The present study examined caspase activation and its modulation by nitric oxide (NO) in a model of oxidative stress induced by injection of malonate (3 micromol), a mitochondrial toxin, into rat striatum. Caspase-3-like enzymatic activity was maximal 6 h after malonate while NO production evaluated by its metabolites nitrites and nitrates was increased at 3 h. The neuronal NO-synthase inhibitor 7-nitroindazole reduced malonate induced-NO production by 50% at 25 mg/kg and enhanced by 32% caspase activation. This result suggests that a moderate production of NO potentiates caspase activation, an effect counterbalanced by NO itself at higher concentrations. Accordingly, complete inhibition of NO production by 7-nitroindazole at 50 mg/kg did not modify malonate-induced caspase activity. Thus NO production by the neuronal isoform of NO-synthase is not the major event leading to caspase activation due to malonate. However, NO seems to have pro- and anti-caspase effects that neutralize each other.