Carnosol, a naturally occurring bioactive phenolic diterpene originating from rosemary and sage, has been shown to exert antioxidant and anti-inflammatory effects. This study examined possible protective effects of carnosol on sodium nitroprusside (SNP)-induced cytotoxicity in C6 glial cells. Carnosol (1-10 microM) dose-dependently attenuated SNP (100 microM)-induced cell death and NO production. SNP-induced apoptotic characteristics, including DNA fragmentation, caspase-3 activation, and c-jun N-terminal protein kinase (JNK) phosphorylation, were significantly suppressed by carnosol (10 microM). In addition, carnosol pretreatment restored the level of reduced glutathione (GSH), which was diminished by SNP treatment. Although both SNP (100 microM) and carnosol (10 microM) stimulated the HO-1 expression time-dependently, SNP caused a temporal increase in HO-1 in early time periods (3-6 h) before cell death occurred. In contrast, carnosol induced the sustained expression of HO-1 until a late time point (24 h). The addition of 1 microM zinc protoporphyrin IX (ZnPP), a specific HO inhibitor, with SNP or carnosol further reduced cell viability. Also, the addition of ZnPP inhibited the protective effect of carnosol against SNP-induced cytotoxicity in C6 cells. These results suggest that carnosol possesses abilities to inhibit SNP-mediated glial cell death through modulation of apoptotic events and induction of HO-1 expression.