Anticonvulsive Properties of Cannabidiol in a Model of Generalized Seizure Are Transient Receptor Potential Vanilloid 1 Dependent.
| Autor: | Gray RA; GW Research Ltd., Cambridge, United Kingdom., Stott CG; GW Pharma Ltd., Cambridge, United Kingdom., Jones NA; GW Research Ltd., Cambridge, United Kingdom., Di Marzo V; Endocannabinoid Research Group, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), Pozzuoli, Italy.; Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Faculty of Medicine and Faculty of Agricultural and Food Sciences, Université Laval, Québec City, Canada., Whalley BJ; GW Research Ltd., Cambridge, United Kingdom.; School of Chemistry, Food and Nutritional Sciences, and Pharmacy, University of Reading, Reading, Berkshire, United Kingdom. |
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| Jazyk: | angličtina |
| Zdroj: | Cannabis and cannabinoid research [Cannabis Cannabinoid Res] 2020 Jun 05; Vol. 5 (2), pp. 145-149. Date of Electronic Publication: 2020 Jun 05 (Print Publication: 2020). |
| DOI: | 10.1089/can.2019.0028 |
| Abstrakt: | Introduction: Highly purified cannabidiol (CBD) (approved as Epidiolex ® in the United States) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut or Dravet syndrome in four randomized controlled trials. CBD possesses affinity for many target classes with functional effects relevant to the pathophysiology of many disease types, including epilepsy. Although the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, transient receptor potential vanilloid 1 (TRPV1) represents a plausible target because (1) CBD activates and then desensitizes TRPV1, (2) TRPV1 is overexpressed in models of temporal lobe epilepsy and patients with epilepsy, (3) and TRPV1 modulates neuronal excitability. Methods: To investigate a potential role of TRPV1 in the anticonvulsive effects of CBD, the effect of CBD on seizure threshold was assessed using a mouse maximal electroshock threshold model of generalized seizure in TRPV1 knockout and wildtype mice. The dose dependence of the CBD effect was determined and compared with that of the positive comparator diazepam and vehicle. Results: At 50 and 100 mg/kg, CBD significantly ( p <0.0001) increased seizure threshold in wildtype mice compared with TRPV1 knockout and vehicle controls. This effect was observed only at 100 mg/kg in TRPV1 knockout mice compared with knockout vehicle mice, in which gene deletion partially attenuated the CBD-increased seizure threshold. The effect of high-dose CBD in wildtype mice was nevertheless significantly different from vehicle-treated TRPV1 knockout mice ( p <0.0001). Bioanalysis confirmed that genotype-specific differential brain exposure to CBD was not responsible for the observed effect on seizure threshold. Conclusion: These data strongly implicate TRPV1 in the potential mechanisms of action for the anticonvulsive effects of CBD. The partial inhibition of the anticonvulsive effect of high-dose CBD in TRPV1 knockout mice may indicate the involvement of targets other than TRPV1. Further characterization of TRPV1 in the anticonvulsive effect of CBD in validated models of seizure is warranted, as is pharmacological investigation of the molecular interaction between CBD and TRPV1. Competing Interests: All authors met the ICMJE authorship criteria. Neither honoraria nor payments were made for authorship. R.A.G., C.G.S., N.A.J., and B.J.W. are employees of GW Research Ltd. and stock shareholders of GW Pharmaceuticals plc. V.D.M. receives research grants from, and is a consultant for, GW Research Ltd. (© Royston A. Gray et al. 2019; Published by Mary Ann Liebert, Inc.) |
| Databáze: | MEDLINE |
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