Oxidative stress, together with mitochondrial dysfunction, has been reported to be involved in the pathogenesis
of epileptogenesis and its associated comorbidities. Phytoflavonoids have shown numerous beneficial ameliorative
effects on different neurological disorders by virtue of their antioxidant effect. The present study investigated
the effect of flavonoid-rich ethyl acetate fraction of the crude fig extract of Ficus religiosa in combination with
phenytoin on seizure severity, depressive behavior, and cognitive deficit in pentylenetetrazol (PTZ)-kindled
mice. The flavonoid-rich ethyl acetate fraction of the crude fig extract was found to show significant antioxidant
potential in various in vitro free radical scavenging assays. Combined treatment of this fraction (2.5, 5, and
10 mg/kg; i.p.) along with a subeffective dose of phenytoin (15 mg/kg; i.p.) in postkindled animals once daily
for fifteen days showed a dose-dependent decrease in the seizure severity score, a decreased number of mistakes,
increased step-down latency in passive shock avoidance paradigm, and decreased immobility time in the tail suspension
test in comparisonwith the phenytoin only-treated group. Biochemical investigations of the brain tissue
showed amelioration of thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) levels, and
reduced catalase and acetylcholinesterase (AChE) activities, thereby indicating suppression of oxidative stress.
In conclusion, the results of the present study showed the protective effect of the flavonoid-rich fraction of
F. religiosa alongwith a subeffective dose of phenytoin in PTZ-kindling-associated cognitive deficit and depressive
behavior with complete suppression of seizures through reduction of oxidative stress, supporting the the need
for clinical evaluation of the supplementation of phytoflavonoids alongwith antiepileptic drugs (AEDs) for management
of epilepsy and its psychiatric and cognitive comorbidities.