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JOURNAL ARTICLE
Neville M Ngum, Muhammad Y A Aziz, Liaque Mohammed Latif, Richard J Wall, Ian R Duce, Ian R Mellor
The human TE671 cell line was originally used as a model of medulloblastoma but has since been reassigned as rhabdomyosarcoma. Despite the characterised endogenous expression of voltage-sensitive sodium currents in these cells, the specific voltage-gated sodium channel (VGSC) subtype underlying these currents remains unknown. To profile the VGSC subtype in undifferentiated TE671 cells, endpoint and quantitative reverse transcription-PCR (qRT-PCR), western blot and whole-cell patch clamp electrophysiology were performed...
May 2022: Journal of Physiology
#22
JOURNAL ARTICLE
Camille Sanson, Rachid Boukaiba, Sylvie Houtmann, Magali-Anne Maizières, Sophie Fouconnier, Michel Partiseti, G Andrees Bohme
Drinking fresh grapefruit juice is associated with a significant prolongation of the QT segment on the electrocardiogram (ECG) in healthy volunteers. Among the prominent polyphenols contained in citrus fruits and primarily in grapefruit, the flavonoid naringenin is known to be a blocker of the human ether-a-go-go related gene (hERG) potassium channel. Here we hypothesized that naringenin could interfere with other major ion channels shaping the cardiac ventricular action potential (AP). To test this hypothesis, we examined the effects of naringenin on the seven channels comprising the Comprehensive in vitro Pro-Arrhythmia (CiPA) ion channel panel for early arrhythmogenic risk assessment in drug discovery and development...
June 2022: Naunyn-Schmiedeberg's Archives of Pharmacology
#23
JOURNAL ARTICLE
Chao-Liang Wu, Chao-Wei Chuang, Hsin-Yen Cho, Tzu-Hsien Chuang, Sheng-Nan Wu
Mirogabalin (MGB, Tarlige® ), an inhibitor of the α2 δ-1 subunit of voltage-gated Ca2+ (CaV ) channels, is used as a way to alleviate peripheral neuropathic pain and diabetic neuropathy. However, to what extent MGB modifies the magnitude, gating, and/or hysteresis of various types of plasmalemmal ionic currents remains largely unexplored. In pituitary tumor (GH3 ) cells, we found that MGB was effective at suppressing the peak (transient, I Na(T) ) and sustained (late, I Na(L) ) components of the voltage-gated Na+ current ( I Na ) in a concentration-dependent manner, with an effective IC50 of 19...
March 31, 2022: International Journal of Molecular Sciences
#24
JOURNAL ARTICLE
Mariana Brozmanova, Tomas Buday, Milena Konarska, Jana Plevkova
Cough in chronic respiratory diseases is a common symptom associated with significant comorbidities including visceral pain. Available antitussive therapy still has limited efficacy. Recent advances in the understanding of voltage-gated sodium channels (NaV s) lead to the rational hypothesis that subtype NaV 1.7 is involved in initiating cough and thus may present a promising therapeutic target for antitussive therapy. We evaluated the antitussive effect of NaV 1.7 blocker PF-05089771 administered systemically and topically in awake guinea pigs using capsaicin cough challenge...
January 31, 2022: Respiratory Physiology & Neurobiology
#25
JOURNAL ARTICLE
Kristopher M Kahlig, Liam Scott, Robert J Hatch, Andrew Griffin, Gabriel Martinez Botella, Zoë A Hughes, Marion Wittmann
OBJECTIVE: This study investigates the effects of PRAX-562 on sodium current (INa ), intrinsic neuronal excitability, and protection from evoked seizures to determine whether a preferential persistent INa inhibitor would exhibit improved preclinical efficacy and tolerability compared to two standard voltage-gated sodium channel (NaV ) blockers. METHODS: Inhibition of INa was characterized using patch clamp analysis. The effect on intrinsic excitability was measured using evoked action potentials recorded from hippocampal CA1 pyramidal neurons in mouse brain slices...
March 2022: Epilepsia
#26
JOURNAL ARTICLE
Elaine Tao, Ben Corry
Voltage-gated sodium channels (Nav) underlie the electrical activity of nerve and muscle cells. Humans have nine different subtypes of these channels, which are the target of small molecule inhibitors commonly used to treat a range of conditions. Structural studies have identified four lateral fenestrations within the Nav pore module that have been shown to influence Nav pore blocker access during resting-state inhibition. However, the structural differences between the nine subtypes are still unclear. In particular, the dimensions of the four individual fenestrations across the Nav subtypes and their differential accessibility to pore blockers is yet to be characterised...
