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      Inhibitory effects of cannabidiol on voltage-dependent sodium currents

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          Abstract

          Cannabis sativa contains many related compounds known as phytocannabinoids. The main psychoactive and nonpsychoactive compounds are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), respectively. Much of the evidence for clinical efficacy of CBD-mediated antiepileptic effects has been from case reports or smaller surveys. The mechanisms for CBD's anticonvulsant effects are unclear and likely involve noncannabinoid receptor pathways. CBD is reported to modulate several ion channels, including sodium channels (Nav). Evaluating the therapeutic mechanisms and safety of CBD demands a richer understanding of its interactions with central nervous system targets. Here, we used voltage-clamp electrophysiology of HEK-293 cells and iPSC neurons to characterize the effects of CBD on Nav channels. Our results show that CBD inhibits hNav1.1–1.7 currents, with an IC 50 of 1.9–3.8 μ m, suggesting that this inhibition could occur at therapeutically relevant concentrations. A steep Hill slope of ∼3 suggested multiple interactions of CBD with Nav channels. CBD exhibited resting-state blockade, became more potent at depolarized potentials, and also slowed recovery from inactivation, supporting the idea that CBD binding preferentially stabilizes inactivated Nav channel states. We also found that CBD inhibits other voltage-dependent currents from diverse channels, including bacterial homomeric Nav channel (NaChBac) and voltage-gated potassium channel subunit Kv2.1. Lastly, the CBD block of Nav was temperature-dependent, with potency increasing at lower temperatures. We conclude that CBD's mode of action likely involves 1) compound partitioning in lipid membranes, which alters membrane fluidity affecting gating, and 2) undetermined direct interactions with sodium and potassium channels, whose combined effects are loss of channel excitability.

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          Most cited references49

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          Protein structure homology modeling using SWISS-MODEL workspace.

          Homology modeling aims to build three-dimensional protein structure models using experimentally determined structures of related family members as templates. SWISS-MODEL workspace is an integrated Web-based modeling expert system. For a given target protein, a library of experimental protein structures is searched to identify suitable templates. On the basis of a sequence alignment between the target protein and the template structure, a three-dimensional model for the target protein is generated. Model quality assessment tools are used to estimate the reliability of the resulting models. Homology modeling is currently the most accurate computational method to generate reliable structural models and is routinely used in many biological applications. Typically, the computational effort for a modeling project is less than 2 h. However, this does not include the time required for visualization and interpretation of the model, which may vary depending on personal experience working with protein structures.
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            Currents carried by sodium and potassium ions through the membrane of the giant axon ofLoligo

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              The core Dravet syndrome phenotype.

              C Dravet (2011)
              Dravet syndrome was described in 1978 by Dravet (1978) under the name of severe myoclonic epilepsy in infancy (SMEI). The characteristics of the syndrome were confirmed and further delineated by other authors over the years. According to the semiologic features, two forms have been individualized: (1) the typical, core, SMEI; and (2) the borderline form, SMEIB, in which the myoclonic component is absent or subtle. Clinical manifestations at the onset, at the steady state, and during the course of the disease are analyzed in detail for the typical Dravet syndrome, and the differential diagnosis is discussed. Onset in the first year of life by febrile or afebrile clonic and tonic-clonic, generalized, and unilateral seizures, often prolonged, in an apparently normal infant is the first symptom, suggesting the diagnosis. Later on, multiple seizure types, mainly myoclonic, atypical absences, and focal seizures appear, as well as a slowing of developmental and cognitive skills, and the appearance of behavioral disorders. Mutation screening for the SCN1A gene confirms the diagnosis in 70-80% of patients. All seizure types are pharmacoresistent, but a trend toward less severe epilepsy and cognitive impairment is usually observed after the age of 5 years. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.
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                Author and article information

                Journal
                J Biol Chem
                J. Biol. Chem
                jbc
                jbc
                JBC
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology (11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A. )
                0021-9258
                1083-351X
                26 October 2018
                14 September 2018
                14 September 2018
                : 293
                : 43
                : 16546-16558
                Affiliations
                From the []Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada and
                the [§ ]Department of Cellular and Molecular Biology, Xenon Pharmaceuticals, Burnaby, British Columbia V5G 4W8, Canada
                Author notes
                [1 ] To whom correspondence should be addressed: Dept. of Cellular and Molecular Biology, Xenon Pharmaceuticals, 3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada. Tel.: 604-484-3300; E-mail: sgoodchild@ 123456xenon-pharma.com .

                Edited by Mike Shipston

                Author information
                https://orcid.org/0000-0002-2171-0744
                Article
                RA118.004929
                10.1074/jbc.RA118.004929
                6204917
                30219789
                0887afc5-4530-48ef-b4a9-5d6bd324c36c
                © 2018 Ghovanloo et al.

                Author's Choice—Final version open access under the terms of the Creative Commons CC-BY license.

                History
                : 17 July 2018
                : 12 September 2018
                Funding
                Funded by: Mitacs , open-funder-registry 10.13039/501100004489;
                Award ID: IT10714
                Categories
                Molecular Biophysics

                Biochemistry
                sodium channel,cannabinoid,neuron,electrophysiology,central nervous system (cns),cannabidiol,epilepsy,kv2.1,phytocannabinoid,voltage-gated sodium channel

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