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Cannabidiol and Sodium Channel Pharmacology: General Overview, Mechanism, and Clinical Implications.

ABSTRACT: Voltage-gated sodium (Nav) channels initiate action potentials in excitable tissues. Altering these channels' function can lead to many pathophysiological conditions. Nav channels are composed of several functional and structural domains that could be targeted pharmacologically as potential therapeutic means against various neurological conditions. Mutations in Nav channels have been suggested to underlie various clinical syndromes in different tissues and in association with conditions ranging from epileptic to muscular problems. Treating those mutations that increase the excitability of Nav channels requires inhibitors that could effectively reduce channel firing. The main non-psychotropic constituent of the cannabis plant, cannabidiol (CBD), has recently gained interest as a viable compound to treat some of the conditions that are associated with Nav malfunctions. In this review, we discuss an overview of Nav channels followed by an in-depth description of the interactions of CBD and Nav channels. We conclude with some clinical implications of CBD use against Nav hyperexcitability based on a series of preclinical studies published to date, with a focus on Nav/CBD interactions.

SUBMITTER: Ghovanloo MR

PROVIDER: S-EPMC9344566 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Cannabidiol and Sodium Channel Pharmacology: General Overview, Mechanism, and Clinical Implications.

Ghovanloo Mohammad-Reza MR Ruben Peter C PC

The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 20210524 4

Voltage-gated sodium (Nav) channels initiate action potentials in excitable tissues. Altering these channels' function can lead to many pathophysiological conditions. Nav channels are composed of several functional and structural domains that could be targeted pharmacologically as potential therapeutic means against various neurological conditions. Mutations in Nav channels have been suggested to underlie various clinical syndromes in different tissues and in association with conditions ranging ...[more]

PMID: 34027742

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Project description:General anesthesia has revolutionized healthcare over the past 200 years and continues to show advancements. However, many phenomena induced by general anesthetics including paradoxical excitation are still poorly understood. Voltage-gated sodium channels (Na V ) were believed to be one of the proteins targeted during general anesthesia. Based on electrophysiological measurements before and after propofol treatments of different concentrations, we mathematically modified the Hodgkin-Huxley sodium channel formulations and constructed a thalamocortical model to investigate the potential roles of Na V . The ion channels of individual neurons were modeled using the Hodgkin-Huxley type equations. The enhancement of propofol-induced GABAa current was simulated by increasing the maximal conductance and the time-constant of decay. Electroencephalogram (EEG) was evaluated as the post-synaptic potential from pyramidal (PY) cells. We found that a left shift in activation of Na V was induced primarily by a low concentration of propofol (0.3-10 μM), while a left shift in inactivation of Na V was induced by an increasing concentration (0.3-30 μM). Mathematical simulation indicated that a left shift of Na V activation produced a Hopf bifurcation, leading to cell oscillations. Left shift of Na V activation around a value of 5.5 mV in the thalamocortical models suppressed normal bursting of thalamocortical (TC) cells by triggering its chaotic oscillations. This led to irregular spiking of PY cells and an increased frequency in EEG readings. This observation suggests a mechanism leading to paradoxical excitation during general anesthesia. While a left shift in inactivation led to light hyperpolarization in individual cells, it inhibited the activity of the thalamocortical model after a certain depth of anesthesia. This finding implies that high doses of propofol inhibit the network partly by accelerating Na V toward inactivation. Additionally, this result explains why the application of sodium channel blockers decreases the requirement for general anesthetics. Our study provides an insight into the roles that Na V plays in the mechanism of general anesthesia. Since the activation and inactivation of Na V are structurally independent, it should be possible to avoid side effects by state-dependent binding to the Na V to achieve precision medicine in the future.

Project description:Mutations in brain isoforms of voltage-gated sodium channels have been identified in patients with distinct epileptic phenotypes. Clinically, these patients often do not respond well to classic anti-epileptics and many remain refractory to treatment. Exogenous as well as endogenous cannabinoids have been shown to target voltage-gated sodium channels and cannabidiol has recently received attention for its potential efficacy in the treatment of childhood epilepsies. In this study, we further investigated the ability of cannabinoids to modulate sodium currents from wild-type and epilepsy-associated mutant voltage-gated sodium channels. We first determined the biophysical consequences of epilepsy-associated missense mutations in both Nav1.1 (arginine 1648 to histidine and asparagine 1788 to lysine) and Nav1.6 (asparagine 1768 to aspartic acid and leucine 1331 to valine) by obtaining whole-cell patch clamp recordings in human embryonic kidney 293T cells with 200 μM Navβ4 peptide in the pipette solution to induce resurgent sodium currents. Resurgent sodium current is an atypical near threshold current predicted to increase neuronal excitability and has been implicated in multiple disorders of excitability. We found that both mutations in Nav1.6 dramatically increased resurgent currents while mutations in Nav1.1 did not. We then examined the effects of anandamide and cannabidiol on peak transient and resurgent currents from wild-type and mutant channels. Interestingly, we found that cannabidiol can preferentially target resurgent sodium currents over peak transient currents generated by wild-type Nav1.6 as well as the aberrant resurgent and persistent current generated by Nav1.6 mutant channels. To further validate our findings, we examined the effects of cannabidiol on endogenous sodium currents from striatal neurons, and similarly we found an inhibition of resurgent and persistent current by cannabidiol. Moreover, current clamp recordings show that cannabidiol reduces overall action potential firing of striatal neurons. These findings suggest that cannabidiol could be exerting its anticonvulsant effects, at least in part, through its actions on voltage-gated sodium channels, and resurgent current may be a promising therapeutic target for the treatment of epilepsy syndromes.

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Cannabidiol and Sodium Channel Pharmacology: General Overview, Mechanism, and Clinical Implications.

Publications

Cannabidiol and Sodium Channel Pharmacology: General Overview, Mechanism, and Clinical Implications.

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