Xanthotoxin enhances the anticonvulsant potency of levetiracetam and valproate in the 6-Hz corneal stimulation model in mice

Xanthotoxin (8-methoxypsoralen; XANT) is a furanocoumarin which has many biological properties, including antiepileptic activity. This study evaluated the effect of XANT on the ability of classical and novel antiepileptic drugs to prevent seizures evoked by the 6-Hz corneal stimulation-induced seizure model, which is thought to be an experimental model of psychomotor (limbic) seizures in humans. XANT (50 mg/kg, administered i.p.) significantly potentiated the anticonvulsant activity of levetiracetam and valproate, decreasing their median effective dose (ED50 ) values from 19.37 to 2.83 mg/kg (P < 0.01) for levetiracetam and from 92.89 to 44.44 mg/kg (P < 0.05) for valproate. Neither XANT (50 mg/kg) alone nor its combination with the anticonvulsant drugs (at their ED50 values from the 6-Hz test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; and grip strength and passive avoidance tests, respectively. Measurement of total brain antiepileptic drug concentrations revealed that XANT (50 mg/kg) had no impact on levetiracetam total brain concentrations, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse 6 Hz model. However, XANT (50 mg/kg, i.p.) significantly increased total brain concentrations of valproate (P < 0.01), indicating the pharmacokinetic nature of interactions between drugs. XANT in combination with levetiracetam exerts beneficial anticonvulsant pharmacodynamic interactions in the 6 Hz mouse psychomotor seizure model.