title: Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo.
abstract: Plant-derived cannabinoids (phytocannabinoids) are compounds with emerging therapeutic potential. Early studies suggested that cannabidiol (CBD) has anticonvulsant properties in animal models and reduced seizure frequency in limited human trials. Here, we examine the antiepileptiform and antiseizure potential of CBD using in vitro electrophysiology and an in vivo animal seizure model, respectively. CBD (0.01-100 muM) effects were assessed in vitro using the Mg(2+)-free and 4-aminopyridine (4-AP) models of epileptiform activity in hippocampal brain slices via multielectrode array recordings. In the Mg(2+)-free model, CBD decreased epileptiform local field potential (LFP) burst amplitude [in CA1 and dentate gyrus (DG) regions] and burst duration (in all regions) and increased burst frequency (in all regions). In the 4-AP model, CBD decreased LFP burst amplitude (in CA1 only at 100 muM CBD), burst duration (in CA3 and DG), and burst frequency (in all regions). CBD (1, 10, and 100 mg/kg) effects were also examined in vivo using the pentylenetetrazole model of generalized seizures. CBD (100 mg/kg) exerted clear anticonvulsant effects with significant decreases in incidence of severe seizures and mortality compared with vehicle-treated animals. Finally, CBD acted with only low affinity at cannabinoid CB(1) receptors and displayed no agonist activity in [(35)S]guanosine 5'-O-(3-thio)triphosphate assays in cortical membranes. These findings suggest that CBD acts, potentially in a CB(1) receptor-independent manner, to inhibit epileptiform activity in vitro and seizure severity in vivo. Thus, we demonstrate the potential of CBD as a novel antiepileptic drug in the unmet clinical need associated with generalized seizures.
authors.affiliation: School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AJ, UK.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Jones
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hill
authors.forename: Imogen
authors.initials: I
authors.lastname: Smith
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Bevan
authors.forename: Claire M
authors.initials: CM
authors.lastname: Williams
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Whalley
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Stephens
mesh_terms: D015761:4-Aminopyridine; D000200:Action Potentials / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D002185:Cannabidiol / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000819:agonists; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008274:Magnesium; D008297:Male; D010433:Pentylenetetrazole; D051381:Rats; D011921:Rats, Inbred WKY; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D000927:Anticonvulsants; D043884:Receptor, Cannabinoid, CB1; D002185:Cannabidiol; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D015761:4-Aminopyridine; D008274:Magnesium; D010433:Pentylenetetrazole