Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling

Warren, Eleanor C.; Dooves, Stephanie; Lugarà, Eleonora; Damstra-Oddy, Joseph; Schaf, Judith; Heine, Vivi M.; Walker, Matthew C.; Williams, Robin S. B.

doi:10.1073/pnas.2008980117

Cited by 44 publications

(49 citation statements)

References 77 publications

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“…146 A limitation of the KD, however, especially in older children and adults, is that it is difficult to maintain; the recent evidence that decanoic acid reduces mTORC1 activity in model systems, including astrocytes derived from TSC patients, suggests that a more sustainable diet rich in decanoic acid may be able to produce similar results to the KD, with better compliance. 109 The EPISTOP trial should hopefully pave the way for evaluating targeted treatments that address the underlying pathophysiology of TSC in a preventative capacity, potentially including EVE and CBD. To date, EVE and CBD have been evaluated only in a conventional setting, while it is certainly valid to hypothesise that prophylactic treatment with these treatments, especially EVE, will be even more favourable than VGB due to the targeted mechanism of action, strengthened by data from some animal studies showing the benefits of early treatment with mTOR inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Review of the treatment options for epilepsy in tuberous sclerosis complex: towards precision medicine

Schubert‐Bast

Strzelczyk

2021

Ther Adv Neurol Disord

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Tuberous sclerosis complex (TSC) is a rare genetic disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that antagonise the mammalian isoform of the target of rapamycin complex 1 (mTORC1) – a key mediator of cell growth and metabolism. TSC is characterised by the development of benign tumours in multiple organs, together with neurological manifestations including epilepsy and TSC-associated neuropsychiatric disorders (TAND). Epilepsy occurs frequently and is associated with significant morbidity and mortality; however, the management is challenging due to the intractable nature of the seizures. Preventative epilepsy treatment is a key aim, especially as patients with epilepsy may be at a higher risk of developing severe cognitive and behavioural impairment. Vigabatrin given preventatively reduces the risk and severity of epilepsy although the benefits for TAND are inconclusive. These promising results could pave the way for evaluating other treatments in a preventative capacity, especially those that may address the underlying pathophysiology of TSC, including everolimus, cannabidiol and the ketogenic diet (KD). Everolimus is an mTOR inhibitor approved for the adjunctive treatment of refractory TSC-associated seizures that has demonstrated significant reductions in seizure frequency compared with placebo, improvements that were sustained after 2 years of treatment. Highly purified cannabidiol, recently approved in the US as Epidiolex® for TSC-associated seizures in patients ⩾1 years of age, and the KD, may also participate in the regulation of the mTOR pathway. This review focusses on the pivotal clinical evidence surrounding these potential targeted therapies that may form the foundation of precision medicine for TSC-associated epilepsy, as well as other current treatments including anti-seizure drugs, vagus nerve stimulation and surgery. New future therapies are also discussed, together with the potential for preventative treatment with targeted therapies. Due to advances in understanding the molecular genetics and pathophysiology, TSC represents a prototypic clinical syndrome for studying epileptogenesis and the impact of precision medicine.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Review of the treatment options for epilepsy in tuberous sclerosis complex: towards precision medicine

Schubert‐Bast

Strzelczyk

2021

Ther Adv Neurol Disord

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“…We initially investigated the effect of CBD, CBG, CBDA and CBDV on mTORC1 signalling in D. discoideum (Figure 1a,b). We employed a western blot approach, using an antibody against the phosphorylated form of the eukaryotic translation initiation factor 4E‐binding protein 1 (4EBP1) as a direct target of mTORC1 in D. discoideum (Chang et al, 2020; Nichols et al, 2020), that is reduced in starvation and following treatment with two established mTOR inhibitors (Warren et al, 2020) (Figure 1b). Cells were treated for 1 h with each phytocannabinoid at 0.25 μM, a concentration similar to that reported in rodent brain tissue following oral dosing of CBD and in human plasma samples from clinical trials with Epidiolex® (Devinsky et al, 2018), and were analysed for phospho‐4EBP1 (p4EBP1) levels (Figure 1c).…”

Section: Resultsmentioning

confidence: 99%

“…as a direct target of mTORC1 in D. discoideum (Chang et al, 2020;Nichols et al, 2020), that is reduced in starvation and following treatment with two established mTOR inhibitors (Warren et al, 2020) (Figure 1b). Cells were treated for 1 h with each phytocannabinoid at 0.25 μM, a concentration similar to that reported in rodent brain tissue following oral dosing of CBD and in human plasma samples from clinical trials with Epidiolex® (Devinsky et al, 2018), and were analysed for phospho-4EBP1 (p4EBP1) levels (Figure 1c).…”

Section: Cbd and Cbg Increase Mtor Activity In Wt D Discoideum Cellsmentioning

confidence: 99%

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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“…However, so far, no sedative or other central nervous system side effects have yet been observed in people and dogs (see Section 5.1). Also, a recent publication found that 300 µmol·L –1 decanoic acid can block the activity of mechanistic target of rapamycin complex 1 in ex vivo rat hippocampus and in tuberous sclerosis complex patient‐derived astrocytes 135 …”

Section: Proposed Antiseizure Mechanisms Of Mctsmentioning

confidence: 99%

Dietary medium chain triglycerides for management of epilepsy: New data from human, dog, and rodent studies

Han

Conboy-Schmidt²,

Rybachuk³

et al. 2021

Epilepsia

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Many studies show that glucose metabolism in epileptic brain areas can be impaired. Energy is crucial to maintain normal brain function, including ion and neurotransmitter balances. Energy deficits can lead to disruption of ion gradients, which can trigger neuronal depolarization and generation of seizures. Thus, perturbed metabolic processing of glucose in epileptogenic brain areas indicates a specific nutritional need for people and animals with epilepsy, as they are likely to benefit from auxiliary brain fuels other than glucose. Ketogenic diets provide the ketone bodies acetoacetate and β‐hydroxybutyrate, which can be used as auxiliary fuel by the brain. In approximately 50% children and adults with certain types of epilepsy, who can tolerate and maintain these dietary regimens, seizure frequency can be effectively reduced. More recent data demonstrate that addition of medium chain triglycerides (MCTs), which provide the medium chain fatty acids octanoic and decanoic acid, as well as ketone bodies as auxiliary brain energy, can be beneficial in rodent seizure models, and dogs and humans with epilepsy. Here, this evidence is reviewed, including tolerance in 65% of humans, efficacy studies in dogs, possible anticonvulsant mechanisms of actions of MCTs, and specifically decanoic acid as well as metabolic and antioxidant mechanisms. In conclusion, MCTs are a promising adjunct to standard pharmacological treatment for both humans and dogs with epilepsy, as they lack central nervous system side effects found with current antiepileptic drugs. There is now a need for larger clinical trials in children, adults, and dogs to find the ideal composition and doses of MCTs and the types of epilepsy that respond best.

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Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling

Cited by 44 publications

References 77 publications

Review of the treatment options for epilepsy in tuberous sclerosis complex: towards precision medicine

Review of the treatment options for epilepsy in tuberous sclerosis complex: towards precision medicine

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

Dietary medium chain triglycerides for management of epilepsy: New data from human, dog, and rodent studies

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