Effects of WIN 55,212-2 mesylate (a synthetic cannabinoid) on the protective action of clonazepam, ethosuximide, phenobarbital and valproate against pentylenetetrazole-induced clonic seizures in mice

The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four classical antiepileptic drugs (AEDs: clonazepam [CZP], ethosuximide [M], phenobarbital [PB], and valproate [VPA]) in the mouse pentylenetetrazole (PTZ)-induced clonic seizure model. WIN (15 mg/kg, i.p.) significantly enhanced the anticonvulsant action of ETS, PB and VPA, but not that of CZP against PTZ-induced clonic seizures. The ED50 values of ETS, PB and VPA were reduced from 148.0, 13.9 and 137.1 mg/kg to 104.0, 8.3 and 85.6 mg/kg, respectively (P<0.05). WIN (5 and 10 mg/kg, i.p.) had no impact on the anticonvulsant action of all studied AEDs against PTZ-induced clonic seizures. WIN (15 mg/kg, i.p.) significantly elevated total brain concentrations of ETS and VPA, but not those of CZP and PB in mice. Moreover, WIN combined with CZP, ETS, PB and VPA significantly impaired motor performance, long-term memory and muscular strength in mice subjected to the chimney, passive avoidance and grip-strength tests, respectively. Pharmacodynamic enhancement of the anticonvulsant action of PB by WIN against VIZ-induced clonic seizures is favorable from a preclinical viewpoint. Advantageous effects of WIN in combination with ETS and VPA against PTZ-induced seizures were pharmacokinetic in nature. However, WIN combined with CZP, ETS, PB and VPA impaired motor coordination and long-term memory as well as reduced skeletal muscular strength in the experimental animals. (C) 2011 Elsevier Inc. All rights reserved.