Cannabidiol counters the effects of a dominant-negative pathogenic Kv7.2 variant

Zhan, Xiaoqin; Drummond-Main, Chris; Greening, Dylan; Yao, Jinjing; Chen, S.W.R.; Appendino, Juan Pablo; Au, Ping Yee Billie; Turner, Ray W.

doi:10.1016/j.isci.2022.105092

Cited by 4 publications

(6 citation statements)

References 50 publications

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“…In recent years, CBD was reported to be useful for ameliorating symptoms related to epilepsy ( Zhan et al, 2022 ; Reddy et al, 2023 ), pain ( Britch and Craft, 2023 ), anxiety ( Fabris et al, 2022 ) as well as other neurological diseases ( Yang et al, 2022 ). The antioxidant effects of CBD have been highlighted.…”

Section: Introductionmentioning

confidence: 99%

Anti-oxidant effects of cannabidiol relevant to intracerebral hemorrhage

Yan,

Zhang,

et al. 2023

Front. Pharmacol.

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Intracerebral hemorrhage (ICH) is a subtype of stroke with a high mortality rate. Oxidative stress cascades play an important role in brain injury after ICH. Cannabidiol, a major non-psychotropic phytocannabinoids, has drawn increasing interest in recent years as a potential therapeutic intervention for various neuropsychiatric disorders. Here we provide a comprehensive review of the potential therapeutic effects of cannabidiol in countering oxidative stress resulting from ICH. The review elaborates on the various sources of oxidative stress post-ICH, including mitochondrial dysfunction, excitotoxicity, iron toxicity, inflammation, and also highlights cannabidiol’s ability to inhibit ROS/RNS generation from these sources. The article also delves into cannabidiol’s role in promoting ROS/RNS scavenging through the Nrf2/ARE pathway, detailing both extranuclear and intranuclear regulatory mechanisms. Overall, the review underscores cannabidiol’s promising antioxidant effects in the context of ICH and suggests its potential as a therapeutic option.

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Section: Introductionmentioning

confidence: 99%

Anti-oxidant effects of cannabidiol relevant to intracerebral hemorrhage

Yan,

Zhang,

et al. 2023

Front. Pharmacol.

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“…Interestingly, CBD reduced the epilepsy symptoms in the patient and restored the altered voltage sensitivity of the channel in vitro. 34 Moreover, mutations with gain of function (GoF) in the Na + -activated K + channel (Slack or KCNT1 gene) are the major cause of infancy epilepsy with migrating focal seizures, a severe drug-resistant epileptic syndrome for which CBD is employed as a frontline treatment. 23 This voltage-operated K + channel, closely related to the BK channel, contributes to action potential repolarization and after hyperpolarization and is inhibited by CBD.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Recent findings indicate that the voltage sensitivity of this channel is impaired when it is expressed with a mutant variant of Kv7.2, identified in an individual with drug-resistant epilepsy. Interestingly, CBD reduced the epilepsy symptoms in the patient and restored the altered voltage sensitivity of the channel in vitro . Moreover, mutations with gain of function (GoF) in the Na + -activated K + channel (Slack or KCNT1 gene) are the major cause of infancy epilepsy with migrating focal seizures, a severe drug-resistant epileptic syndrome for which CBD is employed as a frontline treatment .…”

Section: Resultsmentioning

confidence: 99%

Direct Inhibition of BK Channels by Cannabidiol, One of the Principal Therapeutic Cannabinoids Derived from Cannabis sativa

