The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABA A receptors

Bakas, Tim; Nieuwenhuijzen, Petra S. van; Devenish, Steven O.; McGregor, Iain S.; Arnold, Jonathon C.; Chebib, Mary

doi:10.1016/j.phrs.2017.02.022

Cited by 191 publications

(162 citation statements)

References 80 publications

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“…This explains why increasing inhibitory tone with PAMs of GABA A receptors yields beneficial therapeutic effects. 21 These results provide the first evidence of a pharmacodynamic interaction between CBD and clobazam that could contribute to improved outcomes in patients with Dravet syndrome. 21 In addition, co-application of CBD and clobazam or CBD and N-CLB, potentiated GABA-evoked inhibitory currents to a greater degree than any of the compounds alone.…”

Section: Discussionmentioning

confidence: 66%

“…[34][35][36] Because Na V 1.1 channels are expressed predominantly on GABAergic interneurons, loss-of-function SCN1A mutations found in Dravet syndrome patients impair interneuron function leading to neuronal hyperexcitability. 21 In addition, co-application of CBD and clobazam or CBD and N-CLB, potentiated GABA-evoked inhibitory currents to a greater degree than any of the compounds alone. 37,38 Here we confirm that at concentrations relevant to its anticonvulsant effects, CBD is a weak PAM of the GABA A receptor.…”

Section: Discussionmentioning

confidence: 97%

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Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions

et al. 2019

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Objective: Cannabidiol (CBD) has been approved by the US Food and DrugAdministration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam. Methods: We examined whether CBD inhibits human CYP3A4 and CYP2C19 mediated metabolism of clobazam and N-desmethylclobazam (N-CLB), respectively, and performed studies assessing the effects of CBD on brain and plasma pharmacokinetics of clobazam in mice. We then used the Scn1a +/− mouse model of Dravet syndrome to examine how CBD and clobazam interact. We compared anticonvulsant effects of CBD-clobazam combination therapy to monotherapy against thermally-induced seizures, spontaneous seizures and mortality in Scn1a +/− mice. In addition, we used Xenopus oocytes expressing γ-aminobutyric acid (GABA) A receptors to investigate the activity of GABA A receptors when treated with CBD and clobazam together. Results: CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a +/− mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABA A receptor activation.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 97%

Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions

et al. 2019

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“…19,20,35 Using the approach of membrane microtransplantation, we found that coapplication with 2 μmol/L CBD increased GABA-evoked currents in DS patients (+26.9 ± 4.7%; GABA 50 μmol/L; Figure 5A; n = 28; #1-3, Table 1). 22 The CBD effect was fast and completely reversible after 5 minutes of washing with oocyte Ringer solution (data not shown).…”

Section: Effect Of Cbd On Gaba Currents From Patients Affected By Dsmentioning

confidence: 93%

A novel GABAergic dysfunction in human Dravet syndrome

et al. 2018

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Summary Objective Dravet syndrome is a rare neurodevelopmental disease, characterized by general cognitive impairment and severe refractory seizures. The majority of patients carry the gene mutation SCN1A, leading to a defective sodium channel that contributes to pathogenic brain excitability. A γ‐aminobutyric acid (GABAergic) impairment, as in other neurodevelopmental diseases, has been proposed as an additional mechanism, suggesting that seizures could be alleviated by GABAergic therapies. However, up to now the physiological mechanisms underlying the GABAergic dysfunction in Dravet syndrome are still unknown due to the scarce availability of this brain tissue. Here we studied, for the first time, human GABAA‐evoked currents using cortical brain tissue from Dravet syndrome patients. Methods We transplanted in Xenopus oocytes cell membranes obtained from brain tissues of autopsies of Dravet syndrome patients, tuberous sclerosis complex patients as a pathological comparison, and age‐matched controls. Additionally, experiments were performed on oocytes expressing human α1β2γ2 and α1β2 GABAA receptors. GABAA currents were recorded using the two‐microelectrodes voltage‐clamp technique. Quantitative real‐time polymerase chain reaction, immunohistochemistry, and double‐labeling techniques were carried out on the same tissue samples. Results We found (1) a decrease in GABA sensitivity in Dravet syndrome compared to controls, which was related to an increase in α4‐ relative to α1‐containing GABAA receptors; (2) a shift of the GABA reversal potential toward more depolarizing values in Dravet syndrome, and a parallel increase of the chloride transporters NKCC1/KCC2 expression ratio; (3) an increase of GABAA currents induced by low doses of cannabidiol both in Dravet syndrome and tuberous sclerosis complex comparable to that induced by a classical benzodiazepine, flunitrazepam, that still persists in γ‐less GABAA receptors. Significance Our study indicates that a dysfunction of the GABAergic system, considered as a feature of brain immaturity, together with defective sodium channels, can contribute to a general reduction of inhibitory efficacy in Dravet brain, suggesting that GABAA receptors could be a target for new therapies.

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“…Its activity at these receptors could mediate the anti-inflammatory and immunosuppressive effects of CBD. The activity of CBD at the nuclear receptors PPARγ [52–54], the ligand-gated ion channels glycine [55, 56] and GABA A receptors [57], or at the transient receptor potential channels [29, 30] is summarized in Table 1.…”

Section: Pharmacology Of Selected Phytocannabinoidsmentioning

confidence: 99%