Adjuvant neuronal nitric oxide synthase inhibition for combined treatment of epilepsy and comorbid depression.

BACKGROUND

Elevated nitric oxide (NO) levels in the brain have been apparently associated with depression in kindled animals. Owing to the major role of neuronal nitric oxide synthase (nNOS) in brain and ineffectiveness of antiepileptic drugs (AEDs) in restoring nitrosative stress, the present study was envisaged to evaluate the adjuvant nNOS inhibitor, 7-nitroindazole (7-NI) with valproic acid for combined treatment of epilepsy and associated depression.

METHODS

Pentylenetetrazole kindled animals associated with depression were treated with vehicle, valproate (300mg/kg/day ip), valproate with 7-NI (10mg/kg; 20mg/kg; 40mg/kg)/day ip and 7-NI (40mg/kg/day ip) for 15days. Except naïve, all groups were challenged with pentylenetetrazole (35mg/kg ip) on days 5, 10, and 15 to evaluate seizure severity. Depression was evaluated in all experimental groups using the tail suspension and forced swim test on days 1, 5, 10 and 15. On day 15, biochemical (corticosterone levels) and neurochemical (serotonin, kynurenine, tryptophan, glutamate, GABA, nitrite levels) estimations were carried out in cortical and hippocampal area of mice brain.

RESULTS

Vehicle treated kindled animals were significantly associated with depression. Chronic valproate treatment in kindled animals significantly reduced seizure severity, but could not reverse associated depression. 7-NI per se treatment in kindled animals was also reported unable to restore the associated depression completely. However, 7-NI supplementation with valproate significantly reduced seizure severity score and completely ameliorated depression with restoration of altered biochemical and neurochemical milieu.

CONCLUSION

Adjuvant nNOS inhibition can be previewed as safe therapy with AEDs for the combined management of epilepsy and associated depression.