phenanthrenes and Uveitis

We investigated the suppressive effect of triptolide (TRD), a purified component from a traditional Chinese herb, Tripterygium wilfordii Hook F. (TWHf), on uveitogenic peptide (K2)-induced experimental autoimmune uveoretinitis (EAU). K2-peptide immunized B10.A mice were divided into four groups. One group was EAU control which was treated with PBS. The other two groups were treated with TRD with different time courses (from day 0 to day 28 and from day 14 to day 28). The last group was treated with Cyclosporin A (CsA) as a positive control of the treatment. TRD was administered at dose of 0.1 mg/kg/day (i.p.). CsA was administered at dose of 20 mg/kg/day (i.p.) from day 0 to day 28 during whole period of EAU induction. The data showed that the EAU was suppressed in the whole period of TRD-treated mice, but was not in TRD-treated mice from day 14 to day 28 following immunization. The inhibition of EAU induced by TRD treatment was comparable to CsA-treated mice. The K2-specific lymphocyte proliferation and mRNA expressions of Th1-type cytokines (IL-12p40, IFN-gamma and TNF-alpha) in draining lymph node and inflamed eyes were reduced in TRD-treated mice. The K2-specific IFN-gamma production in the draining lymph node cells (LNC) of TRD-treated mice (whole period) was significantly inhibited. This effect was not related to an apoptotic effect of TRD on CD4+ T cells. Our results suggested that TRD suppressed the induction of EAU by down-regulating Th1-type response in B10.A mice. This preventive effect on EAU induction may be related to the inhibition of TRD on T cell priming and activation.

Topics: Animals; Autoimmune Diseases; Cytokines; Disease Models, Animal; Diterpenes; Down-Regulation; Epoxy Compounds; Female; Immunosuppressive Agents; Injections, Intraperitoneal; Mice; Mice, Inbred Strains; Phenanthrenes; Retinitis; Th1 Cells; Uveitis

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.. 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.. 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.. 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.

Topics: Adenosine Triphosphate; Animals; Anti-Inflammatory Agents; Arthritis; Colitis; Collagen; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Endotoxemia; Enzyme Inhibitors; Male; Mice; Mice, Inbred DBA; NAD; Peritonitis; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Uveitis