Modulation of inflammatory arthritis by inhibition of poly(ADP ribose) polymerase.
Poly(ADPR) polymerase (PARP; EC 2.4.2.30) is a nuclear enzyme, which, when activated by oxygen- and nitrogen-radical-induced DNA strand breaks, transfers ADP ribose units to nuclear proteins and initiates apoptosis by depletion of cellular NAD and ATP pools. The present study investigates whether the oxidative stress-dependent activation of PARP plays a role in the etiopathogenesis of arthritis. The antiarthritic reactivity of the biogenic PARP inhibitor nicotinamide was tested in DBA/1 x B10A(4R) mice suffering from potassium peroxochromate-induced arthritis. Daily doses of 4 mmol/kg of NA suppressed the arthritis by 35% and inhibited the phagocytic generation of reactive oxygen species, which increases sixfold during the development of arthritis. The onset, progression, and remission of arthritis correlated positively to the phorbolester-activated respiratory burst of neutrophils and monocytes, and a dose-dependent inhibition of NADPH oxidase activity was determined with human phagocytes. Our data support the hypothesis that oxidative stress-induced alterations in cellular signal transduction pathways play a pivotal role in the development of arthritis, which can be suppressed by the simultaneous inhibition of poly(ADPR) polymerase and NADPH oxidase.
Miesel
R
R
Department of Biochemistry, Deutsches RheumaForschungsZentrum, Berlin, Germany.
Kurpisz
M
M
Kröger
H
H
D000818:Animals; D017209:Apoptosis; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D002840:Chromates / Q000633:toxicity; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019255:NADPH Oxidases; D009536:Niacinamide / Q000494:pharmacology*; D018384:Oxidative Stress; D010545:Peroxides / Q000633:toxicity; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002840:Chromates; D010545:Peroxides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; C019537:potassium tetraperoxochromate; D009536:Niacinamide; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D011065:Poly(ADP-ribose) Polymerases; D013755:Tetradecanoylphorbol Acetate