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Modulation of inflammatory arthritis by inhibition of poly(ADP ribose) polymerase
R Miesel1, M Kurpisz, H Kröger
1Department of Biochemistry, Deutsches RheumaForschungsZentrum, Berlin, Germany.
Abstract:
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.
Insights
Nicotinamide, a poly(ADPR) polymerase (PARP) inhibitor, suppressed arthritis by 35% in mice. This suggests inhibiting PARP and NADPH oxidase may treat arthritis by reducing oxidative stress.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Poly(ADPR) polymerase (PARP) is a nuclear enzyme activated by DNA strand breaks.
- PARP activation contributes to apoptosis by depleting cellular NAD and ATP.
- Oxidative stress is implicated in the pathogenesis of inflammatory diseases like arthritis.
Purpose of the Study:
- To investigate the role of oxidative stress-dependent PARP activation in arthritis.
- To evaluate the antiarthritic effects of nicotinamide (NA), a biogenic PARP inhibitor.
Main Methods:
- Potassium peroxochromate-induced arthritis model in DBA/1 x B10A(4R) mice.
- Administration of daily doses of nicotinamide (4 mmol/kg).
- Measurement of reactive oxygen species (ROS) generation and NADPH oxidase activity in phagocytes.
Main Results:
- Nicotinamide suppressed arthritis by 35% and inhibited ROS generation.
- Arthritis onset, progression, and remission correlated with neutrophil and monocyte respiratory burst.
- A dose-dependent inhibition of NADPH oxidase activity was observed in human phagocytes.
Conclusions:
- Oxidative stress-induced alterations in cellular signaling pathways are crucial in arthritis development.
- Simultaneous inhibition of PARP and NADPH oxidase shows potential for suppressing arthritis.