Differential Inhibition of Human Nav1.2 Resurgent and Persistent Sodium Currents by Cannabidiol and GS967

Mason, Emily; Cummins, Theodore R.

doi:10.3390/ijms21072454

Cited by 29 publications

(21 citation statements)

References 68 publications

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“…The conclusion that CBD prevents the opening of Nav channels is further affirmed by the observation of CBD's inhibition of resurgent currents in Nav1.2 and Nav1.6 (Ghovanloo and others 2018c; Mason and Cummins 2020;Patel and others 2016). CBD also does not alter the open state fast inactivation time constants of neuronal Nav channels, suggesting that it does not interact with the sodium conduction pathway when the channel is open.…”

Section: Cbd Is An Inhibitor Of Voltage-dependent Sodium Currentsmentioning

confidence: 88%

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

Ghovanloo

Ruben

2021

Neuroscientist

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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.

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Section: Cbd Is An Inhibitor Of Voltage-dependent Sodium Currentsmentioning

confidence: 88%

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

Ghovanloo

Ruben

2021

Neuroscientist

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“…Interestingly, several compounds exist that have been shown to selectively target pathological currents produced by Na v 1.6. For instance, cannabidiol and GS967 (otherwise known as Prax330) have been shown to preferentially reduce aberrant persistent and resurgent currents over transient sodium currents, however these compounds do not appear to be selective for Na v 1.6 and can target currents in other isoforms, like Na v 1.2 [ 91 , 114 , 115 , 116 ]. More recently, anti-epileptic compound screens in zebrafish models of epilepsy revealed two novel blocking compounds, MV1312 and MV1369 [ 117 ].…”

Section: Na V 16 Overviewmentioning

confidence: 99%

Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability

Zybura

Hudmon

Cummins

2021

Cells

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Voltage-gated sodium channels (Navs) are critical determinants of cellular excitability. These ion channels exist as large heteromultimeric structures and their activity is tightly controlled. In neurons, the isoform Nav1.6 is highly enriched at the axon initial segment and nodes, making it critical for the initiation and propagation of neuronal impulses. Changes in Nav1.6 expression and function profoundly impact the input-output properties of neurons in normal and pathological conditions. While mutations in Nav1.6 may cause channel dysfunction, aberrant changes may also be the result of complex modes of regulation, including various protein-protein interactions and post-translational modifications, which can alter membrane excitability and neuronal firing properties. Despite decades of research, the complexities of Nav1.6 modulation in health and disease are still being determined. While some modulatory mechanisms have similar effects on other Nav isoforms, others are isoform-specific. Additionally, considerable progress has been made toward understanding how individual protein interactions and/or modifications affect Nav1.6 function. However, there is still more to be learned about how these different modes of modulation interact. Here, we examine the role of Nav1.6 in neuronal function and provide a thorough review of this channel’s complex regulatory mechanisms and how they may contribute to neuromodulation.

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“…A previously study demonstrated that CBD at 1μM inhibit preferably resurgent currents than transient current in Nav1.6 WT and also inhibit peak resurgent current in Nav1.6 mutant N1768D, with less effect in current density and without alters voltage dependence of activation ( Patel et al., 2016 ) Possibly the modulation of CBD over mutations in SCN8A that promotes a phenotype with increased resurgent currents would cause a reduction in the causative excitability of epileptic seizures. CBD also showed its ability to preferential inhibit resurgent currents in the NaV1.2 channel ( Mason and Cummins, 2020 ). Due the role of Nav1.2 and Nav1.6 in excitatory neurons, preferentially inhibition in resurgent currents by CBD could possibly reduce the excitability in that subset of neurons and decrease the frequency of seizures by a change in threshold of activation and repetitive fire ( Lewis and Raman, 2014 ).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review

et al. 2020

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Epilepsy is a disease characterized by abnormal brain activity and a predisposition to generate epileptic seizures, leading to neurobiological, cognitive, psychological, social, and economic impacts for the patient. There are several known causes for epilepsy; one of them is the malfunction of ion channels, resulting from mutations. Voltage-gated sodium channels (NaV) play an essential role in the generation and propagation of action potential, and malfunction caused by mutations can induce irregular neuronal activity. That said, several genetic variations in NaV channels have been described and associated with epilepsy. These mutations can affect channel kinetics, modifying channel activation, inactivation, recovery from inactivation, and/or the current window. Among the NaV subtypes related to epilepsy, NaV1.1 is doubtless the most relevant, with more than 1500 mutations described. Truncation and missense mutations are the most observed alterations. In addition, several studies have already related mutated NaV channels with the electrophysiological functioning of the channel, aiming to correlate with the epilepsy phenotype. The present review provides an overview of studies on epilepsy-associated mutated human NaV1.1, NaV1.2, NaV1.3, NaV1.6, and NaV1.7.

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Differential Inhibition of Human Nav1.2 Resurgent and Persistent Sodium Currents by Cannabidiol and GS967

Cited by 29 publications

References 68 publications

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

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

Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability

Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review

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