Cannabidiol modulates phosphorylated rpS6 signalling in a zebrafish model of Tuberous Sclerosis Complex

Serra, Ines; Scheldeman, Chloë; Bazelot, Michaël; Whalley, Benjamin J.; Dallas, Mark L.; Witte, Peter de; Williams, Claire

doi:10.1016/j.bbr.2019.01.040

Cited by 22 publications

(11 citation statements)

References 90 publications

(124 reference statements)

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“…It was approved by the U.S. FDA in 2018 for epilepsy in children, in particular, for Dravet Syndrome and Lennox-Gastaut Syndrome. [38][39][40][41][42] CBD is also being investigated for its effectiveness in other diseases, including Tuberous Sclerosis, a genetic condition that causes growth of benign tumors all over the body, 43,44 schizophrenia, 45 and refractory epileptic encephalopathy. 46 In addition to the federally approved uses of CBD as Epidolex Ò , CBD, usually as CBD oil, is widely used for putative medical benefit in several states, and is certainly used in states in which cannabis has been decriminalized, or legalized, for recreational use.…”

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confidence: 99%

Immune Responses Regulated by Cannabidiol

Nichols

Kaplan

2020

Cannabis and Cannabinoid Research

185

176

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Introduction: Cannabidiol (CBD) as Epidiolex Ò (GW Pharmaceuticals) was recently approved by the U.S. Food and Drug Administration (FDA) to treat rare forms of epilepsy in patients 2 years of age and older. Together with the increased societal acceptance of recreational cannabis and CBD oil for putative medical use in many states, the exposure to CBD is increasing, even though all of its biological effects are not understood. Once such example is the ability of CBD to be anti-inflammatory and immune suppressive, so the purpose of this review is to summarize effects and mechanisms of CBD in the immune system. It includes a consideration of reports identifying receptors through which CBD acts, since the ' 'CBD receptor,' ' if a single one exists, has not been definitively identified for the myriad immune system effects. The review then provides a summary of in vivo and in vitro effects in the immune system, in autoimmune models, with a focus on experimental autoimmune encephalomyelitis, and ends with identification of knowledge gaps. Conclusion: Overall, the data overwhelmingly support the notion that CBD is immune suppressive and that the mechanisms involve direct suppression of activation of various immune cell types, induction of apoptosis, and promotion of regulatory cells, which, in turn, control other immune cell targets.

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confidence: 99%

Immune Responses Regulated by Cannabidiol

Nichols

Kaplan

2020

Cannabis and Cannabinoid Research

185

176

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“…Phytocannabinoids have demonstrated efficacy in preclinical models of MS (Feliu et al, 2015; Giacoppo et al, 2017) and in clinical studies relating to spasticity associated with MS (Etges et al, 2016; Novotna et al, 2011). In addition, CBD has been shown to be effective in preclinical models of psychosis (Renard et al, 2016; Renard, Norris, Rushlow, & Laviolette, 2017), breast cancer (Sultan et al, 2018) and tuberous sclerosis complex (Serra et al, 2019). One suggested mechanism for CBD treatment of epilepsy and cancer is through the downregulation of hyperactivated mTORC1 found in the disease state (Serra et al, 2019; Sultan et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, in a rat model of induced schizophrenia, mTOR signalling is reduced (Renard et al, 2016), whereas CBD treatment increased mTOR activity and reversed symptoms. 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%

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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“…In rodent studies of PTE, the mTOR inhibitor, rapamycin, has demonstrated antiepileptogenic effects 34 . Although mTOR signaling alterations have been shown in various zebrafish models of seizures, 38–40 they have not been investigated in zebrafish TBI or PTE. Similar to rodent studies, we describe increased mTOR activity as evidenced by an increased ratio of phosphorylated/total Akt after pHIFU in zebrafish.…”

Section: Discussionmentioning

confidence: 99%

Zebrafish model of posttraumatic epilepsy

et al. 2020

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Objective: Posttraumatic epilepsy (PTE) is defined as recurrent and unprovoked seizures occurring >1 week after traumatic brain injury (TBI). Animal studies of PTE are lengthy and expensive. In this study, we developed a cost-effective PTE animal model using zebrafish to bridge the gap between in vitro studies and low-throughput animal studies. Methods: We used two different sets of parameters (G1 and G2) to induce closedhead TBI in adult zebrafish using pulsed high-intensity focused ultrasound. Injured fish and naive controls were evaluated for behavioral deficits and spontaneous behavioral seizure activity up to 21 days postinjury (DPI). We also assessed behavioral seizure susceptibility to a subconvulsive dose of pentylenetetrazole (PTZ; 2.5 mmol•L-1) and recorded electrophysiological signals to confirm seizure activity up to 40 DPI. In addition, we investigated injury-related changes in the blood-brain barrier and expression levels of various proteins altered in rodent and human TBI. Results: The G2 parameters resulted in a more severe TBI, with a mortality rate of 25%, as well as motor dysfunction and heightened anxiety persisting at 21 DPI. One hundred percent of the G2 group showed spontaneous myocloniclike behavior, and 80% demonstrated tonic-clonic-like behavioral seizures by 21 DPI. Such activities were not detected in the naive group. After the application of 2.5 mmol•L-1 PTZ, 100% of injured zebrafish had cloniclike seizures at 21 DPI, versus 30% of the naive group. We also demonstrated electrographic seizure activity at 40 DPI, which was not detected in the naive controls. Lastly, we observed acute blood-brain barrier dysfunction and increased levels of HMGB1 and ratios of phosphorylated/total Akt and tau through 21 DPI. Significance: Together, the results indicate that severe TBI in the adult zebrafish leads to similar behavioral and physiological changes to those of more traditional models, including the development of PTE, and suggest this may be a useful model that can accelerate research in TBI/PTE.

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Cannabidiol modulates phosphorylated rpS6 signalling in a zebrafish model of Tuberous Sclerosis Complex

Cited by 22 publications

References 90 publications

Immune Responses Regulated by Cannabidiol

Immune Responses Regulated by Cannabidiol

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

Zebrafish model of posttraumatic epilepsy

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