A new mechanism for Cannabidiol in regulating the one‐carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models

Christopher J Perry; Paul Finch; Annette Muller-Taubenberger; Kit-Yi Leung; Eleanor C Warren; Joseph Damstra-Oddy; Devdutt Sharma; Pabitra H Patra; Sarah Glyn; Joanna Boberska; Balint Stewart; Amy Baldwin; Fabiana Piscitelli; Robert J Harvey; Adrian Harwood; Christopher Thompson; Sandrine Claus; Nicholas D E Greene; Alister McNeish; Claire M Williams; Benjamin J Whalley; Robin S B Williams

doi:10.1111/bph.14892

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A new mechanism for Cannabidiol in regulating the one‐carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models

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A new mechanism for Cannabidiol in regulating the one‐carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models

Christopher J Perry, Paul Finch, Annette Muller-Taubenberger, Kit-Yi Leung, Eleanor C Warren, Joseph Damstra-Oddy, Devdutt Sharma, Pabitra H Patra, Sarah Glyn, Joanna Boberska, …

British Journal of Pharmacology, Vol.177(4), pp.912-928

2020

DOI: https://doi.org/10.1111/bph.14892

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Abstract

cannabidiol

Dictyostelium discoideum

epilepsy

glycine cleavage system

one-carbon cycle

Background and Purpose: EpidiolexTM, a form of highly purified cannabidiol (CBD) derived from Cannabis plants has demonstrated seizure control activity in patients with Dravet syndrome, without a fully-elucidated mechanism of action. We have employed an unbiased approach to investigate this mechanism at a cellular level. Experimental Approach: We use a tractable biomedical model organism, Dictyostelium, to identify protein controlling the effect of CBD and characterize this mechanism. We then translate these results to a Dravet Syndrome mouse model and an acute in vitro seizure model. Key Results: CBD activity is partially dependent upon the mitochondrial glycine cleavage system component, GcvH1 in Dictyostelium, orthologous to the human GCSH protein, which is functionally linked to folate one-carbon metabolism (FOCM). Analysis of FOCM components identified a mechanism for CBD in directly inhibiting methionine synthesis. Analysis of brain tissue from a Dravet syndrome mouse model also showed drastically altered levels of one-carbon components including methionine, and an in vitro rat seizure model showed an elevated level of methionine that is attenuated following CBD treatment. Conclusions and Implications: Our results suggest a novel mechanism for CBD in the regulating methionine levels, and identify altered one-carbon metabolism in Dravet syndrome and seizure activity.

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Title: A new mechanism for Cannabidiol in regulating the one‐carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models
Authors: Christopher J Perry (Author) - Royal Holloway University of London
Paul Finch (Author) - Royal Holloway University of London
Annette Muller-Taubenberger (Author)
Kit-Yi Leung (Author) - UCL Great Ormond Street Institute of Child Health, United Kingdom
Eleanor C Warren (Author) - Royal Holloway University of London
Joseph Damstra-Oddy (Author) - Royal Holloway University of London
Devdutt Sharma (Author) - Royal Holloway University of London
Pabitra H Patra (Author) - University of Reading
Sarah Glyn (Author) - University of Reading
Joanna Boberska (Author) - University of Reading
Balint Stewart (Author) - University of Manchester
Amy Baldwin (Author) - Cardiff University
Fabiana Piscitelli (Author) - Consiglio Nazionale delle Ricerche, Italy
Robert J Harvey (Author) - University of the Sunshine Coast - School of Health & Sport Sciences
Adrian Harwood (Author) - Cardiff University
Christopher Thompson (Author) - University of Manchester
Sandrine Claus (Author) - University of Reading
Nicholas D E Greene (Author) - University of Reading
Alister McNeish (Author) - University of Reading
Claire M Williams (Author) - University of Reading
Benjamin J Whalley (Author) - University of Reading, United Kingdom
Robin S B Williams (Corresponding Author) - Royal Holloway University of London, United Kingdom
Publication details: British Journal of Pharmacology, Vol.177(4), pp.912-928
Publisher: John Wiley & Sons Ltd.
Date published: 2020
DOI: 10.1111/bph.14892
ISSN: 0007-1188
Copyright note: Copyright (c) 2020. This is the accepted version of the following article: Perry, CJ, Finch, P, Müller‐Taubenberger, A, et al. A new mechanism for cannabidiol in regulating the one‐carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models. Br J Pharmacol. 2020; 177: 912– 928, which has been published in final form at https://doi.org/10.1111/bph.14892
Organisation Unit: School of Health; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99450737902621
Output Type: Journal article

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