Anti-inflammatory effects of a novel, potent inhibitor of poly (ADP-ribose) polymerase

Details

Serval ID
serval:BIB_1D14FF38DF8C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Anti-inflammatory effects of a novel, potent inhibitor of poly (ADP-ribose) polymerase
Journal
Inflammation Research
Author(s)
Mabley  J. G., Jagtap  P., Perretti  M., Getting  S. J., Salzman  A. L., Virag  L., Szabo  E., Soriano  F. G., Liaudet  L., Abdelkarim  G. E., Hasko  G., Marton  A., Southan  G. J., Szabo  C.
ISSN
1023-3830 (Print)
Publication state
Published
Issued date
11/2001
Volume
50
Number
11
Pages
561-9
Notes
Journal Article
Research Support, U.S. Gov't, P.H.S. --- Old month value: Nov
Abstract
OBJECTIVE AND DESIGN: Oxygen- and nitrogen-derived free radicals and oxidants play an important role in the pathogenesis of various forms of inflammation. Recent work emphasizes the importance of oxidant-induced DNA strand breakage and activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) in the pathogenesis of various inflammatory diseases. We have recently demonstrated the efficacy of PJ34, a novel, potent phenanthridinone derivative PARP inhibitor, in rodent models of diabetic vascular dysfunction and stroke. Here we tested the efficacy of PARP inhibition in various models of local inflammation in rodents. MATERIALS AND METHODS: PJ34 (at doses of 0.03-30 mg/kg) was tested in rats and mice subjected to standard models of inflammation, with relevant parameters of inflammation measured using standard methods. RESULTS: PJ34 treatment (s.c, i.p. and i.v.) dose-dependently suppressed neutrophil infiltration and nitric oxide (but not KC and IL-1beta) production in peritonitis. In a model of systemic endotoxemia, PJ34 pretreatment significantly reduced plasma levels of TNF-alpha, IL-1beta and nitrite/nitrate (breakdown products of nitric oxide) production. PJ34 treatment (oral gavage) induced a significant suppression of the inflammatory response in dextran sulfate colitis, multiple low dose streptozotocin diabetes and cyclophosphamide-accelerated autoimmune diabetes in the non-obese diabetic mice, and reduced the degree of mononuclear cell infiltration into the iris in an endotoxin-induced uveitis model. Delaying the start of PJ34 administration in the colitis model conferred significant protective effects, while in the arthritis model the post-treatment paradigm lacked protective effects. CONCLUSIONS: PJ34 provides significant, dose-dependent, anti-inflammatory effects in a variety of local inflammation models. Some of its actions are maintained in the post-treatment regimen and/or after discontinuation of treatment. We conclude that PARP inhibition offers a powerful means for reducing the severity of various forms of local inflammatory responses.
Keywords
Adenosine Triphosphate/metabolism Animals Anti-Inflammatory Agents/*pharmacology Arthritis/drug therapy Colitis/drug therapy Collagen/immunology Diabetes Mellitus, Experimental/drug therapy Dose-Response Relationship, Drug Endotoxemia/drug therapy Enzyme Inhibitors/*pharmacology Male Mice Mice, Inbred DBA NAD/metabolism Peritonitis/drug therapy Phenanthrenes/*pharmacology Poly(ADP-ribose) Polymerases/*antagonists & inhibitors Uveitis/drug therapy
Pubmed
Web of science
Create date
24/01/2008 17:01
Last modification date
20/08/2019 12:53
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