The neurotoxic effects of the dopamine-selective neurotoxin MPTP (15 mg/kg, s.c.), in mice, were totally prevented by systemic administration of salicylate (ED50 = 40 mg/kg, i.p.), aspirin (ED50 = 60 mg/kg, i.p.), or the soluble lysine salt of aspirin, Aspegic (ED50 = 80 mg/kg, i.p.). The protective effects of aspirin are unlikely to be related to cyclooxygenase inhibition as paracetamol (100 mg/kg, i.p.), diclofenac (100 mg/kg, i.p.), ibuprofen (20 mg/kg, i.p.) and indomethacin (100 mg/kg, i.p.) were ineffective. Dexamethasone (3-30 mg/kg, i.p.), which, like aspirin and salicylate, has been reported to inhibit the transcription factor NF-kappaB, was also ineffective. Aspirin or salicylate (100 microM) had no effect on dopamine uptake into striatal synaptosomes or on monoamine oxidase B activity. The neuroprotective effects of salicylate derivatives could perhaps be related to hydroxyl radical scavenging. This was suggested by the fact that hydroxylated metabolites of salicylate (2,3- and 2,5-dihydrobenzoic acid) were recovered in brain tissue following the combined administration of MPTP and aspirin to a greater extent than following aspirin alone. The surprising neuroprotective effects of aspirin in an animal model of Parkinson's disease warrant further clinical investigation.