Anticonvulsant effect of fisetin by modulation of endogenous biomarkers

Epilepsy is a group of disorders of the central nervous system (CNS) bearing its pathological origin in paroxysysmal cerebral dysrhythmia, clinically consisting episodes (seizure) of loss of consciousness. Fisetin is a tetrahydroxy flavone that possesses antiyperlipidemic, antioxidant, anti-inflammatory and antidiabetic potential. The aim of present investigation was to investigate the anticonvulsant activity of fisetin (5, 10 and 25 mg/kg) against pentylenetetrazole (PTZ), strychnine (STR), isoniazid (INH) and maximal electroshock (MES) induced convulsions in mice as well as electrical kindling seizures in rats. Diazepam and phenytoin were used as reference anticonvulsant drugs for comparison. Intraperitoneal administration of PTZ (90 mg/kg), strychnine (5 mg/kg) and isoniazid (300 mg/kg) resulted in hind limb, tonic-clonic convulsion along with lethality in mice, whereas twice daily auricular stimulation resulted progressive severity of seizures in rats. It also significantly altered levels of brain gamma amino butyric acid (GABA) along with nitric oxide (NO) and xanthine oxidase (XO) in mice. Treatment with fisetin (10 and 25 mg/kg) delayed onset of convulsion along with duration of tonic-clonic convulsions as well as it significantly reduced PTZ and STR-induced mortality in mice (P < 0.05 – P < 0.001). It also significantly (P < 0.001) reduced severity of electrically kindled seizures in rats and total number of rats seizure per group. Mice treated with fisetin (10 and 25 mg/kg) significantly increased level of brain GABA whereas it significantly decreased elevated level of brain NO and XO. In conclusion, the findings of present study provide pharmacological credence to anticonvulsant profile of fisetin. The protection against the convulsions and restoration of endogenous enzyme level give an innuendo to its probable mechanism of action which may be mediated through the GABAergic pathway and inhibition of oxidative injury.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Convulsions was produced by administration of pentylenetetrazole, strychnine, isoniazid in mice. ► Electric shocks of 21 mA for 0.1 sec produced kindling seizures in rats. ► Fisetin was administered at a dose of (5, 10 and 25 mg/kg, p.o.). ► Fisetin delayed onset of convulsion, decreased duration of tonic convulsion and mortality. ► Fisetin decreased seizure intensity. ► Fisetin produced significant increase in brain gamma amino butyric acid (GABA). ► Fisetin reduced brain nitric oxide and xanthine oxidase level. ► Fisetin dose dependently ameliorates convulsions and restored endogenous enzyme level.