A new mechanism for cannabidiol in regulating the one‐carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models. (3rd January 2020)

• Record Type: Journal Article
• Authors: Perry, Christopher J.; Finch, Paul; Müller‐Taubenberger, Annette; Leung, Kit‐Yi; Warren, Eleanor C.; Damstra‐Oddy, Joseph; Sharma, Devdutt; Patra, Pabitra H.; Glyn, Sarah; Boberska, Joanna; Stewart, Balint; Baldwin, Amy; Piscitelli, Fabiana; Harvey, Robert J.; Harwood, Adrian; Thompson, Christopher; Claus, Sandrine P.; Greene, Nicholas D.E.; McNeish, Alister J.; Williams, Claire M.; Whalley, Benjamin J.; Williams, Robin S.B.
• Is Part Of: British journal of pharmacology. Volume 177:Number 4(2020)
• Page Start: 912
• Page End: 928
• Publication Date: 2020-01-03
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.14892
• Languages: English
• ISSNs: 0007-1188

Abstract

Abstract : 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.