Sodium fusidate ameliorates the course of diabetes induced in mice by multiple low doses of streptozotocin

We studied the effects of the immunosuppressant sodium fusidate (fusidin) o n murine immunoinflammatory diabetes mellitus (DM) induced by multiple low doses of streptozotocin (SZ). Fusidin was given by gavage to three strains of mice (C57KsJ, C57BL/6, CD1) at doses 10 or 100 mg/kg body weight every o ther day. The drug was administered as an early or late prophylactic regime starting either 1 day prior to the first or after the fifth and last injec tion of SZ. In both situations the largest dose of fusidin successfully red uced the clinical, chemical and histological signs of DM, the treated mice having significantly lower glycaemic values and milder (often absent) insul itis compared with sham-treated animals or controls given SZ alone. The ant idiabetogenic effect was long-lasting as it was maintained up to 1 month af ter cessation of therapy. In contrast, fusidin prophylaxis failed to preven t development of hyperglycaemia acutely induced by one single and high (160 mg/kg) dose of SZ, which is a model of DM primarily due to the toxic actio n of SZ on the beta cells and does not involve immunopathogenetic mechanism s. On day 14 after SZ, fusidin markedly altered the circulating cytokine profi le induced in vivo by ConA, reducing the levels of IFN-gamma, IL-2 and TNF- alpha and augmenting the level of IL-6. However, only the inhibitory effect of the drug on the synthesis/release of IFN-gamma seemed to be causally re lated to its capacity to counteract the SZ-induced DM. In fact, the disease was prevented by a neutralizing monoclonal antibody (mAb) against IFN-gamm a, but not by anti-IL-2 receptor mAb, a soluble form of TNF-receptor type 1 or recombinant human IL-6. The prevention of disease by fusidin was also p artly reversed by exogenously administered recombinant mouse IFN-gamma. The data provide further in-vivo evidence for the anti-diabetogenic and imm unomodulatory properties of fusidin and indicate that this drug could have a role in prevention and treatment of human type 1 DM. (C) 2000 Academic Pr ess.