We have previously shown that pirlindole and dehydropirlindole, two monoamine oxidase type-A inhibitors, protect cultured brain cells against iron-induced toxicity through a mechanism unrelated to monoamine oxidase type-A inhibition. The current study was performed to test whether the protective effect of pirlindole and dehydropirlindole could be extended to a nitric oxide (NO)-induced insult. A comparison with other monoamine oxidase inhibitors (brofaromine, moclobemide and deprenyl) and with trolox was made. In a first series of experiments, rat hippocampal or cortical cultured cells were exposed to a drug for 3 h, then 5 microM sodium nitroprusside, a NO donor, was added and the incubation was continued for 16 h. Cell survival assessment showed that pirlindole, dehydropirlindole and trolox significantly protected cultures against NO-induced toxicity in a concentration-dependent manner with respective EC(50)'s of 7, 3 and 17 microM. Similarly, pirlindole, dehydropirlindole or trolox, at a concentration of 50 microM, significantly decreased both intracellular peroxide production and lipoperoxidation. Other drugs were ineffective. In a post-hoc treatment protocol (3- or 6-h pre-incubation in the presence of sodium nitroprusside, then addition of one of the above mentioned compounds), only pirlindole and dehydropirlindole significantly improved cell survival in a concentration-dependent manner with respective EC(50)'s of 9 and 4 microM. The maximal protection in terms of cell survival was 90% and 78% after 3 and 6 h, respectively. They also reduced the production of both lipoperoxides and endoperoxides. Our results show that pirlindole and dehydropirlindole protect neurons against NO-induced toxicity at pharmacologically relevant concentrations. Moreover, their protective effect is still apparent when they are applied after the start of the insult. Therefore, our preclinical study suggests a new strategy that may be efficient to reduce NO-induced damage in the central nervous system.