Potent beta-cell protection in vitro by an isoquinolinone-derived PARP inhibitor.
Activation of the nuclear enzyme poly(ADP-ribose)polymerase (PARP) is a critical step in beta-cell death in response to exposure with free radicals or other DNA damaging agents. Nicotinamide, a B vitamin, exerts its beta-cell protective action primarily via its ability to block excessive PARP activity. We show here that the isoquinolinone derivative PD128763, a specific PARP inhibitor, provides protection from cell death in islet cells exposed in vitro to nitric oxide or oxygen radical generating compounds or to the beta-cell toxin streptozotocin, at concentrations 100 times less than required for nicotinamide. Furthermore, while the protective action of nicotinamide is rapidly lost after washing of islet cells, the effects of PD128763 are more long lasting. Both compounds had little capacity to rescue damaged islet cells from subsequent lysis. We conclude that the isoquinolinone derivative PD128763 is superior to nicotinamide in enhancing the resistance of beta-cells towards inflammatory attacks.
Burkart
V
V
German Diabetes Research Institute at the University of Düsseldorf.
Blaeser
K
K
Kolb
H
H
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001402:B-Lymphocytes / Q000201:enzymology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000166:cytology* / Q000201:enzymology; D007546:Isoquinolines / Q000494:pharmacology*; D007700:Kinetics; D009536:Niacinamide / Q000494:pharmacology; D018384:Oxidative Stress / Q000276:immunology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C110881:S-nitro-N-acetylpenicillamine; C068870:3,4-dihydro-5-methyl-1(2H)-isoquinolinone; D009536:Niacinamide; D013311:Streptozocin; D010396:Penicillamine