Abstract

Background and PurposeEpidiolex™, 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 ApproachWe 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 ResultsCBD 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 ImplicationsOur results suggest a novel mechanism for CBD in the regulating methionine levels and identify altered one‐carbon metabolism in Dravet syndrome and seizure activity.

Highlights

  • The use of Cannabis extracts as a medicinal treatment has been recorded for nearly 2,000 years (BRAND & ZHAO, 2017), covering a range of disorders including pain management, multiple sclerosis, and epilepsy (Devinsky et al, 2014)

  • We investigated potential mechanisms underlying the molecular function of CBD using D. discoideum as a tractable 3Rs model organism that has been used in a range of other pharmacogenetic studies including those focused on epilepsy (Chang et al, 2012; Kelly et al, 2018; Warren et al, 2018)

  • Using this model enabled the identification of a mechanism for CBD dependent upon the mitochondrial glycine cleavage system (GCS) protein, Dictyostelium glycine cleavage system component H1 (GCVH1), a component of folate onecarbon metabolism (FOCM), where this role that is conserved with the human orthologue (GCSH)

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Summary

| INTRODUCTION

The use of Cannabis extracts as a medicinal treatment has been recorded for nearly 2,000 years (BRAND & ZHAO, 2017), covering a range of disorders including pain management, multiple sclerosis, and epilepsy (Devinsky et al, 2014). Using D. discoideum, insertional mutant libraries have been employed to identify genes controlling the effect of a natural product or medicinal treatment (Cocorocchio et al, 2018; Waheed et al, 2014), including treatments for epilepsy (Chang et al, 2012; Warren et al, 2018) and bipolar disorder (Kelly, Sharma, Wilkinson, & Williams, 2018; Williams, Cheng, Mudge, & Harwood, 2002) In many of these studies, discoveries based in D. discoideum have been subsequently validated in mammalian models (Chang et al, 2013; Chang et al, 2015; Chang, Walker, & Williams, 2014; Waheed et al, 2014). Location of the blasticidin S deaminase (bsR) insertion was identified using whole-genome next-generation sequencing (NGS)

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