Abstracts

Rationale: To determine the effect of ACEA (a highly selective cannabinoid CB1 receptor agonist) on the protective activity of four classical antiepileptic drugs (AEDs: clonazepam, ethosuximide, phenobarbital and valproate) in the mouse pentylenetetrazole (PTZ)-induced clonic seizure model. Methods: Clonic convulsions (seizure activity) were evoked in adult male albino Swiss mice by a subcutaneous administration of PTZ at a dose of 98 mg/kg. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug 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: ACEA administered intraperitoneally at doses up to 5 mg/kg at 10 min. before the PTZ test had no impact on the threshold for PTZ-induced clonic seizure in mice. In the mouse PTZ-induced clonic seizure model, ACEA administered at a dose of 5 mg/kg significantly enhanced the anticonvulsant action of valproate. In contrast, ACEA at a dose of 5 mg/kg did not affect the protective action of clonazepam, ethosuximide or phenobarbital against PTZ-induced clonic seizures in mice. Evaluation of acute adverse effects in animals, receiving ACEA alone and in combination with classical AEDs at doses from the PTZ test, revealed that ACEA (5 mg/kg) concomitantly administered with classical AEDs significantly reduced skeletal muscular strength in the tested mice. In the chimney test, ACEA combined with phenobarbital and valproate, but not with clonazepam or ethosuximide, significantly impaired motor coordination in the tested animals. Moreover, the combinations of ACEA with ethosuximide, phenobarbital and valproate significantly disturbed long-term memory in the mice challenged with the passive avoidance task. Pharmacokinetic study revealed that only the combination of ACEA with ethosuximide was complicated by a significant increase in total brain concentration of the later AED, while the interactions of ACEA with clonazepam, phenobarbital and valproate in the mouse PTZ model were pharmacodynamic in nature. Conclusions: The advantageous combination of ACEA with valproate deserves a special attention from a preclinical point of view, due to significant seizure suppression and pharmacodynamic interaction between the drugs. This study was supported by a MISTRZ grant from the Foundation for Polish Science (Warszawa, Poland).