A new mechanism for cannabidiol in regulating the one‐carbon cycle and methionine levels in <scp><i>Dictyostelium</i></scp> and in mammalian epilepsy models

Perry, Campbell; Finch, Paul; Müller‐Taubenberger, Annette; Leung, Kit‐Yi; Warren, Eleanor C.; Damstra-Oddy, Joseph; Sharma, Devdutt; Patra, Pabitra Hriday; Glyn, Sarah; Boberska, Joanna; Stewart, Balint; Baldwin, Amy; Piscitelli, Fabiana; Harvey, Robert J.; Harwood, Adrian J.; Thompson, Christopher; Claus, Sandrine P.; Greene, Nicholas D. E.; McNeish, Alister J.; Williams, Claire; Whalley, Benjamin J.; Williams, Robin S. B.

doi:10.1111/bph.14892

Cited by 21 publications

(26 citation statements)

References 73 publications

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“…First, although CBD extended lifespan and increased measures of health span in this C. elegans model, future research is needed to determine potential mechanisms for these findings. Similar to metformin, 15 CBD can inhibit folate and methionine metabolism, 16 suggesting at least one mechanism for future exploration. Second, data from this study can only be used to inform our understanding of toxicity associated with CBD isolate.…”

Section: Discussionmentioning

confidence: 99%

Effect of Cannabidiol on the Long-Term Toxicity and Lifespan in the Preclinical Model Caenorhabditis elegans

Land¹,

Tóth²,

Vanapalli

et al. 2021

Cannabis and Cannabinoid Research

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Introduction: Despite widespread use of cannabidiol (CBD), no lifelong toxicity study has been published to date. Caenorhabditis elegans is often used in preclinical lifelong toxicity studies, due to an estimated 60-80% of their genes having a human ortholog, and their short lifespan of *2-3 weeks. In this study, we examined both acute and long-term exposure studies of CBD at physiologically relevant concentrations. Materials and Methods: Acute toxicity was determined by treating day 1 adults with a wide range of CBD concentrations (0.4 lM to 4 mM) and assessing mortality and motility compared to control animals. Thermotolerance was examined by treating adult animals with CBD (0.4 lM to 4 mM) and exposing them to 37°C for 4 h, and then scoring for the number of alive animals treated with CBD compared to controls. Long-term toxicity was assessed by exposing day 1 adults to 10, 40, and 100 lM CBD until all animals perished. Control animals had no active drug exposure. Results: We report both acute and long-term exposure studies of CBD to adult C. elegans at physiologically relevant concentrations. Acute toxicity results showed that no animal died when exposed to 0.4-4000 lM CBD. The thermotolerance study showed that 40 lM CBD, but not other treatment levels, significantly increased resistance to heat stress by 141% compared to the untreated controls. Notably, whole-life exposure of C. elegans to 10-100 lM CBD revealed a maximum life extension of 18% observed at 40 lM CBD. In addition, motility analysis of the same groups revealed an increase in late-stage life activity by up to 206% compared to controls. Conclusion: These results serve as the only CBD lifelong exposure data in an in vivo model to date. While further research into the lifelong use of CBD should be carried out in mammalian models, the C. elegans model indicates a lack of long-term toxicity at physiologically relevant concentrations.

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Section: Discussionmentioning

confidence: 99%

Effect of Cannabidiol on the Long-Term Toxicity and Lifespan in the Preclinical Model Caenorhabditis elegans

Land¹,

Tóth²,

Vanapalli

et al. 2021

Cannabis and Cannabinoid Research

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“…Many Dictyostelium proteins are more homologous to human proteins than to those of unicellular fungi, making it a valuable organism for studying processes relevant to humans (32). The generation of libraries of Dictyostelium mutants has enabled pharmacogenetic studies leading to the identification of targets for compounds (33,34). This approach allows rapid identification of proteins that control sensitivity to a compound, thus implicating the proteins or the wider pathways in the action of the compound.…”

Section: Significancementioning

confidence: 99%

Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling

Warren

Dooves

Lugarà

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Low-glucose and -insulin conditions, associated with ketogenic diets, can reduce the activity of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, potentially leading to a range of positive medical and health-related effects. Here, we determined whether mTORC1 signaling is also a target for decanoic acid, a key component of the medium-chain triglyceride (MCT) ketogenic diet. Using a tractable model system, Dictyostelium, we show that decanoic acid can decrease mTORC1 activity, under conditions of constant glucose and in the absence of insulin, measured by phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). We determine that this effect of decanoic acid is dependent on a ubiquitin regulatory X domain-containing protein, mediating inhibition of a conserved Dictyostelium AAA ATPase, p97, a homolog of the human transitional endoplasmic reticulum ATPase (VCP/p97) protein. We then demonstrate that decanoic acid decreases mTORC1 activity in the absence of insulin and under high-glucose conditions in ex vivo rat hippocampus and in tuberous sclerosis complex (TSC) patient-derived astrocytes. Our data therefore indicate that dietary decanoic acid may provide a new therapeutic approach to down-regulate mTORC1 signaling.

