Nitroxide stable radical suppresses autoimmune uveitis in rats

Abstract

Free radicals have been implicated in the pathogenesis of experimental autoimmune uveoretinitis (EAU). Nitroxides are stable radicals with a superoxide-dismutase-mimicking activity, which exert an anti-inflammatory effect in various animal models of oxidative damage and inflammation, such as experimental colitis and head trauma. We examined the use of the SOD mimic nitroxide 4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-N-oxyl (TPL) to suppress EAU. Adult male Lewis rats were immunized with 125 μg/rat synthetic human retinal S-Ag, emulsified with Freund’s adjuvant. Intravenous pertussis toxin was simultaneously injected. Beginning on Day 6, rats were injected with a daily intraperitoneal dose of 35, 175 or 350 μmol/rat of the nitroxide TPL. Control rats received intraperitoneal normal saline. The animals were examined daily, and on the 19th day the eyes were enucleated. Aqueous protein concentrations and retinal lipid peroxidation product levels (ketodienes and conjugated dienes) were determined. Histological sections were stained and examined microscopically. TPL was found to penetrate the aqueous humor readily. Beginning on day 12, rats developed a severe pan-uveitis. Rats in the treatment group had a lower mean clinical and histological score than that of controls. Levels of aqueous humor protein, retinal conjugated diens and ketodiens were all significantly lower in the treatment group. This effect was more pronounced with the lower TPL concentration. We conclude that TPL reduces clinical, biochemical and histopathological severity of S-Ag induced EAU in Lewis rats. This effect is probably mediated by removal of superoxide radicals, but other mechanisms may also be involved.