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Δ⁹-Tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult rats.

AbstractPURPOSE:
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.
AuthorsAndrew J Hill, Samantha E Weston, Nicholas A Jones, Imogen Smith, Sarah A Bevan, Elizabeth M Williamson, Gary J Stephens, Claire M Williams, Benjamin J Whalley
JournalEpilepsia (Epilepsia) Vol. 51 Issue 8 Pg. 1522-32 (Aug 2010) ISSN: 1528-1167 [Electronic] United States
PMID20196794 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightWiley Periodicals, Inc. © 2010 International League Against Epilepsy.
Chemical References
  • Phosphorus Isotopes
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • tetrahydrocannabivarin 9
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Dronabinol
  • Rimonabant
  • Pentylenetetrazole
Topics
  • Animals
  • Cerebral Cortex (drug effects, physiology)
  • Competitive Bidding (methods)
  • Disease Models, Animal
  • Dronabinol (analogs & derivatives, pharmacology, therapeutic use)
  • Drug Interactions
  • Epilepsy (chemically induced, drug therapy, 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, antagonists & inhibitors)
  • Rimonabant

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