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

Objective and design: Oxygen- and nitrogen-derived free radicals and oxidan ts play an important role in the pathogenesis of various forms of inflammat ion. Recent work emphasizes the importance of oxidant-induced DNA strand br eakage and activation of the nuclear enzyme poly(ADP-ribose) polymerase (PA RP) in the pathogenesis of various inflammatory diseases. We have recently demonstrated the efficacy of PJ34, a novel, potent phenanthridinone derivat ive PARP inhibitor, in rodent models of diabetic vascular dysfunction and s troke. 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 parame ters of inflammation measured using standard methods. Results: PJ34 treatment (s.c, i.p. and i.v.) dose-dependently suppressed ne utrophil infiltration and nitric oxide (but not KC and IL-1 beta) productio n in peritonitis. In a model of systemic endotoxemia, PJ34 pretreatment sig nificantly reduced plasma levels of TNF-alpha, IL-1 beta and nitrite/nitrat e (breakdown products of nitric oxide) production. PJ34 treatment (oral gav age) induced a significant suppression of the inflammatory response in dext ran sulfate colitis, multiple low dose streptozotocin diabetes and cyclopho sphamide-accelerated autoimmune diabetes in the non-obese diabetic mice, an d reduced the degree of mononuclear cell infiltration into the iris in an e ndotoxin-induced uveitis model. Delaying the start of PJ34 administration i n the colitis model conferred significant protective effects, while in the arthritis model the posttreatment paradigm lacked protective effects. Conclusions: PJ34 provides significant, dose-dependent, anti-inflammatory e ffects in a variety of local inflammation models. Some of its actions are m aintained in the post-treatment regimen and/or after discontinuation of tre atment, We conclude that PARP inhibition offers a powerful means for reduci ng the severity of various forms of local inflammatory responses.