Abstracts

Rationale: To evaluate interaction of WIN 55,212-2 mesylate (WIN - a potent non-selective cannabinoid receptor agonist) with four classical antiepileptic drugs (AEDs), clonazepam, ethosuximide, phenobarital, and valproate in the mouse pentylenetetrazole-induced seizure model. Methods: Clonic phase of pentylenetetrazole-induced convulsions was taken as the endpoint for the occurrence of seizure activity. Total brain concentrations of AEDs were measured by immunofluorescence. The experimental procedures were approved by the Local Ethics Committee at the Medical University of Lublin. Results: In the dose range of 5-15 mg/kg, WIN given intraperitoneally 20 min prior to the convulsive test, did not affect the convulsive threshold to pentylenetetrazole. When administered at 15 mg/kg in combinations with intraperitoneal AEDs, WIN enhanced the protective activity of ethosuximide, phenobarbital, and valproate, reducing their ED50 values against pentylenetetrazole (85 mg/kg subcutaneously) from 148, 13,9, and 137 mg/kg to 104, 8.3, and 85.6 mg/kg, respectively. At lower doses of 5-10 mg/kg, WIN was without effect upon the anticonvulsant action of classical AEDs. Pharmacokinetic estimations revealed that WIN (15 mg/kg) significantly elevated the total brain concentrations of ethosuximide and valproate, by 26 and 50%, respectively. Conclusions: Out of four combined treatments of WIN with AEDs, three were encouraging. However, only that with phenobarbital was pharmacodynamic in nature. This study was supported by the grant Mistrz awarded by the Polish Science Foundation (Warszawa, Poland).