GPI 6150 Prevents H2O2 Cytotoxicity by Inhibiting Poly(ADP-ribose) Polymerase

Zhang, Jie; Lautar, Susan; Huang, Shirley; Ramsey, Cynthia; Cheung, A.C.M.; Li, Jia He

doi:10.1006/bbrc.2000.3816

Cited by 44 publications

(34 citation statements)

References 48 publications

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“…The ability of PND to weakly discriminate between PARP-1 and PARP-2 by a factor of 3 has been previously reported (Perkins et al, 2001) and was confirmed in the present study, whereas PJ34 and 3-AB have been characterized as unselective inhibitors (Iwashita et al, 2004b). In accordance with previous data (Zhang et al, 2000), there was no selectivity for GPI-6150 between PARP isoenzymes.…”

Section: Discussionsupporting

confidence: 93%

Imidazoquinolinone, Imidazopyridine, and Isoquinolindione Derivatives as Novel and Potent Inhibitors of the Poly(ADP-ribose) Polymerase (PARP): A Comparison with Standard PARP Inhibitors

Eltze¹,

Boer²,

Wagner³

et al. 2008

Mol Pharmacol

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We have identified three novel structures for inhibitors of the poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA and implicated in DNA repair, apoptosis, organ dysfunction or necrosis., and 4-(1-methyl-1H-pyrrol-2-ylmethylene)-4H-isoquinolin-1,3-dione (BYK204165) inhibited cell-free recombinant human PARP-1 with pIC 50 values of 8. 36, 7.81, 6.40, and 7.35 (pK i 7.97, 7.43, 5.90, and 7.05), and murine PARP-2 with pIC 50 values of 7.50, 7.55, 5.71, and 5.38, respectively. BYK49187, BYK236864, and BYK20370 displayed no selectivity for PARP-1/2, whereas BYK204165 displayed 100-fold selectivity for PARP-1. The IC 50 values for inhibition of poly(ADPribose) synthesis in human lung epithelial A549 and cervical carcinoma C4I cells as well in rat cardiac myoblast H9c2 cells after PARP activation by H 2 O 2 were highly significantly correlated with those at cell-free PARP-1 (r 2 ϭ 0.89 -0.96, P Ͻ 0.001) but less with those at PARP-2 (r 2 ϭ 0.78 -0.84, P Ͻ 0.01). The infarct size caused by coronary artery occlusion and reperfusion in the anesthetized rat was reduced by 22% (P Ͻ 0.05) by treatment with BYK49187 (3 mg/kg i.v. bolus and 3 mg/kg/h i.v. during 2-h reperfusion), whereas the weaker PARP inhibitors, BYK236864 and BYK20370, were not cardioprotective. In conclusion, the imidazoquinolinone BYK49187 is a potent inhibitor of human PARP-1 activity in cell-free and cellular assays in vitro and reduces myocardial infarct size in vivo. The isoquinolindione BYK204165 was found to be 100-fold more selective for PARP-1. Thus, both compounds might be novel and valuable tools for investigating PARP-1-mediated effects.Poly(ADP-ribose) polymerases (PARP) 1 and 2 are abundant nuclear enzymes in eukaryotic cells that have been implicated in the cellular response to DNA damage (Schreiber et al., 2006). PARPs catalyze an energy-consuming reaction by transferring ADP-ribose moieties from the substrate NAD ϩ to nuclear acceptor proteins, including PARP itself, and to existing ADP-ribose adducts on protein, thus forming chains of poly(ADP-ribose) (PAR), to render damaged DNA accessible to the repair system and to maintain cell survival, genomic stability, and mammalian longevity (D'Amours et al., 1999). This beneficial, cytoprotective effect of PARP activity is apparent under conditions of low to modArticle, publication date, and citation information can be found at

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Section: Discussionsupporting

confidence: 93%

Imidazoquinolinone, Imidazopyridine, and Isoquinolindione Derivatives as Novel and Potent Inhibitors of the Poly(ADP-ribose) Polymerase (PARP): A Comparison with Standard PARP Inhibitors