December 24, 2021: Biophysical Journal
#27
JOURNAL ARTICLE
Gregory L Adams, Parul S Pall, Steven M Grauer, Xiaoping Zhou, Jeanine E Ballard, Marissa Vavrek, Richard L Kraus, Pierre Morissette, Nianyu Li, Stefania Colarusso, Elisabetta Bianchi, Anandan Palani, Rebecca Klein, Christopher T John, Deping Wang, Matthew Tudor, Andrew F Nolting, Mirlinda Biba, Timothy Nowak, Alexey A Makarov, Mikhail Reibarkh, Alexei V Buevich, Wendy Zhong, Erik L Regalado, Xiao Wang, Qi Gao, Aurash Shahripour, Yuping Zhu, Daniele de Simone, Tommaso Frattarelli, Nicolo' Maria Pasquini, Paola Magotti, Roberto Iaccarino, Yuxing Li, Kelli Solly, Keun-Joong Lee, Weixun Wang, Feifei Chen, Haoyu Zeng, Jixin Wang, Hilary Regan, Rupesh P Amin, Christopher P Regan, Christopher S Burgey, Darrell A Henze, Chengzao Sun, David M Tellers
Inhibitor cystine knot peptides, derived from venom, have evolved to block ion channel function but are often toxic when dosed at pharmacologically relevant levels in vivo . The article describes the design of analogues of ProTx-II that safely display systemic in vivo blocking of Nav 1.7, resulting in a latency of response to thermal stimuli in rodents. The new designs achieve a better in vivo profile by improving ion channel selectivity and limiting the ability of the peptides to cause mast cell degranulation...
December 21, 2021: Journal of Medicinal Chemistry
#28
JOURNAL ARTICLE
Daigo Asano, Syoya Hamaue, Hamim Zahir, Hideyuki Shiozawa, Yumi Nishiya, Takako Kimura, Miho Kazui, Naotoshi Yamamura, Marie Ikeguchi, Takahiro Shibayama, Shin-Ichi Inoue, Tsuyoshi Shinozuka, Toshiyuki Watanabe, Chizuko Yahara, Nobuaki Watanabe, Kouichi Yoshinari
Predicting human disproportionate metabolites is difficult, especially when drugs undergo species-specific metabolism mediated by cytochrome P450s (P450s) and/or non-P450 enzymes. This study assessed human metabolites of DS-1971a, a potent Nav 1.7-selective blocker, by performing human mass balance studies and characterizing DS-1971a metabolites, in accordance with the Metabolites in Safety Testing (MIST) guidance. In addition, we investigated the mechanism by which the major human disproportionate metabolite (M1) was formed...
December 20, 2021: Drug Metabolism and Disposition: the Biological Fate of Chemicals
#29
JOURNAL ARTICLE
Al-Shaimaa A Al-Kandery, Muddanna S Rao, Ahmed Z El-Hashim
BACKGROUND: Cough hypersensitivity is a major characteristic feature associated with several types of cough, including chronic cough, but its underlying mechanisms remain to be fully understood. Inflammatory mediators, such as prostaglandin E2 (PGE2 ), have been implicated in both peripheral induction and sensitization of the cough reflex. In this study, using a conscious guinea pig model of cough, we investigated whether PGE2 can sensitize the cough reflex via central actions and, if so, via which mechanisms...
November 18, 2021: Respiratory Research
#30
JOURNAL ARTICLE
Xin Rui Lim, Eamonn Bradley, Caoimhin S Griffin, Mark A Hollywood, Gerard P Sergeant, Keith D Thornbury
BACKGROUND AND PURPOSE: Corpus cavernosum smooth muscle (CCSM) exhibits phasic contractions that are coordinated by ion channels. Mouse models are commonly used to study erectile dysfunction, but there are few published electrophysiological studies of mouse CCSM. We describe the voltage-dependent sodium (NaV ) currents in mouse CCSM and investigate their function. EXPERIMENTAL APPROACH: We used electrophysiological, pharmacological and immunocytochemical methods to study the NaV currents in isolated CCSM cells from C57BL/6 mice...
