Table 4

Effect of PARP inhibition in selected animal models of disease

OrganDisease ModelMethod of Targeting PARPMain FindingReference
VasculatureDiabetic endothelial dysfunctionPJ34Prevention by PJ34 of diabetic endothelial dysfunction Soriano et al., 2001c
Diabetic endothelial dysfunctionPJ34Reversal of diabetic endothelial dysfunction by PARP inhibition Soriano et al., 2001b
Endocrine pancreasDiabetesPicolinamideProtection by picolinamide from streptozotocin-induced depression of proinsulin synthesis and reduction of NAD content in pancreatic islets Yamamoto and Okamoto, 1980
DiabetesNicam, 3-ABPretreatment with poly(ADP-ribose) synthetase inhibitors was found to protect against alloxan- or streptozotocin-induced decrease in proinsulin synthesis Uchigata et al., 1983
Diabetes3-AB3-AB prevents the appearance of overt diabetes in streptozotocin-treated rats Masiello et al., 1985
DiabetesKnockout (Wang)Resistance of PARP-deficient mice to the development of diabetes induced by the β-cell toxin streptozocin Burkart et al., 1999
DiabetesKnockout (Masutani)Resistance of PARP-deficient mice to the development of diabetes induced by the β-cell toxin streptozocin Masutani et al., 1999
DiabetesKnockout (Wang)Partial protection in PARP+/- animals and full protection in PARP-/- animals from streptozotocin-induced diabetes Pieper et al., 1999
DiabetesNicam, 3-ABPARP inhibitors protect insulin-producing cells from STZ-induced damage Shima et al., 1987
DiabetesINH2BP, knockout (Wang)INH2BP and the PARP−/− phenotype provides protection in a multiple low dose streptozotocin model Mabley et al., 2001b
LungInterstitial pulmonary fibrosisNicamCombined treatment with taurine and niacin almost completely ameliorated the bleomycin-induced increases in the lung collagen accumulation Giri and Wang, 1992
ARDSBenzamide, PJ34, 5-AIQPARP 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 tractColitisKnockout (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
Colitis3-ABAfter 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 injuryKnockout 3-AB, nicam, GPI6150, PJ34Protection 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 musclesArthritisNicamPowerful synergistic inhibition of arthritis by thalidomide + PARP inhibition Kroger et al., 1996b
ArthritisNicamProtection by NA from potassium peroxochromate-induced arthritis Miesel et al., 1995
Reperfusion injury of skeletal muscle3-AB3-AB reduces I/R-induced injury in skeletal muscle and in myocardium Thiemermann et al., 1997
KidneyBenzamide, 3-ABPARP inhibitors accelerate the recovery of normal renal function after I/R injury Martin et al., 2000
LiverAcetaminophen toxicityNicamPARP inhibition prevents potentiating effect of thalidomide on acetaminophen-induced hepatotoxicity Kroger et al., 1995
Acetaminophen toxicityNicam, benzamidePARP inhibitors suppress AAP-induced liver damage Kroger et al., 1996a, 1997
Acetaminophen toxicity4-AB, nicamPARP inhibitors suppress AAP-induced liver damage Ray et al., 2001
EyeUveitisPJ34Protection by PARP inhibition from leukocyte migration in an LPS-induced model of experimental uveitis Mabley et al., 2001a
Retinal I/R3-AB3-AB ameliorated the ischemic/reperfusion damage to the retina Lam, 1997
EarCochlear I/R injury3-AB3-AB improved I/R-induced cochlear dysfunction Tabuchi et al., 2001
SkinSulfur mustard-induced vesication3-ABProtection by 3-AB from sulfur mustard-induced NAD depletion in the mouse skin Gross et al., 1985
Sulfur mustard-induced vesicationNicamNiacinamide inhibited microvesicle formation after sulfur mustard application Yourick et al., 1991
Multiple organsHemorrhagic 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 shock3-AB3-AB improves hemodynamics and prolongs survival in a porcine model of hemorrhagic shock Szabo et al., 1998a
Hemorrhagic shockINH2BPINH2BP improved survival rate in a severe rat model of hemorrhagic shock Szabo, 1998
Endotoxin shock3-AB3-AB significantly reduced the lipopolysaccharide-induced hyperpermeability in both organs, without affecting neutrophil deposition Szabo et al., 1998b
Endotoxin shock3-AB, PJ343-AB and PJ34 improved survival in lethal murine endotoxic shock Szabo et al., 1996b; Jagtap et al., 2002
Endotoxin shock3-ABPARP inhibition prevented suppression of endothelium-dependent relaxant responses in aorta rings obtained from endotoxemic rats Szabo et al., 1997a;Jagtap et al., 2002
MOF3-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)PJ34Inhibition 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.