Monat,

Altieri,

Enrique

et al. 2024

J. Nat. Prod.

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Cannabidiol (CBD), one of the main Cannabis sativa bioactive compounds, is utilized in the treatment of major epileptic syndromes. Its efficacy can be attributed to a multimodal mechanism of action that includes, as potential targets, several types of ion channels. In the brain, CBD reduces the firing frequency in rat hippocampal neurons, partly prolonging the duration of action potentials, suggesting a potential blockade of voltage-operated K + channels. We postulate that this effect might involve the inhibition of the large-conductance voltage-and Ca 2+operated K + channel (BK channel), which plays a role in the neuronal action potential's repolarization. Thus, we assessed the impact of CBD on the BK channel activity, heterologously expressed in HEK293 cells. Our findings, using the patch-clamp technique, revealed that CBD inhibits BK channel currents in a concentration-dependent manner with an IC 50 of 280 nM. The inhibition is through a direct interaction, reducing both the unitary conductance and voltage-dependent activation of the channel. Additionally, the cannabinoid significantly delays channel activation kinetics, indicating stabilization of the closed state. These effects could explain the changes induced by CBD in action potential shape and duration, and they may contribute to the observed anticonvulsant activity of this cannabinoid.

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“…It is among over 100 cannabinoids present in the plant and has been shown to be effective in treating various medical conditions, such as epilepsy, bipolar disorder, inflammation, and cancer [1][2][3][4][5]. Recent studies have demonstrated that CBD can modify the activity in the hypothalamic-pituitary-adrenal axis [6,7] and can modulate different types of transmembrane ionic currents in electrically excitable cells, including the voltage-gated Na + current (I Na ) and the M-type K + currents (I K(M) ) [5,8,9]. Thus, further clarification is necessary to determine the effects of CBD or related compounds on ionic currents present in the membranes of electrically excitable cells.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the magnitude of I K(M) is believed to regulate the availability of voltage-gated Na + (Na V ) channels during prolonged high-frequency firing [16]. Previous studies have shown that CBD can modify the magnitude of I K(M) [9,17]. However, it is still largely unclear whether and how exposure to CBD can perturb the magnitude or gating properties of I K(M) .…”

Section: Introductionmentioning

confidence: 99%

Cannabidiol Modulates M-Type K+ and Hyperpolarization-Activated Cation Currents

Liu,

So,

2023

Biomedicines

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Cannabidiol (CBD) is a naturally occurring compound found in the Cannabis plant that is known for its potential therapeutic effects. However, its impact on membrane ionic currents remains a topic of debate. This study aimed to investigate how CBD modifies various types of ionic currents in pituitary GH3 cells. Results showed that exposure to CBD led to a concentration-dependent decrease in M-type K+ currents (IK(M)), with an IC50 of 3.6 μM, and caused the quasi-steady-state activation curve of the current to shift to a more depolarized potential with no changes in the curve’s steepness. The CBD-mediated block of IK(M) was not reversed by naloxone, suggesting that it was not mediated by opioid receptors. The IK(M) elicited by pulse-train stimulation was also decreased upon exposure to CBD. The magnitude of erg-mediated K+ currents was slightly reduced by adding CBD (10 μM), while the density of voltage-gated Na+ currents elicited by a short depolarizing pulse was not affected by it. Additionally, CBD decreased the magnitude of hyperpolarization-activated cation currents (Ih) with an IC50 of 3.3 μM, and the decrease was reversed by oxaliplatin. The quasi-steady-state activation curve of Ih was shifted in the leftward direction with no changes in the slope factor of the curve. CBD also diminished the strength of voltage-dependent hysteresis on Ih elicited by upright isosceles-triangular ramp voltage. Collectively, these findings suggest that CBD’s modification of ionic currents presented herein is independent of cannabinoid or opioid receptors and may exert a significant impact on the functional activities of excitable cells occurring in vitro or in vivo.

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Cannabidiol counters the effects of a dominant-negative pathogenic Kv7.2 variant

Cited by 4 publications

References 50 publications

Anti-oxidant effects of cannabidiol relevant to intracerebral hemorrhage

Anti-oxidant effects of cannabidiol relevant to intracerebral hemorrhage

Direct Inhibition of BK Channels by Cannabidiol, One of the Principal Therapeutic Cannabinoids Derived from Cannabis sativa

Cannabidiol Modulates M-Type K+ and Hyperpolarization-Activated Cation Currents

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