Oral idebenone attenuates murine lupus

Abstract

Abstract A role for mitochondrial dysfunction has been proposed in the immune dysregulation and organ damage characteristic of systemic lupus erythematous (SLE) disease pathogenesis. We have now examined the role of drugs that may improve mitochondrial function in SLE symptomatology in murine models of lupus. Idebenone is a synthetic quinone analog compound of coenzyme Q10 that has been safely used in humans to treat diverse diseases where mitochondria function is deficient. Idebenone is considered a strong antioxidant able to protect cells against enhanced reactive oxygen species’ toxicity. Idebenone also improves electron transfer chain function in overloaded and/or damaged mitochondria. Idebenone was administered 250 mg/day/kg orally to two different mouse models of SLE starting in preclinical stages (10 weeks of age) for 6 weeks (MRL/lpr mice) or 4 months (NZM2328 mice). Disease attenuation was observed in both models at euthanasia. Specifically, proteinuria, intestinal inflammation and splenomegaly were decreased in both models upon exposure to idebenone, while levels of autoantibodies were not affected. In the MRL/lpr mouse model, skin lesions characteristic of this model were significantly decreased. In addition, levels of proinflammatory cytokines, type I IFNs and inflammasome-related genes were significantly decreased. No obvious toxicity was observed following exposure to idebenone. In conclusion, idebenone modulates lupus disease activity and organ damage severity and future studies should further address mechanism of action and potential role in human disease.