Seizure-induced oxidative stress in rat brain regions: blockade by nNOS inhibition

Abstract

Free radicals have been implicated in the pathogenesis of various neurological disorders including epilepsy. Experimental seizures are often accompanied by the generation of free radicals that cause lipid peroxidation (LPO), which may subsequently cause neurodegeneration observed in certain types of human epilepsy. We recently reported a trigger role for nitric oxide (NO) derived by activation of neuronal isoform of nitric oxide synthase (nNOS) and that the action of conventional antiepileptic drugs (AEDs) was potentiated by inhibition of nNOS. In the present study, we extend our observations to understand the significance of blockade of the nNOS pathway on seizure-induced oxidative stress. Increased NO and LPO levels was observed at the time that corresponded to the onset of generalized seizures in rat brain regions following administration of GABA A receptor antagonist, picrotoxin (PCT). Treatment with the selective nNOS inhibitor, 7-nitroindazole (7-NI), decreased NO and LPO levels. The AEDs, diazepam and phenobarbitone also prevented seizure-induced increase in NO and LPO levels. Seizures resulted in a significant increase in the activity of antioxidant enzymes, superoxide dismutase in the frontal cortex and hippocampus. On the other hand, the activity of glutathione peroxidase was decreased in the hippocampus and midbrain. Whereas treatment with 7-NI could minimize the effects of PCT, the AEDs per se did not have any significant impact on the activity of the antioxidant enzymes, though co-treatment with 7-NI and AEDs could significantly decrease seizure-induced alterations in antioxidant enzyme activities. These observations suggest that the AEDs may not have a significant role in modulating the activities of antioxidant enzymes and that their ability to decrease LPO is realized more likely by their ability to prevent free radical formation. In conclusion, the present study demonstrates that NO contributes to LPO observed following seizures induced by PCT. The study also provides evidence for the ability of the AEDs to inhibit seizure-induced increase in LPO levels, the effect being enhanced by co-treatment with 7-NI suggesting that 7-NI and the AEDs together could prevent the neurotoxic cascade induced by oxidative stress.