Δ⁹-Tetrahydrocannabivarin Suppresses in Vitro Epileptiform and in Vivo Seizure Activity in Adult Rats

Epilepsia. 2010 Aug;51(8):1522-32. doi: 10.1111/j.1528-1167.2010.02523.x. Epub 2010 Feb 26.

Abstract

Purpose: We assessed the anticonvulsant potential of the phytocannabinoid Δ⁹-tetrahydrocannabivarin (Δ⁹-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: Δ⁹-THCV was applied before (10 μm Δ⁹-THCV) or during (10-50 μm Δ⁹-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 Δ⁹-THCV on CB1 receptors were examined using [³H]SR141716A competition binding and [³⁵S]GTPγS assays in rat cortical membranes. Effects of Δ⁹-HCV (0.025-2.5 mg/kg) on pentylenetetrazole (PTZ)-induced seizures in adult rats were also assessed.

Results: After induction of stable spontaneous epileptiform activity, acute Δ⁹ -THCV application (≥ 20 μm) significantly reduced burst complex incidence and the amplitude and frequency of paroxysmal depolarizing shifts (PDSs). Furthermore, slices pretreated with 10 μm Δ⁹-THCV prior to induction of epileptiform activity exhibited significantly reduced burst complex incidence and PDS peak amplitude. In radioligand-binding experiments, Δ⁹-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]GTPγS binding. In PTZ-induced seizures in vivo, 0.25 mg/kg Δ⁹-THCV significantly reduced seizure incidence.

Discussion: These data demonstrate that Δ⁹-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / physiology
  • Competitive Bidding / methods
  • Disease Models, Animal
  • Dronabinol / analogs & derivatives*
  • Dronabinol / pharmacology
  • Dronabinol / therapeutic use
  • Drug Interactions
  • Epilepsy / chemically induced
  • Epilepsy / drug therapy*
  • Epilepsy / physiopathology*
  • Evoked Potentials / drug effects*
  • Female
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • In Vitro Techniques
  • Male
  • Pentylenetetrazole
  • Phosphorus Isotopes / metabolism
  • Piperidines / pharmacokinetics
  • Pyrazoles / pharmacokinetics
  • Rats
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Rimonabant

Substances

  • Phosphorus Isotopes
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • tetrahydrocannabivarin 9
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Dronabinol
  • Rimonabant
  • Pentylenetetrazole