9-Tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult rats

Abstract

Purpose: We assessed the anticonvulsant potential of the phytocannabinoid 9-tetrahydrocannabivarin (9-THCV) by investigating its effects in an in vitro piriform cortex (PC) brain slice model of epileptiform activity, on cannabinoid CB1 receptor radioligand-binding assays and in a generalized seizure model in rats. Methods: 9-THCV was applied before (10 m9-THCV) or during (10-50 m9-THCV) epileptiform activity induced by Mg2+-free extracellular media in adult rat PC slices and measured using multielectrode array (MEA) extracellular electrophysiologic techniques. The actions of 9-THCV on CB1 receptors were examined using [3H]SR141716A competition binding and [ 35S]GTPS assays in rat cortical membranes. Effects of 9-THCV (0.025-2.5 mgkg) on pentylenetetrazole (PTZ)-induced seizures in adult rats were also assessed. Results: After induction of stable spontaneous epileptiform activity, acute 9-THCV application (≥20 m) significantly reduced burst complex incidence and the amplitude and frequency of paroxysmal depolarizing shifts (PDSs). Furthermore, slices pretreated with 10 m9-THCV prior to induction of epileptiform activity exhibited significantly reduced burst complex incidence and PDS peak amplitude. In radioligand-binding experiments, 9-THCV acted as a CB1 receptor ligand, displacing 0.5 nm [3H]SR141716A with a Ki∼290 nm, but exerted no agonist stimulation of [35S]GTPS binding. In PTZ-induced seizures in vivo, 0.25 mgkg 9-THCV significantly reduced seizure incidence. Discussion: These data demonstrate that 9-THCV exerts antiepileptiform and anticonvulsant properties, actions that are consistent with a CB1 receptor-mediated mechanism and suggest possible therapeutic application in the treatment of pathophysiologic hyperexcitability states. © 2010 International League Against Epilepsy.