Theophylline is a methylxanthine bronchodilator with a narrow therapeutic index and is prone to induce seizures, the mechanisms for which are not clearly defined. Free radicals have considerable neurotoxic potential and the present study evaluated the possible involvement of these bioactive moieties in aminophylline-induced seizures in mice. Aminophylline (50-250 mg/kg) induced convulsions and mortality in mice in a dose-dependent manner. The anti-oxidants, melatonin (25-100 mg/kg) and N-actylcysteine (100 and 200 mg/kg) attenuated aminophylline seizures and mortality. Similar antagonism of aminophylline seizures was also observed after pretreatments with nitric oxide (NO) synthase inhibitors, L-NAME (3 and 10 mg/kg) and 7-nitroindazole (10 and 30 mg/kg). Further, combined treatment with otherwise sub-effective doses of melatonin and L-NAME or 7-nitroindazole produced marked protective effects against these seizures. Aminophylline-induced seizures enhanced malondialdehyde (MDA) concentrations and NO metabolite (NOx) levels in the brain homogenates of mice, and these were attenuated by melatonin and L-NAME pretreatments. The results are suggestive of the possible involvement of free radicals (reactive oxygen and reactive nitrogen species) in the convulsiogenic effects of aminophylline.