ORCID Profile
0000-0001-8802-3407
Current Organisation
London Institute of Medical Sciences
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Publisher: Wiley
Date: 18-01-2021
DOI: 10.1111/BPH.15351
Abstract: 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. 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 in iduals and from people with MS (pwMS). 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 in iduals and decreased mTORC1 activity in cells derived from pwMS. 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.
Publisher: MDPI AG
Date: 29-10-2021
Abstract: Ketogenic diets, used in epilepsy treatment, are considered to work through reduced glucose and ketone generation to regulate a range of cellular process including autophagy induction. Recent studies into the medium-chain triglyceride (MCT) ketogenic diet have suggested that medium-chain fatty acids (MCFAs) provided in the diet, decanoic acid and octanoic acid, cause specific therapeutic effects independent of glucose reduction, although a role in autophagy has not been investigated. Both autophagy and MCFAs have been widely studied in Dictyostelium, with findings providing important advances in the study of autophagy-related pathologies such as neurodegenerative diseases. Here, we utilize this model to analyze a role for MCFAs in regulating autophagy. We show that treatment with decanoic acid but not octanoic acid induces autophagosome formation and modulates autophagic flux in high glucose conditions. To investigate this effect, decanoic acid, but not octanoic acid, was found to induce the expression of autophagy-inducing proteins (Atg1 and Atg8), providing a mechanism for this effect. Finally, we demonstrate a range of related fatty acid derivatives with seizure control activity, 4BCCA, 4EOA, and Epilim (valproic acid), also function to induce autophagosome formation in this model. Thus, our data suggest that decanoic acid and related compounds may provide a less-restrictive therapeutic approach to activate autophagy.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Proceedings of the National Academy of Sciences
Date: 02-09-2020
Abstract: The mTORC1 complex provides a critical role in cell function, regulating a variety of processes including growth and autophagy. mTORC1 signaling is hyperactivated in a range of common diseases including cancer, epilepsy, and neurodegenerative disorders. Hence, mTORC1 signaling provides an important target for regulation in many contexts. Here, we show that decanoic acid, a key component of a widely used medicinal diet, reduces mTORC1 activity. We identify this in a tractable model system, and validate it in ex vivo rat brain tissue and in human iPSC-derived astrocytes from patients with a clinically relevant disease. Thus, we provide insight into an easily accessible therapeutic approach for a range of diseases.
Publisher: Wiley
Date: 03-01-2020
DOI: 10.1111/BPH.14892
Publisher: Informa UK Limited
Date: 21-03-2019
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Eleanor Warren.