Late sodium current: incomplete inactivation triggers seizures, myotonias, arrhythmias, and pain syndromes

Fouda, Mohamed A.; Ghovanloo, Mohammad‐Reza; Ruben, Peter C.

doi:10.1113/jp282768

Cited by 15 publications

(18 citation statements)

References 156 publications

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“…An increased persistent sodium current (I Nap ) is a manifestation of destabilized fast inactivation (Goldin, 2003). A large I Nap is associated with a range of pathological conditions, including LQT3 (Fouda & Ghovanloo, 2022; Ghovanloo et al, 2016; Wang et al, 1995). To determine the effects of LPS on the stability of Na V 1.5 inactivation, we held the membrane potential at −130 mV, then depolarized to 0 mV for 200 ms.…”

Section: Resultsmentioning

confidence: 99%

Anti‐inflammatory effects of cannabidiol against lipopolysaccharides in cardiac sodium channels

Fouda

Mohamed

Fernandez

et al. 2022

British J Pharmacology

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Background Sepsis, caused by a dysregulated response to infections, can lead to cardiac arrhythmias. However, the mechanisms underlying sepsis‐induced inflammation, and how inflammation provokes cardiac arrhythmias, are not well understood. We hypothesized that cannabidiol (CBD) may ameliorate lipopolysaccharide (LPS)‐induced cardiotoxicity, via Toll‐like receptors (TLR4) and cardiac sodium channels (NaV1.5). Methods and results We incubated human immune cells (THP‐1 macrophages) with LPS for 24 h, then extracted the THP‐1 incubation media. ELISA assays showed that LPS (1 or 5 μg·ml−1), in a concentration‐dependent manner, or MPLA (TLR4 agonist, 5 μg·ml−1) stimulated the THP‐1 cells to release inflammatory cytokines (TNF‐α and IL‐6). Prior incubation (4 h) with CBD (5 μM) or C34 (TLR4 antagonist: 5 μg·ml−1) inhibited LPS and MPLA‐induced release of both IL‐6 and TNF‐α. Human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CM) were subsequently incubated for 24 h in the media extracted from THP‐1 cells incubated with LPS, MPLA alone, or in combination with CBD or C34. Voltage‐clamp experiments showed a right shift in the voltage dependence of NaV1.5 activation, steady state fast inactivation (SSFI), increased persistent current and prolonged in silico action potential duration in hiSPC‐CMs incubated in the LPS or MPLA‐THP‐1 media. Co‐incubation with CBD or C34 rescued the biophysical dysfunction caused by LPS and MPLA. Conclusion Our results suggest that CBD may protect against sepsis‐induced inflammation and subsequent arrhythmias through (i) inhibition of the release of inflammatory cytokines, antioxidant and anti‐apoptotic effects and/or (ii) a direct effect on NaV1.5.

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Section: Resultsmentioning

confidence: 99%

Anti‐inflammatory effects of cannabidiol against lipopolysaccharides in cardiac sodium channels

Fouda

Mohamed

Fernandez

et al. 2022

British J Pharmacology

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“…Among the CBD targets, the family of Nav channels are particularly interesting for three reasons. First, Dravet syndrome, the most notable condition for which CBD is efficacious, is commonly linked to genetic mutations in Nav1.1 (Yu et al, 2006;Kalume et al, 2007Kalume et al, , 2015Dravet, 2011;Devinsky et al, 2014;Peters et al, 2016;Gorman et al, 2021;Fouda et al, 2022). Nav1.1 is a key regulator of excitability in inhibitory circuits within the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

“…Second, CBD is reputed to have therapeutic value, substantiated by preclinical and animal studies, for a variety of excitability related disorders including pain, seizures, muscular problems, and arrhythmias, among others Iannotti et al, 2019;Ghovanloo and Ruben, 2021). Dysfunction of various Nav channels in different tissues could trigger any of the noted conditions (Ghovanloo et al, 2016;Fouda et al, 2022). Third, amphiphilic compounds (e.g., Triton X-100) (Lundbaek et al, 2010) that modulate membrane elasticity (with properties that are similar to CBD) have been shown to allosterically stabilize Nav channel inactivation (Lundbaek, 2005;Lundbaek et al, 2010;Ghovanloo et al, 2022b).…”

Section: Introductionmentioning

confidence: 99%

Non-psychotropic phytocannabinoid interactions with voltage-gated sodium channels: An update on cannabidiol and cannabigerol

et al. 2022

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Phytocannabinoids, found in the plant, Cannabis sativa, are an important class of natural compounds with physiological effects. These compounds can be generally divided into two classes: psychoactive and non-psychoactive. Those which do not impart psychoactivity are assumed to predominantly function via endocannabinoid receptor (CB) -independent pathways and molecular targets, including other receptors and ion channels. Among these targets, the voltage-gated sodium (Nav) channels are particularly interesting due to their well-established role in electrical signalling in the nervous system. The interactions between the main non-psychoactive phytocannabinoid, cannabidiol (CBD), and Nav channels were studied in detail. In addition to CBD, cannabigerol (CBG), is another non-psychoactive molecule implicated as a potential therapeutic for several conditions, including pain via interactions with Nav channels. In this mini review, we provide an update on the interactions of Nav channels with CBD and CBG.

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“…Importantly, V D1 from the small bin was significantly more hyperpolarized than the large bin, which is consistent with a stronger presence of Nav1.6 than Nav1.7 in the larger cells (p < 0.05). Next, we measured the amount of non-inactivating current at the most positive potential (+25 mV) from the steady-state inactivation curves 43 ( Figure 3 I). We found that the small capacitance cells had significantly larger persistent currents than either medium or large capacitance neurons (p < 0.05).…”

Section: Resultsmentioning

confidence: 99%

High-throughput combined voltage-clamp/current-clamp analysis of freshly isolated neurons

Ghovanloo

Tyagi

Zhao

et al. 2023

Cell Reports Methods

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Late sodium current: incomplete inactivation triggers seizures, myotonias, arrhythmias, and pain syndromes

Abstract: support-information-section).

Cited by 15 publications

References 156 publications

Anti‐inflammatory effects of cannabidiol against lipopolysaccharides in cardiac sodium channels

Anti‐inflammatory effects of cannabidiol against lipopolysaccharides in cardiac sodium channels

Non-psychotropic phytocannabinoid interactions with voltage-gated sodium channels: An update on cannabidiol and cannabigerol

High-throughput combined voltage-clamp/current-clamp analysis of freshly isolated neurons

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