Cytokines produced by immune cells infiltrating pancreatic islets are important mediators of beta-cell destruction in insulin-dependent diabetes mellitus. Scoparone (6,7-dimethoxycoumarin) is known to have a wide range of pharmacological properties in vitro. In this study, the effects of scoparone on cytokine-induced beta-cell dysfunction were examined. Presence of scoparone significantly protected interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma)-mediated cytotoxicity of RINm5F, a rat insulinoma cell line, and preserved glucose-stimulated insulin secretion in rat pancreatic islets. Scoparone also resulted in a significant reduction in IL-1beta and IFN-gamma-induced nitric oxide (NO) production, a finding that correlated well with reduced levels of the inducible form of NO synthase (iNOS) mRNA and protein. The molecular mechanism by which scoparone inhibited iNOS gene expression appeared to involve the inhibition of NF-kappaB activation. These results revealed the possible therapeutic value of scoparone for the prevention of diabetes mellitus progression.