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Br J Pharmacol. 2019 Nov 6. doi: 10.1111/bph.14892. [Epub ahead of print]

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

Author information

1
Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham, Surrey, TW20 0EX.
2
Department of Cell Biology, Biomedical Center, LMU Munich, 82152 Planegg-, Martinsried, Germany.
3
Development Biology and Cancer Program, UCL Great Ormond Street Institute of Child Health.
4
The School of Chemistry, Food Biosciences & Pharmacy, University of Reading, Reading, RG6 6UR.
5
Faculty of Life Sciences, Manchester University, Manchester, M13 9PL.
6
Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, CF24 4HQ.
7
Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Italy.
8
School of Health and Sport Sciences, University of the Sunshine Coast, Sippy Downs, QLD.
9
Sunshine Coast Health Institute, Birtinya, QLD, Australia.

Abstract

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.

KEYWORDS:

Dictyostelium discoideum; cannabidiol; epilepsy; glycine cleavage system; one-carbon cycle

PMID:
31693171
DOI:
10.1111/bph.14892

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