Ficus religiosa L. figs - A potential herbal adjuvant to phenytoin for improved management of epilepsy and associated behavioral comorbidities

- Flavonoidal fraction of Ficus religiosa fruits possesses in vitro antioxidant activity.
- Phenytoin only at sub-effective dose (15 mg/kg; i.p.) was found to be ineffective in treating seizure severity while it augmented epilepsy-induced memory impairment.
- Flavonoid-rich fraction of Ficus religiosa in combination with sub-effective dose of phenytoin showed significant protection against seizures, epilepsy-induced cognition deficit, and depressive behavior in kindled animals.
- Flavonoid-rich fraction of Ficus religiosa in combination with sub-effective dose of phenytoin reduced oxidative stress, showed by decreased TBARS and increased GSH and CAT levels, indicating that protection was due to antioxidant effects.
- Flavonoid-rich fraction of Ficus religiosa in combination with sub-effective dose of phenytoin reduced AChE activity, responsible for its memory enhancing effect.

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 comparison with 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 along with 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 along with antiepileptic drugs (AEDs) for management of epilepsy and its psychiatric and cognitive comorbidities.