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

J. G. Mabley, P. Jagtap, M. Perretti, S. J. Getting, A. L. Salzman, L. Virág, É Szabó, F. G. Soriano, L. Liaudet, G. E. Abdelkarim, G. Haskó, A. Marton, G. J. Southan, Csaba Szabo

Research output: Contribution to journalArticle

106 Citations (Scopus)

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-1β) production in peritonitis. In a model of systemic endotoxemia, PJ34 pretreatment significantly reduced plasma levels of TNF-α, IL-1β 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.

Original languageEnglish (US)
Pages (from-to)561-569
Number of pages9
JournalInflammation Research
Volume50
Issue number11
StatePublished - 2001
Externally publishedYes

Fingerprint

Anti-Inflammatory Agents
Poly(ADP-ribose) Polymerases
Inflammation
Colitis
Interleukin-1
Oxidants
Medical problems
Infiltration
Rodentia
Nitric Oxide
Dextran Sulfate
Inbred NOD Mouse
Enzyme Activation
Endotoxemia
Experimental Diabetes Mellitus
Neutrophil Infiltration
Uveitis
Iris
Nitrites
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride

Keywords

  • Arthritis
  • Colitis
  • Nitric oxide
  • Pleurisy
  • Uveitis

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology (medical)
  • Immunology
  • Cell Biology

Cite this

Mabley, J. G., Jagtap, P., Perretti, M., Getting, S. J., Salzman, A. L., Virág, L., ... Szabo, C. (2001). Anti-inflammatory effects of a novel, potent inhibitor of poly(ADP-ribose) polymerase. Inflammation Research, 50(11), 561-569.

Anti-inflammatory effects of a novel, potent inhibitor of poly(ADP-ribose) polymerase. / Mabley, J. G.; Jagtap, P.; Perretti, M.; Getting, S. J.; Salzman, A. L.; Virág, L.; Szabó, É; Soriano, F. G.; Liaudet, L.; Abdelkarim, G. E.; Haskó, G.; Marton, A.; Southan, G. J.; Szabo, Csaba.

In: Inflammation Research, Vol. 50, No. 11, 2001, p. 561-569.

Research output: Contribution to journalArticle

Mabley, JG, Jagtap, P, Perretti, M, Getting, SJ, Salzman, AL, Virág, L, Szabó, É, Soriano, FG, Liaudet, L, Abdelkarim, GE, Haskó, G, Marton, A, Southan, GJ & Szabo, C 2001, 'Anti-inflammatory effects of a novel, potent inhibitor of poly(ADP-ribose) polymerase', Inflammation Research, vol. 50, no. 11, pp. 561-569.
Mabley JG, Jagtap P, Perretti M, Getting SJ, Salzman AL, Virág L et al. Anti-inflammatory effects of a novel, potent inhibitor of poly(ADP-ribose) polymerase. Inflammation Research. 2001;50(11):561-569.
Mabley, J. G. ; Jagtap, P. ; Perretti, M. ; Getting, S. J. ; Salzman, A. L. ; Virág, L. ; Szabó, É ; Soriano, F. G. ; Liaudet, L. ; Abdelkarim, G. E. ; Haskó, G. ; Marton, A. ; Southan, G. J. ; Szabo, Csaba. / Anti-inflammatory effects of a novel, potent inhibitor of poly(ADP-ribose) polymerase. In: Inflammation Research. 2001 ; Vol. 50, No. 11. pp. 561-569.
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AU - Salzman, A. L.

AU - Virág, L.

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AU - Soriano, F. G.

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