Eltze¹,

Boer²,

Wagner³

et al. 2008

Mol Pharmacol

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“…The initial velocity of an increase in absorbance at 340 nm due to the formation of NADH was measured with a Hitachi U-2000 A spectrophotometer for 1 min. ADH activity was measured as described previously (Zhang et al, 2000) with some modifications. The mixture (200 l) containing 50 mM Bicine buffer (pH 7.6), 2 mM NAD ϩ , and 1.25 g/ml ADH was preincubated with 0, 1, 10, or 100 M DR2313 for 10 min at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…LDH activity was also measured as described previously (Zhang et al, 2000), with some modifications. The mixture (300 l) containing 83 mM potassium phosphate buffer (pH 7.4), 2 mM NADH, and 3.3 g/ml LDH was preincubated with 0, 1, 10, or 100 M DR2313 for 10 min at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…For the treatment of acute ischemic stroke, a compound should ideally be soluble in aqueous vehicle such as saline and deliverable by bolus injection or infusion. Thus, to develop a new class of PARP inhibitor as a neuroprotectant for stroke, many efforts have been focused on enhancing the potency, improving the pharmacokinetic characteristics, and increasing the water solubility (Abdelkarim et al, 2001;Chiarugi et al, 2003;Ferraris et al, 2003;Komjati et al, 2004;Zhang et al, 2000).…”

mentioning

confidence: 99%

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A Newly Synthesized Poly(ADP-Ribose) Polymerase Inhibitor, DR2313 [2-Methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]-pyrimidine-4-one]: Pharmacological Profiles, Neuroprotective Effects, and Therapeutic Time Window in Cerebral Ischemia in Rats

Nakajima

Kakui

Ohkuma

et al. 2004

J Pharmacol Exp Ther

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We investigated the pharmacological profiles of DR2313 [2-methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]pyrimidine-4-one], a newly synthesized poly(ADP-ribose) polymerase (PARP) inhibitor, and its neuroprotective effects on ischemic injuries in vitro and in vivo. DR2313 competitively inhibited poly(ADPribosyl)ation in nuclear extracts of rat brain in vitro (K i ϭ 0.23 M). Among several NAD ϩ -utilizing enzymes, DR2313 was specific for PARP but not selective between PARP-1 and PARP-2. DR2313 also showed excellent profiles in water solubility and rat brain penetrability. In in vitro models of cerebral ischemia, exposure to hydrogen peroxide or glutamate induced cell death with overactivation of PARP, and treatment with DR2313 reduced excessive formation of poly(ADP-ribose) and cell death. In both permanent and transient focal ischemia models in rats, pretreatment with DR2313 (10 mg/kg i.v. bolus and 10 mg/kg/h i.v. infusion for 6 h) significantly reduced the cortical infarct volume. To determine the therapeutic time window of neuroprotection by DR2313, the effect of posttreatment was examined in transient focal ischemia model and compared with that of a free radical scavenger, MCI-186 (3-methyl-1-phenyl-2-pyrazolone-5-one). Pretreatment with MCI-186 (3 mg/kg i.v. bolus and 3 mg/kg/h i.v. infusion for 6 h) significantly reduced the infarct volume, whereas the posttreatment failed to show any effects. In contrast, posttreatment with DR2313 (same regimen) delaying for 2 h after ischemia still prevented the progression of infarction. These results indicate that DR2313 exerts neuroprotective effects via its potent PARP inhibition, even when the treatment is initiated after ischemia. Thus, a PARP inhibitor like DR2313 may be more useful in treating acute stroke than a free radical scavenger.The excessive release of the excitotoxic amino acid glutamate plays a critical role in the pathogenesis of neuronal cell death following cerebral ischemia. NO produced by nNOS has been implicated in N-methyl-D-asparate (NMDA) receptor-mediated neurotoxicity of glutamate in cerebral ischemia . NMDA receptor activation causes an increase in intracellular calcium concentration leading to activation of nNOS. A part of the neurotoxicity evoked by NO is a result of the reaction of NO with superoxide anion to form a highly toxic radical, peroxynitrite Pieper et al., 1999). Postischemic injury is also exacerbated by the increased formation of hydroxyl radical, the most reactive molecule of all oxygen radicals (Chan, 2001). These reactive oxygen species (ROS) can contribute to the DNA strand breakage, which is followed by overactivation of poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30) (Szabo and Dawson, 1998;Pieper et al., 1999).PARP-1 is an abundant nuclear protein which is activated Article, publication date, and citation information can be found at

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“…Future work must investigate whether the improvement by PARP inhibition of the early functional alterations in diabetes (such as the endothelial dysfunction) can also translate to improvements in the more delayed severe vascular and extravascular changes, including accelerated atherosclerosis, hypertension, and foot ulceration. 29 -31 Although several series of novel, potent PARP inhibitors are in various stages of preclinical development for a variety of therapeutic indications, [32][33][34] there are presently no potent, selective PARP inhibitors available for human trials. Nicotinamide is a weak PARP inhibitor, 35 which, nevertheless, has an excellent safety profile in humans.…”

