Abstracts

Rationale: To determine the effect of WIN 55,212-2 mesylate (WIN - a highly potent cannabinoid CB1 and CB2 receptor agonist) on the protective activity of four classical antiepileptic drugs (AEDs: carbamazepine, phenytoin, phenobarbital and valproate) in the mouse maximal electroshock (MES)-induced seizure model. Methods: Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain AED concentrations. The experimental protocols and procedures performed in this study were approved by the Local Ethics Committee at the Medical University of Lublin (Poland). Results: WIN administered intraperitoneally at a dose of 15 mg/kg at 20 min. before electroconvulsions significantly elevated the threshold for electroconvulsions, while WIN at lower doses of 5 and 10 mg/kg had no impact on this effect in mice. In the mouse MES model, WIN administered at a dose of 10 mg/kg significantly potentiated the anticonvulsant action of carbamazepine, phenytoin, phenobarbital and valproate. Moreover, WIN at a dose of 5 mg/kg enhanced the protective action of carbamazepine and valproate, but not that of phenytoin and phenobarbital against MES-induced seizures in mice. Evaluation of acute adverse effects in animals, receiving WIN alone and in combination with classical AEDs at doses from the MES test, revealed that WIN at a dose of 10 mg/kg administered alone significantly reduced skeletal muscular strength in the tested mice. Similarly, all combinations of WIN with classical AEDs at doses from the MES test considerably reduced skeletal muscular strength in the tested animals. In the chimney test, WIN combined with phenobarbital and valproate, but not with phenytoin and carbamazepine, significantly impaired motor coordination in the experimental animals. Moreover, the combinations of WIN with phenobarbital, phenytoin and valproate significantly disturbed long-term memory in mice challenged with the passive avoidance task. Pharmacokinetic study revealed that WIN did not alter total brain AED concentrations and thus, all the observed interactions between WIN and four classical AEDs in the mouse MES model were pharmacodynamic in nature. Conclusions: The combinations of WIN with carbamazepine, phenytoin, phenobarbital and valproate exerted favorable interactions with respect to seizure suppression in the mouse MES model, although these combinations were associated with acute adverse effects in experimental animals. This study was supported by a MISTRZ grant from the Foundation for Polish Science (Warszawa, Poland).