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.
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Authors | Andrew 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 |
Journal | Epilepsia
(Epilepsia)
Vol. 51
Issue 8
Pg. 1522-32
(Aug 2010)
ISSN: 1528-1167 [Electronic] United States |
PMID | 20196794
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Wiley 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
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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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