Abstract
Accumulating evidence indicates that cannabinoid CB1 receptor ligands play a pivotal role in seizures, not only in preclinical studies on animals, but also in clinical settings. This study was aimed at characterizing the influence of arachidonyl-2′-chloroethylamide (ACEA–a selective cannabinoid CB1 receptor agonist) co-administered with phenylmethylsulfonyl fluoride (PMSF) on the anticonvulsant potency of various antiepileptic drugs (clobazam, lacosamide, levetiracetam, phenobarbital, tiagabine and valproate) in the 6-Hz corneal stimulation model. Psychomotor seizures in male albino Swiss mice were evoked by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via corneal electrodes. Potential adverse effects produced by the antiepileptic drugs in combination with ACEA+PMSF were assessed using the chimney test (motor performance), passive avoidance task (remembering and acquisition of learning), and grip-strength test (muscular strength). Brain concentrations of antiepileptic drugs were measured by HPLC to exclude any pharmacokinetic contribution to the observed effect. ACEA (5 mg/kg, i.p.) + PMSF (30 mg/kg, i.p.) significantly potentiated the anticonvulsant potency of levetiracetam (P<0.05), but not that of clobazam, lacosamide, phenobarbital, tiagabine or valproate in the 6-Hz corneal stimulation model. Moreover, ACEA+PMSF did not significantly affect total brain concentrations of levetiracetam in mice. No behavioral side effects were observed in animals receiving combinations of the studied antiepileptic drugs with ACEA+PMSF. In conclusion, the combined administration of ACEA+PMSF with levetiracetam is associated with beneficial anticonvulsant pharmacodynamic interaction in the 6-Hz corneal stimulation model. The selective activation of cannabinoid CB1 receptor-mediated neurotransmission in the brain may enhance levetiracetam-related suppression of seizures in epilepsy patients, contributing to the efficacious treatment of epilepsy in future.
Highlights
Despite major advances in the treatment of epilepsy and the availability of a wide range of antiepileptic drugs, there is still more than 30% of patients who still suffer from seizures because of inadequate selection of the antiepileptic drugs to monotherapy [1, 2]
When animals receiving the cannabinoid receptor CB1 agonist (ACEA) (5 mg/kg) was administered systemically (i.p.) in combination with phenylmethylsulfonyl fluoride (PMSF) (30 mg/kg), they significantly potentiated the anticonvulsant potency of levetiracetam in the 6-Hz corneal stimulation model, by lowering the ED50 of levetiracetam by 48% (F(3,92) = 4.812, p = 0.0037; Fig 1F)
We found that ACEA (5 mg/kg) co-administered with PMSF (30 mg/kg) significantly potentiated the anticonvulsant action of levetiracetam in mice subjected to the 6-Hz corneal stimulation model
Summary
Despite major advances in the treatment of epilepsy and the availability of a wide range of antiepileptic drugs, there is still more than 30% of patients who still suffer from seizures because of inadequate selection of the antiepileptic drugs to monotherapy [1, 2]. These refractory patients require novel therapeutic and more efficacious strategies involving combined administration of two or even more antiepileptic drugs in order to suppress seizures and improve their quality of living [3, 4]. There is a strong need to look for cannabimimetic substances which would offer antiseizure properties and no harmful side effects
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