title: Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability.
abstract: Epilepsy is the most common neurological disorder, with over 50 million people worldwide affected. Recent evidence suggests that the transient receptor potential cation channel subfamily V member 1 (TRPV1) may contribute to the onset and progression of some forms of epilepsy. Since the two nonpsychotropic cannabinoids cannabidivarin (CBDV) and cannabidiol (CBD) exert anticonvulsant activity in vivo and produce TRPV1-mediated intracellular calcium elevation in vitro, we evaluated the effects of these two compounds on TRPV1 channel activation and desensitization and in an in vitro model of epileptiform activity. Patch clamp analysis in transfected HEK293 cells demonstrated that CBD and CBDV dose-dependently activate and rapidly desensitize TRPV1, as well as TRP channels of subfamily V type 2 (TRPV2) and subfamily A type 1 (TRPA1). TRPV1 and TRPV2 transcripts were shown to be expressed in rat hippocampal tissue. When tested on epileptiform neuronal spike activity in hippocampal brain slices exposed to a Mg(2+)-free solution using multielectrode arrays (MEAs), CBDV reduced both epileptiform burst amplitude and duration. The prototypical TRPV1 agonist, capsaicin, produced similar, although not identical effects. Capsaicin, but not CBDV, effects on burst amplitude were reversed by IRTX, a selective TRPV1 antagonist. These data suggest that CBDV antiepileptiform effects in the Mg(2+)-free model are not uniquely mediated via activation of TRPV1. However, TRPV1 was strongly phosphorylated (and hence likely sensitized) in Mg(2+)-free solution-treated hippocampal tissue, and both capsaicin and CBDV caused TRPV1 dephosphorylation, consistent with TRPV1 desensitization. We propose that CBDV effects on TRP channels should be studied further in different in vitro and in vivo models of epilepsy.
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry (ICB), National Council of Research (CNR) , 80078 Pozzuoli (NA) Italy.
authors.forename: Fabio Arturo
authors.initials: FA
authors.lastname: Iannotti
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Hill
authors.forename: Antonio
authors.initials: A
authors.lastname: Leo
authors.forename: Ahlam
authors.initials: A
authors.lastname: Alhusaini
authors.forename: Camille
authors.initials: C
authors.lastname: Soubrane
authors.forename: Enrico
authors.initials: E
authors.lastname: Mazzarella
authors.forename: Emilio
authors.initials: E
authors.lastname: Russo
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Whalley
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Stephens
mesh_terms: D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D008274:Magnesium / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects* / Q000235:genetics; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D051381:Rats; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: D002186:Cannabinoids; D004224:Diterpenes; C493466:Slc17a7 protein, rat; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels; C480976:Trpa1 protein, rat; C493922:Trpv1 protein, rat; C476722:Trpv2 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; C485184:enhanced green fluorescent protein; C468130:iodoresiniferatoxin; D049452:Green Fluorescent Proteins; D008274:Magnesium; D002211:Capsaicin
keywords: Cannabinoid; TRP channels; epilepsy; multi electrode arrays (MEAs); patch clamp