March 2022: British Journal of Pharmacology
#31
JOURNAL ARTICLE
Hue N T Tran, Poanna Tran, Jennifer R Deuis, Kirsten L McMahon, Kuok Yap, David J Craik, Irina Vetter, Christina I Schroeder
Double-knotted peptides identified in venoms and synthetic bivalent peptide constructs targeting ion channels are emerging tools for the study of ion channel pharmacology and physiology. These highly complex and disulfide-rich peptides contain two individual cystine knots, each comprising six cysteines and three disulfide bonds. Until now, native double-knotted peptides, such as Hi1a and DkTx, have only been isolated from venom or produced recombinantly, whereas engineered double-knotted peptides have successfully been produced through enzymatic ligation using sortase A to form a seamless amide bond at the ligation site between two knotted toxins, and by alkyne/azide click chemistry, joining two peptide knots via a triazole linkage...
November 17, 2021: Bioconjugate Chemistry
#32
JOURNAL ARTICLE
Michaela Kocmalova, Ivana Kazimierova, Jana Barborikova, Marta Joskova, Sona Franova, Martina Sutovska
BACKGROUND: The presented study evaluated the suppositional changes in the airway expression of Nav1.8 and Nav1.7 and their role in the airway defense mechanisms in healthy animals and in an experimental asthma model. METHODS: The effects of the blockers inhalation on the reactivity of guinea pig airways, number of citric-acid-induced coughs and ciliary beating frequency (CBF) were tested in vivo. Chronic inflammation simulating asthma was induced by repetitive exposure to ovalbumin...
July 7, 2021: Membranes
#33
JOURNAL ARTICLE
He-Ling Niu, Ya-Ni Liu, Deng-Qi Xue, Li-Ying Dong, Hui-Jie Liu, Jing Wang, Yi-Lin Zheng, An-Ruo Zou, Li-Ming Shao, KeWei Wang
Voltage-gated sodium channel Nav1.7 robustly expressed in peripheral nociceptive neurons has been considered as a therapeutic target for chronic pain, but there is no selective Nav1.7 inhibitor available for therapy of chronic pain. Ralfinamide has shown anti-nociceptive activity in animal models of inflammatory and neuropathic pain and is currently under phase III clinical trial for neuropathic pain. Based on ralfinamide, a novel small molecule (S)-2-((3-(4-((2-fluorobenzyl) oxy) phenyl) propyl) amino) propanamide (QLS-81) was synthesized...
June 8, 2021: Acta Pharmacologica Sinica
#34
JOURNAL ARTICLE
Li Yu, Kojun Tsuji, Izumi Ujihara, Qi Liu, Nikoleta Pavelkova, Takanori Tsujimura, Makoto Inoue, Sonya Meeker, Eric Nisenbaum, Jeff S McDermott, Jeff Krajewski, Bradley J Undem, Marian Kollarik, Brendan J Canning
Our previous studies implicated the voltage-gated sodium channel subtype NaV 1.7 in the transmission of action potentials by the vagal afferent nerves regulating cough and thus identified this channel as a rational therapeutic target for antitussive therapy. But it is presently unclear whether a systemically administered small molecule inhibitor of NaV 1.7 conductance can achieve therapeutic benefit in the absence of side effects on cardiovascular function, gastrointestinal motility or respiration. To this end, we have evaluated the antitussive effects of the NaV 1...
May 16, 2021: European Journal of Pharmacology
#35
JOURNAL ARTICLE
Ivan Tochitsky, Sooyeon Jo, Nick Andrews, Masakazu Kotoda, Benjamin Doyle, Jaehoon Shim, Sebastien Talbot, David Roberson, Jinbo Lee, Louise Haste, Stephen M Jordan, Bruce D Levy, Bruce P Bean, Clifford J Woolf
BACKGROUND AND PURPOSE: Many pain-triggering nociceptor neurons express TRPV1 or TRPA1, cation-selective channels with large pores that enable permeation of QX-314, a cationic analogue of lidocaine. Co-application of QX-314 with TRPV1 or TRPA1 activators can silence nociceptors. In this study, we describe BW-031, a novel more potent cationic sodium channel inhibitor, and test whether its application alone can inhibit pain associated with tissue inflammation and whether this strategy can also inhibit cough...
