Free radicals play a crucial role in health and disease and both
reactive oxygen species (ROS) and
reactive nitrogen species (RNS) have been implicated in CNS effects like excitotoxicity.
Theophylline, a re-emerging drug for the treatment of obstructive airway disease, has a narrow therapeutic index which precludes its safe use. The present study evaluated the possible involvement of
free radicals in
theophylline induced
seizures in mice.
Aminophylline (100-250 mg/kg) consistently induced
seizures and post-ictal mortality, and conventional
anticonvulsants and
adenosine agonists were ineffective in antagonizing them. Further,
phosphodiesterase inhibitors, per se, also did not show any significant seizurogenic potential. Pretreatments with
antioxidants,
ascorbic acid,
alpha-tocopherol and
melatonin, all dose dependently reduced seizure incidence and mortality after
aminophylline, whereas,
antioxidant depletion potentiated such excitotoxicity. Pretreatments with the
NO synthase inhibitors,
L-NAME and 7-NI blocked
aminophylline seizures, whereas, the NO mimetics,
L-arginine and
glyceryl trinitrate, tended to potentiate this phenomenon. Sub-effective doses of
aminophylline (100 mg/kg) also induced
seizures when combined with subthreshold intensity of electroshock, and such
seizures were similarly antagonized by the
antioxidants and
NO synthase inhibitors. Biochemical assay of brain homogenates showed that
aminophylline seizures were associated with enhancements in brain MDA and NOx (NO metabolites) levels, whereas, SOD activity was reduced, and these changes were attenuated after
melatonin and
L-NAME pretreatments. The pharmacological and biochemical data are strongly suggestive of the involvement of both ROS and RNS during
theophylline-induced
seizures.