A new mechanism for cannabidiol in regulating the one-carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models.
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
24
04
2019
revised:
06
09
2019
accepted:
17
09
2019
pubmed:
7
11
2019
medline:
22
6
2021
entrez:
7
11
2019
Statut:
ppublish
Résumé
Epidiolex™, 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. We use a tractable biomedical model organism, Dictyostelium, to identify a 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. CBD activity is partially dependent upon the mitochondrial glycine cleavage system component, GcvH1 in Dictyostelium, orthologous to the human glycine cleavage system component H 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. 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.
Sections du résumé
BACKGROUND AND PURPOSE
Epidiolex™, 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 a 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 glycine cleavage system component H 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.
Identifiants
pubmed: 31693171
doi: 10.1111/bph.14892
pmc: PMC7024701
doi:
Substances chimiques
Anticonvulsants
0
Cannabidiol
19GBJ60SN5
Methionine
AE28F7PNPL
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
912-928Subventions
Organisme : GW Pharmaceuticals Ltd
Pays : International
Organisme : Action Medical Research
ID : GN2403
Pays : International
Organisme : Biotechnology and Biological Sciences Research Council
Pays : United Kingdom
Organisme : Bioimaging core facility
Pays : International
Organisme : GW Research Ltd
Pays : International
Organisme : Great Ormond Street Hospital Children's Charity
Pays : International
Organisme : Medical Research Council
ID : MR/N003713/1
Pays : United Kingdom
Organisme : University of Reading
Pays : International
Organisme : Medical Research Council
ID : N003713
Pays : United Kingdom
Organisme : National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London
Pays : International
Informations de copyright
© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
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