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 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
URI	https://reading-clone.eprints-hosting.org/id/eprint/86405
Identification Number/DOI	10.1111/bph.14892
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
Publisher	Wiley
Download/View statistics	View download statistics for this item