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


CONCLUSIONS
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.
Hill
Andrew J
AJ
School of Pharmacy, University of Reading, Whiteknights, Reading, Berkshire, UK.
Weston
Samantha E
SE
Jones
Nicholas A
NA
Smith
Imogen
I
Bevan
Sarah A
SA
Williamson
Elizabeth M
EM
Stephens
Gary J
GJ
Williams
Claire M
CM
Whalley
Benjamin J
BJ
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D003164:Competitive Bidding / Q000379:methods; D004195:Disease Models, Animal; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004347:Drug Interactions; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D005071:Evoked Potentials / Q000187:drug effects*; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D010433:Pentylenetetrazole; D010759:Phosphorus Isotopes / Q000378:metabolism; D010880:Piperidines / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000493:pharmacokinetics; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors; D000077285:Rimonabant
D010759:Phosphorus Isotopes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C003403:tetrahydrocannabivarin 9; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013759:Dronabinol; D000077285:Rimonabant; D010433:Pentylenetetrazole