October 2021: British Journal of Pharmacology
#36
JOURNAL ARTICLE
Lijo Cherian Ozhathil, Jean-Sébastien Rougier, Prakash Arullampalam, Maria C Essers, Daniela Ross-Kaschitza, Hugues Abriel
Transient receptor potential melastatin member 4 (TRPM4) encodes a Ca2+ -activated, non-selective cation channel that is functionally expressed in several tissues, including the heart. Pathogenic mutants in TRPM4 have been reported in patients with inherited cardiac diseases, including conduction blockage and Brugada syndrome. Heterologous expression of mutant channels in cell lines indicates that these mutations can lead to an increase or decrease in TRPM4 expression and function at the cell surface. While the expression and clinical variant studies further stress the importance of TRPM4 in cardiac function, the cardiac electrophysiological phenotypes in Trpm4 knockdown mouse models remain incompletely characterized...
March 26, 2021: International Journal of Molecular Sciences
#37
JOURNAL ARTICLE
Kun Tong, Ruotian Zhang, Fengzhi Ren, Tao Zhang, Junlin He, Jingchao Cheng, Zixing Yu, Fengxia Ren, Yatong Zhang, Weiguo Shi
Novel α-aminoamide derivatives containing different benzoheterocyclics moiety were synthesized and evaluated as voltage-gated sodium ion channels blocks the treatment of pain. Compounds 6a , 6e , and 6f containing the benzofuran group displayed more potent in vivo analgesic activity than ralfinamide in both the formalin test and the writhing assay. Interestingly, they also exhibited potent in vitro anti-Nav 1.7 and anti-Nav 1.8 activity in the patch-clamp electrophysiology assay. Therefore, compounds 6a , 6e , and 6f , which have inhibitory potency for two pain-related Nav targets, could serve as new leads for the development of analgesic medicines...
March 19, 2021: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
#38
JOURNAL ARTICLE
Jérôme Montnach, Stephan De Waard, Sébastien Nicolas, Sophie Burel, Nancy Osorio, Claude Zoukimian, Massimo Mantegazza, Rachid Boukaiba, Rémy Béroud, Michel Partiseti, Patrick Delmas, Céline Marionneau, Michel De Waard
BACKGROUND AND PURPOSE: Protoxin II (ProTx II) is a high affinity gating modifier that is thought to selectively block the Nav 1.7 voltage-dependent Na+ channel, a major therapeutic target for the control of pain. We aimed at producing ProTx II analogues entitled with novel functionalities for cell distribution studies and biochemical characterization of its Nav channel targets. EXPERIMENTAL APPROACH: We took advantage of the high affinity properties of the peptide, combined to its slow off rate, to design a number of new tagged analogues useful for imaging and biochemistry purposes...
July 2021: British Journal of Pharmacology
#39
JOURNAL ARTICLE
Pedro Alvarez, Oliver Bogen, Paul G Green, Jon D Levine
Adult rats previously submitted to neonatal limited bedding (NLB), a model of early-life stress, display muscle mechanical hyperalgesia and nociceptor hyperexcitability, the underlying mechanism for which is unknown. Since voltage-gated sodium channel subtype 7 (NaV 1.7) contributes to mechanical hyperalgesia in several preclinical pain models and is critical for nociceptor excitability, we explored its role in the muscle hyperalgesia exhibited by adult NLB rats. Western blot analyses demonstrated increased NaV 1...
July 2021: Journal of Pain
#40
JOURNAL ARTICLE
Liting Sun, Ruilong Xia, Jinwen Jiang, Ting Wen, Zhuoya Huang, Ran Qian, Ming-Dong Zhang, Mingcheng Zhou, Changgeng Peng
Voltage-gated sodium channels (Nav s) 1.7, 1.8, and 1.9 are predominately expressed in peripheral sensory neurons and are critical for action potential propagation in nociceptors. Unexpectedly, we found that expression of SCN9A, SCN10A, SCN11A, and SCN2A, the alpha subunit of Nav 1.7, Nav 1.8, Nav 1.9 and Nav 1.2, respectively, are up-regulated in spinal dorsal horn (SDH) neurons of miR-96 knockout mice. These mice also have de-repression of CACNA2D1/2 in DRG and display heat and mechanical allodynia that could be attenuated by intrathecal or intraperitoneal injection of Nav 1...
February 23, 2021: Progress in Neurobiology
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