Accessibility navigation


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

Perry, C. J., Finch, P., Muller-Taubenberger, A., Leung, K.-Y., Warren, E. C., Damstra-Oddy, J., Sharma, D., Patra, P. H., Glyn, S., Boberska, J., Stewart, B., Baldwin, A., Piscitelli, F., Harvey, R. J., Harwood, A., Thompson, C., Claus, S. P., Greene, N. D. E., McNeish, A. J., Williams, C. M. ORCID: https://orcid.org/0000-0003-4452-671X , Whalley, B. J. and Williams, R. S. B. (2020) A new mechanism for Cannabidiol in regulating the one-carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models. British Journal of Pharmacology, 177 (4). pp. 912-928. ISSN 0007-1188

[img]
Preview
Text (Open access) - Published Version
· Available under License Creative Commons Attribution.
· Please see our End User Agreement before downloading.

6MB
[img] Text - Accepted Version
· Restricted to Repository staff only

1MB

It is advisable to refer to the publisher's version if you intend to cite from this work. See Guidance on citing.

To link to this item DOI: 10.1111/bph.14892

Abstract/Summary

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 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. voltage-dependent anion selective channel proteins, VDAC1.

Item Type:Article
Refereed:Yes
Divisions:Interdisciplinary Research Centres (IDRCs) > Centre for Integrative Neuroscience and Neurodynamics (CINN)
Life Sciences > School of Psychology and Clinical Language Sciences > Department of Psychology
Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
ID Code:86405
Publisher:Wiley

Downloads

Downloads per month over past year

University Staff: Request a correction | Centaur Editors: Update this record

Page navigation