Effect of PARP inhibition in selected animal models of disease
| Organ | Disease Model | Method of Targeting PARP | Main Finding | Reference |
|---|---|---|---|---|
| Vasculature | Diabetic endothelial dysfunction | PJ34 | Prevention by PJ34 of diabetic endothelial dysfunction | Soriano et al., 2001c |
| Diabetic endothelial dysfunction | PJ34 | Reversal of diabetic endothelial dysfunction by PARP inhibition | Soriano et al., 2001b | |
| Endocrine pancreas | Diabetes | Picolinamide | Protection by picolinamide from streptozotocin-induced depression of proinsulin synthesis and reduction of NAD content in pancreatic islets | Yamamoto and Okamoto, 1980 |
| Diabetes | Nicam, 3-AB | Pretreatment with poly(ADP-ribose) synthetase inhibitors was found to protect against alloxan- or streptozotocin-induced decrease in proinsulin synthesis | Uchigata et al., 1983 | |
| Diabetes | 3-AB | 3-AB prevents the appearance of overt diabetes in streptozotocin-treated rats | Masiello et al., 1985 | |
| Diabetes | Knockout (Wang) | Resistance of PARP-deficient mice to the development of diabetes induced by the β-cell toxin streptozocin | Burkart et al., 1999 | |
| Diabetes | Knockout (Masutani) | Resistance of PARP-deficient mice to the development of diabetes induced by the β-cell toxin streptozocin | Masutani et al., 1999 | |
| Diabetes | Knockout (Wang) | Partial protection in PARP+/- animals and full protection in PARP-/- animals from streptozotocin-induced diabetes | Pieper et al., 1999 | |
| Diabetes | Nicam, 3-AB | PARP inhibitors protect insulin-producing cells from STZ-induced damage | Shima et al., 1987 | |
| Diabetes | INH2BP, knockout (Wang) | INH2BP and the PARP−/− phenotype provides protection in a multiple low dose streptozotocin model | Mabley et al., 2001b | |
| Lung | Interstitial pulmonary fibrosis | Nicam | Combined treatment with taurine and niacin almost completely ameliorated the bleomycin-induced increases in the lung collagen accumulation | Giri and Wang, 1992 |
| ARDS | Benzamide, PJ34, 5-AIQ | PARP inhibition suppresses NMDA receptor mediated lung edema formation and endotoxin-induced or zymosan-activated plasma-induced lung injury | Said et al., 1996; Cuzzocrea et al., 2002; Liaudet et al., 2002 | |
| Gastrointestinal tract | Colitis | Knockout (Wang) | Shortened course of colitis, reduced neutrophil infiltration, lipid peroxidation, nitrosative damage, and ICAM-1 expression in PARP−/− mice in a TNBS-induced model of colonic injury | Zingarelli et al., 1999 |
| Colitis | 3-AB | After 14 days of treatment with the PARP inhibitor 3-aminobenzamide, IL-10 gene-deficient mice demonstrated normalized colonic permeability; reduced tumor necrosis factor-α and interferon-γ secretion, inducible nitric-oxide synthase expression, and nitrotyrosine levels; and significantly attenuated inflammation. | Jijon et al., 2000 | |
| Mesenteric I/R injury | Knockout 3-AB, nicam, GPI6150, PJ34 | Protection against histological damage, neutrophil infiltration, and mucosal barrier failure in PARP−/− mice and animals treated with PARP inhibitors | Cuzzocrea et al., 1997;Liaudet et al., 2000b; Jagtap et al., 2002; Mazzon et al., 2002 | |
| Joints and skeletal muscles | Arthritis | Nicam | Powerful synergistic inhibition of arthritis by thalidomide + PARP inhibition | Kroger et al., 1996b |
| Arthritis | Nicam | Protection by NA from potassium peroxochromate-induced arthritis | Miesel et al., 1995 | |
| Reperfusion injury of skeletal muscle | 3-AB | 3-AB reduces I/R-induced injury in skeletal muscle and in myocardium | Thiemermann et al., 1997 | |
| Kidney | Benzamide, 3-AB | PARP inhibitors accelerate the recovery of normal renal function after I/R injury | Martin et al., 2000 | |
| Liver | Acetaminophen toxicity | Nicam | PARP inhibition prevents potentiating effect of thalidomide on acetaminophen-induced hepatotoxicity | Kroger et al., 1995 |
| Acetaminophen toxicity | Nicam, benzamide | PARP inhibitors suppress AAP-induced liver damage | Kroger et al., 1996a, 1997 | |
| Acetaminophen toxicity | 4-AB, nicam | PARP inhibitors suppress AAP-induced liver damage | Ray et al., 2001 | |
| Eye | Uveitis | PJ34 | Protection by PARP inhibition from leukocyte migration in an LPS-induced model of experimental uveitis | Mabley et al., 2001a |
| Retinal I/R | 3-AB | 3-AB ameliorated the ischemic/reperfusion damage to the retina | Lam, 1997 | |
| Ear | Cochlear I/R injury | 3-AB | 3-AB improved I/R-induced cochlear dysfunction | Tabuchi et al., 2001 |
| Skin | Sulfur mustard-induced vesication | 3-AB | Protection by 3-AB from sulfur mustard-induced NAD depletion in the mouse skin | Gross et al., 1985 |
| Sulfur mustard-induced vesication | Nicam | Niacinamide inhibited microvesicle formation after sulfur mustard application | Yourick et al., 1991 | |
| Multiple organs | Hemorrhagic shock, septic shock (polymicrobial) | Knockout (Wang) | PARP−/− mice were protected from the rapid decrease in blood pressure after resuscitation and showed an increased survival time, decreased gut hyperpermeability as well as reduced lung neutrophil sequestration | Liaudet et al., 2000a;Soriano et al., 2002 |
| Hemorrhagic shock | 3-AB | 3-AB improves hemodynamics and prolongs survival in a porcine model of hemorrhagic shock | Szabo et al., 1998a | |
| Hemorrhagic shock | INH2BP | INH2BP improved survival rate in a severe rat model of hemorrhagic shock | Szabo, 1998 | |
| Endotoxin shock | 3-AB | 3-AB significantly reduced the lipopolysaccharide-induced hyperpermeability in both organs, without affecting neutrophil deposition | Szabo et al., 1998b | |
| Endotoxin shock | 3-AB, PJ34 | 3-AB and PJ34 improved survival in lethal murine endotoxic shock | Szabo et al., 1996b; Jagtap et al., 2002 | |
| Endotoxin shock | 3-AB | PARP inhibition prevented suppression of endothelium-dependent relaxant responses in aorta rings obtained from endotoxemic rats | Szabo et al., 1997a;Jagtap et al., 2002 | |
| MOF | 3-AB and knockout (Wang) | Inhibition of PARP prevented neutrophil recruitment, and reduced organ injury in rodent models of inflammation and multiple organ failure elicited by intraperitoneal injection of zymosan | Szabo et al., 1997b | |
| Septic shock (E. coli) | PJ34 | Inhibition of PARP improved survival and maintained cardiac function in an LD100 sepsis model in the pig | Goldfarb et al., 2002 |
3-AB, 3-aminobenzamide; STZ, streptozotocin; I/R, ischemia-reperfusion; AAP, acetaminophen; ARDS, acute respiratory distress syndrome; MOF, multiple organ failure; nicam, nicotinamide; TNBS, 2,4,6-trinitrobenzene sulfonic acid sodium salt.