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“…In contrast, several preclinical studies focused on tuberous sclerosis complex (TSC)‐associated epilepsy and breast cancer, showing pathology‐associated elevated mTORC1 activity and showing that CBD treatment reduced pathway activity (Serra et al, 2019; Sultan, Marie, & Sheweita, 2018). Despite numerous suggested mechanisms for CBD on the G protein‐coupled receptor 55 (GPR55) (Kaplan, Stella, Catterall, & Westenbroek, 2017), adenosine signalling (Liou et al, 2008), transient receptor potential vanilloid type 1 (TRPV1) (Costa, Giagnoni, Franke, Trovato, & Colleoni, 2004) and the folate one‐carbon cycle (Perry, Finch, Muller‐Taubenberger, Leung, & Williams, 2019), these mechanisms do not provide direct insight to the effect of these phytocannabinoids on mTOR signalling.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The model system Dictyostelium discoideum has been instrumental in identifying molecular mechanisms of action of a range of drugs and natural products (Chang et al, 2012; Kelly, Sharma, Wilkinson, & Williams, 2018; Perry et al, 2019). This organism contains many human protein orthologues and conserved signalling pathways linked to disease‐related processes (Schaf, Damstra‐Oddy, & Williams, 2019) and enables a range of advantageous research approaches, including the ability to screen mutant libraries providing an unbiased approach to identifying cellular mechanism of action of drugs (Chang et al, 2012; Kelly et al, 2018; Schaf et al, 2019), including effects of CBD on cell growth and folate one‐carbon metabolism (Perry et al, 2019). Characterisation of related molecular effects and restoration of sensitivity by the expression of human orthologous proteins (Chang et al, 2012; Kelly et al, 2018; Perry et al, 2019; Schaf et al, 2019) provide insight to the mechanism of action of the compound translatable to mammalian models (Chang et al, 2012; Chang et al, 2013; Chang et al, 2015; Kelly et al, 2018; Perry et al, 2019; Schaf et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Phytocannabinoid‐dependent mTORC1 regulation is dependent upon inositol polyphosphate multikinase activity

Damstra-Oddy

Warren

Perry

et al. 2021

British J Pharmacology

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Background and Purpose Cannabidiol (CBD) has been shown to differentially regulate the mechanistic target of rapamycin complex 1 (mTORC1) in preclinical models of disease, where it reduces activity in models of epilepsies and cancer and increases it in models of multiple sclerosis (MS) and psychosis. Here, we investigate the effects of phytocannabinoids on mTORC1 and define a molecular mechanism. Experimental Approach A novel mechanism for phytocannabinoids was identified using the tractable model system, Dictyostelium discoideum. Using mouse embryonic fibroblasts, we further validate this new mechanism of action. We demonstrate clinical relevance using cells derived from healthy individuals and from people with MS (pwMS). Key Results Both CBD and the more abundant cannabigerol (CBG) enhance mTORC1 activity in D. discoideum. We identify a mechanism for this effect involving inositol polyphosphate multikinase (IPMK), where elevated IPMK expression reverses the response to phytocannabinoids, decreasing mTORC1 activity upon treatment, providing new insight on phytocannabinoids' actions. We further validated this mechanism using mouse embryonic fibroblasts. Clinical relevance of this effect was shown in primary human peripheral blood mononuclear cells, where CBD and CBG treatment increased mTORC1 activity in cells derived from healthy individuals and decreased mTORC1 activity in cells derived from pwMS. Conclusion and Implications Our findings suggest that both CBD and the abundant CBG differentially regulate mTORC1 signalling through a mechanism dependent on the activity of the upstream IPMK signalling pathway, with potential relevance to the treatment of mTOR‐related disorders, including MS.

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

Cited by 21 publications

References 73 publications

Effect of Cannabidiol on the Long-Term Toxicity and Lifespan in the Preclinical Model Caenorhabditis elegans

Effect of Cannabidiol on the Long-Term Toxicity and Lifespan in the Preclinical Model Caenorhabditis elegans

Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling

Phytocannabinoid‐dependent mTORC1 regulation is dependent upon inositol polyphosphate multikinase activity

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