Section: Soriano Et Al Diabetic Endothelial Dysfunction and Parpmentioning

confidence: 99%

Rapid Reversal of the Diabetic Endothelial Dysfunction by Pharmacological Inhibition of Poly(ADP-Ribose) Polymerase

Soriano

Pacher

Mabley

et al. 2001

Circulation Research

189

181

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Abstract-Oxygen-and nitrogen-derived free radicals and oxidants play an important role in the pathogenesis of diabetic endothelial dysfunction. Recently we proposed the importance of oxidant-induced DNA strand breakage and activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) in the pathogenesis of diabetic endothelial dysfunction.In this study, we tested whether established diabetic endothelial dysfunction is reversible by PARP inhibition. The novel PARP inhibitor PJ34 (10 mg/kg per day PO) was given at various lengths (4 weeks or 3 days) for established streptozotocin-diabetic animals. In addition, we also tested whether incubation of the aortic rings with PJ34 (3 mol/L) or a variety of other PARP inhibitors for 1 hour affects the diabetic vascular changes. Both 4-week and 3-day PARP-inhibitor treatment of streptozotocin-diabetic mice with established endothelial dysfunction fully reversed the acetylcholine-induced endothelium-dependent relaxations in vitro. Furthermore, 1-hour in vitro incubation of aortae from streptozotocin-diabetic mice with various PARP inhibitors was able to reverse the endothelial dysfunction. ATP, NAD ϩ , and NADPH levels were markedly reduced in diabetic animals, and PARP-inhibitor treatment was able to restore these alterations. Unexpectedly, pharmacological inhibition of PARP not only prevents the development of the endothelial dysfunction but is also able to rapidly reverse it. Thus, PARP activation and the associated metabolic compromise represent an ongoing process in diabetic blood vessels. Pharmacological inhibition of this process is able to reverse diabetic endothelial dysfunction. Key Words: diabetes Ⅲ endothelium Ⅲ nitric oxide Ⅲ necrosis Ⅲ apoptosis P oly(ADP-ribose) polymerase (PARP) is an abundant nuclear enzyme that has been implicated in the cellular response to DNA injury. 1 We recently proposed a role for PARP activation in the pathogenesis of diabetic endothelial dysfunction. Endothelial cells and vascular rings from PARP ϩ/ϩ mice incubated in high glucose were found to exhibit metabolic suppression and loss of endotheliumdependent relaxant function, effects that did not develop in the vascular rings from PARP Ϫ/Ϫ mice and were prevented by pharmacological inhibition of PARP. 2 Ex vivo experiments, examining the immunohistochemical profile and the endothelium-dependent relaxant function of diabetic aortae, demonstrated intravascular production of reactive nitrogen species, the development of DNA strand breakage, and the activation of PARP. 2 Finally, in vivo treatment with PJ34, a novel potent phenanthridinone PARP inhibitor, was found to prevent the development of diabetic endothelial dysfunction in streptozotocin-diabetic mice. 2 In this study we report our recent, unexpected findings that demonstrate that pharmacological PARP inhibition not only prevents the development of diabetic vascular dysfunction but also rapidly restores the function of established diabetic blood vessels.

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GPI 6150 Prevents H2O2 Cytotoxicity by Inhibiting Poly(ADP-ribose) Polymerase

Cited by 44 publications

References 48 publications

Imidazoquinolinone, Imidazopyridine, and Isoquinolindione Derivatives as Novel and Potent Inhibitors of the Poly(ADP-ribose) Polymerase (PARP): A Comparison with Standard PARP Inhibitors

Imidazoquinolinone, Imidazopyridine, and Isoquinolindione Derivatives as Novel and Potent Inhibitors of the Poly(ADP-ribose) Polymerase (PARP): A Comparison with Standard PARP Inhibitors

A Newly Synthesized Poly(ADP-Ribose) Polymerase Inhibitor, DR2313 [2-Methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]-pyrimidine-4-one]: Pharmacological Profiles, Neuroprotective Effects, and Therapeutic Time Window in Cerebral Ischemia in Rats

Rapid Reversal of the Diabetic Endothelial Dysfunction by Pharmacological Inhibition of Poly(ADP-Ribose) Polymerase

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