underlying EP-mediated neuroprotection remains to be elucidated. Because peroxynitrite has been extensively implicated in the pathogenesis of various forms of neurodegenerative disorders via its cytotoxic effects, this study was undertaken to investigate whether the neuroprotective effect of EP is associated with inhibition of peroxynitrite-induced DNA strand breaks, a critical event leading to peroxynitrite elicited cytotoxicity. Incubation of phiX-174 plasmid DNA with 3-morpholinosydnonimine (SIN-1), a peroxynitrite generator, led to the formation of both single- and double-stranded DNA breaks in a concentration- and time- dependent manner. The presence of EP (0.5-10 mM) was found to significantly inhibit SIN-1-induced DNA strand breaks in a concentration-dependent fashion. The consumption of oxygen induced by 250 microM SIN-1 was found to be decreased in the presence of EP (0.5-10 mM), indicating that EP might affect the auto-oxidation of SIN-1. It was observed that incubation of the plasmid DNA with authentic peroxynitrite caused significant DNA strand breaks, which could also be dramatically inhibited by EP (0.5-10 mM). EPR spectroscopy in combination with spin-trapping technique using 5,5-dimethylpyrroline-N- oxide (DMPO) as a spin trap demonstrated the formation of DMPO-hydroxyl radical adducts (DMPO-OH) from authentic peroxynitrite, and that EP at 0.5-10 mM inhibited the adduct signal in a concentration-dependent manner. Taken together, these results demonstrate for the first time that EP can inhibit peroxynitrite-mediated DNA damage and hydroxyl radical generation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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“…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.…”

mentioning

confidence: 99%

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

Mashimo

Katō

Moss

2013

Proc. Natl. Acad. Sci. U.S.A.

137

156

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Poly (ADP ribose) (PAR) formation catalyzed by PAR polymerase 1 in response to genotoxic stress mediates cell death due to necrosis and apoptosis. PAR glycohydrolase (PARG) has been thought to be the only enzyme responsible for hydrolysis of PAR in vivo. However, we show an alternative PAR-degradation pathway, resulting from action of ADP ribosyl-acceptor hydrolase (ARH) 3. PARG and ARH3, acting in tandem, regulate nuclear and cytoplasmic PAR degradation following hydrogen peroxide (H 2 O 2 ) exposure. PAR is responsible for induction of parthanatos, a mechanism for caspaseindependent cell death, triggered by apoptosis-inducing factor (AIF) release from mitochondria and its translocation to the nucleus, where it initiates DNA cleavage. PARG, by generating protein-free PAR from poly-ADP ribosylated protein, makes PAR translocation possible. A protective effect of ARH3 results from its lowering of PAR levels in the nucleus and the cytoplasm, thereby preventing release of AIF from mitochondria and its accumulation in the nucleus. Thus, PARG release of PAR attached to nuclear proteins, followed by ARH3 cleavage of PAR, is essential in regulating PAR-dependent AIF release from mitochondria and parthanatos.posttranslational modification | cytotoxicity P oly-ADP ribosylation is a reversible posttranslational modification of proteins, which results from the covalent attachment of branched polymers of ADP ribose moieties to amino acid residues of target proteins, in a reaction catalyzed by poly (ADP ribose) polymerases (PARP) (1-3). PARP1, a well-characterized member of the PARP family, is a nuclear protein that acts as a molecular sensor of DNA-strand breaks. Upon binding to sites of single-strand DNA breaks, PARP1 catalyzes the formation of a branched, long poly (ADP ribose) (PAR) chain attached to glutamate or aspartate residues of acceptor proteins including histones, DNA polymerases, topoisomerases, DNA ligase-2, transcription factors, and PARP1 itself (4-7). Poly-ADP ribosylation of these acceptor proteins alters their physical and biological properties, leading to DNA repair and the maintenance of genomic stability. In contrast, PARP1 overactivation, resulting from widespread DNA damage, accelerates

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“…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.…”

Section: Parp-1mentioning

confidence: 99%

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

Gk¹,

Yenmiş²,

Koc³

2014

Interdiscip J Microinflammation

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Poly (ADP-ribose) polymerase-1 (PARP-1) has various roles in cellular processes such as DNA repair, genomic stability, transcription, stress response, and cell death via regulating death and inflammation signalling pathways. On the other hand, PARP-1 inhibition has been shown to provide benefits in experimental models of animals with inflammatory diseases such as asthma, atherosclerosis and diabetes. PARP-1 also acts a transcriptional coactivator of nuclear factor kappa B (NFKB). The NFKB is a ubiquitous transcription factor that controls the expression of genes encoding cell adhesion molecules, growth factors, cytokines, and some acute phase proteins. Inappropriate activation of NFKB has been mostly searched with inflammatory events. In complete and persistent inhibition studies of NFKB, apoptosis, inappropriate immune cell development and delayed cell growth were investigated. These findings might provide new perceptions in the pathogenesis of inflammatory disorders regarding the roles of PARP-1 and NFKB1 proteins. In this review, we focus on some variations (rs28362491, rs696, rs1136410, rs2793378, rs7527192) of PARP-1 and NFKB1 genes in relation to susceptibility to common inflammatory diseases including rheumatoid arthritis, systemic lupus erythematosus, allergic rhinitis, Graves' disease, Hashimoto's thyroiditis, asthma and Behcet's disease.

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

Cited by 50 publications

References 160 publications

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

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

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

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

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