Jacob Bell
New Member
Nicholas A. Jones,
Andrew J. Hill,
Imogen Smith,
Sarah A. Bevan,
Claire M. Williams,
Benjamin J. Whalley and
Gary J. Stephens
- Author Affiliations
School of Pharmacy (N.A.J., A.J.H., I.S., S.A.B., B.J.W., G.J.S.) and School of Psychology (N.A.J., A.J.H., C.M.W.), University of Reading, Whiteknights, Reading, United Kingdom
Address correspondence to:
Dr. Gary Stephens,
School of Pharmacy, University of Reading, Whiteknights, P.O. Box 228, Reading RG6 6AJ, UK.
E-mail: g.j.stephens@reading.ac.uk
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 μM) effects were assessed in vitro using the Mg2+-free and 4-aminopyridine (4-AP) models of epileptiform activity in hippocampal brain slices via multielectrode array recordings. In the Mg2+-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 μM 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 CB1 receptors and displayed no agonist activity in [35S]guanosine 5′-O-(3-thio)triphosphate assays in cortical membranes. These findings suggest that CBD acts, potentially in a CB1 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.
Footnotes
This work was supported by a GW Pharmaceuticals and Otsuka Pharmaceuticals award, by a University of Reading Research Endowment Trust Fund award; and The Wellcome Trust [Grant 070739].
Article, publication date, and citation information can be found at Journal of Pharmacology and Experimental Therapeutics.
doi:10.1124/jpet.109.159145
↵Graphic The online version of this article (available at Journal of Pharmacology and Experimental Therapeutics) contains supplemental material.
ABBREVIATIONS:
CNS
central nervous system
CB
cannabinoid
eCB
endocannabinoid
Δ9-THC
Δ9-tetrahydrocannabinol
CBD
cannabidiol
AED
antiepileptic drug
MEA
multielectrode array
aCSF
artificial cerebrospinal fluid
4-AP
4-aminopyridine
LFP
local field potential
NMDA
N-methyl-d-aspartate
BSA
bovine serum albumin
SR141716A
N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide
AM251
N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide
GTPγS
guanosine 5′-O-(3-thio)triphosphate
WIN55,212-2
[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone
PTZ
pentylenetetrazole.
Received July 22, 2009.
Accepted November 9, 2009.
Source: Cannabidiol Displays Antiepileptiform and Antiseizure Properties In Vitro and In Vivo
Andrew J. Hill,
Imogen Smith,
Sarah A. Bevan,
Claire M. Williams,
Benjamin J. Whalley and
Gary J. Stephens
- Author Affiliations
School of Pharmacy (N.A.J., A.J.H., I.S., S.A.B., B.J.W., G.J.S.) and School of Psychology (N.A.J., A.J.H., C.M.W.), University of Reading, Whiteknights, Reading, United Kingdom
Address correspondence to:
Dr. Gary Stephens,
School of Pharmacy, University of Reading, Whiteknights, P.O. Box 228, Reading RG6 6AJ, UK.
E-mail: g.j.stephens@reading.ac.uk
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 μM) effects were assessed in vitro using the Mg2+-free and 4-aminopyridine (4-AP) models of epileptiform activity in hippocampal brain slices via multielectrode array recordings. In the Mg2+-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 μM 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 CB1 receptors and displayed no agonist activity in [35S]guanosine 5′-O-(3-thio)triphosphate assays in cortical membranes. These findings suggest that CBD acts, potentially in a CB1 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.
Footnotes
This work was supported by a GW Pharmaceuticals and Otsuka Pharmaceuticals award, by a University of Reading Research Endowment Trust Fund award; and The Wellcome Trust [Grant 070739].
Article, publication date, and citation information can be found at Journal of Pharmacology and Experimental Therapeutics.
doi:10.1124/jpet.109.159145
↵Graphic The online version of this article (available at Journal of Pharmacology and Experimental Therapeutics) contains supplemental material.
ABBREVIATIONS:
CNS
central nervous system
CB
cannabinoid
eCB
endocannabinoid
Δ9-THC
Δ9-tetrahydrocannabinol
CBD
cannabidiol
AED
antiepileptic drug
MEA
multielectrode array
aCSF
artificial cerebrospinal fluid
4-AP
4-aminopyridine
LFP
local field potential
NMDA
N-methyl-d-aspartate
BSA
bovine serum albumin
SR141716A
N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide
AM251
N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide
GTPγS
guanosine 5′-O-(3-thio)triphosphate
WIN55,212-2
[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone
PTZ
pentylenetetrazole.
Received July 22, 2009.
Accepted November 9, 2009.
Source: Cannabidiol Displays Antiepileptiform and Antiseizure Properties In Vitro and In Vivo
