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Nav 1.7 blocker

Fernanda C Cardoso, Zoltan Dekan, K Johan Rosengren, Andelain Erickson, Irina Vetter, Jennifer R Deuis, Volker Herzig, Paul F Alewood, Glenn F King, Richard J Lewis
Spider venoms are a rich source of ion channel modulators with therapeutic potential. Given the analgesic potential of subtype-selective inhibitors of voltage-gated sodium (NaV) channels, we screened spider venoms for inhibitors of human NaV1.7 (hNaV1.7) using a high-throughput fluorescent assay. Here, we describe the discovery of a novel NaV1.7 inhibitor, μ-TRTX-Tp1a (Tp1a), isolated from the venom of the Peruvian green-velvet tarantula Thrixopelma pruriens. Recombinant and synthetic forms of this 33-residue peptide preferentially inhibited hNaV1...
August 2015: Molecular Pharmacology
Niklas Telinius, Jens Majgaard, Sukhan Kim, Niels Katballe, Einar Pahle, Jørn Nielsen, Vibeke Hjortdal, Christian Aalkjaer, Donna Briggs Boedtkjer
Voltage-gated sodium channels (VGSC) play a key role for initiating action potentials (AP) in excitable cells. VGSC in human lymphatic vessels have not been investigated. In the present study, we report the electrical activity and APs of small human lymphatic collecting vessels, as well as mRNA expression and function of VGSC in small and large human lymphatic vessels. The VGSC blocker TTX inhibited spontaneous contractions in six of 10 spontaneously active vessels, whereas ranolazine, which has a narrower VGSC blocking profile, had no influence on spontaneous activity...
July 15, 2015: Journal of Physiology
Sudhish Mishra, Vitaliy Reznikov, Victor A Maltsev, Nidas A Undrovinas, Hani N Sabbah, Albertas Undrovinas
KEY POINTS: Late Na(+) current (INaL) contributes to action potential remodelling and Ca(2+)/Na(+) changes in heart failure. The molecular identity of INaL remains unclear. The contributions of different Na(+) channel isoforms, apart from the cardiac isoform, remain unknown. We discovered and characterized a substantial contribution of neuronal isoform Nav1.1 to INaL. This new component is physiologically relevant to the control of action potential shape and duration, as well as to cell Ca(2+) dynamics, especially in heart failure...
March 15, 2015: Journal of Physiology
Justin K Murray, Joseph Ligutti, Dong Liu, Anruo Zou, Leszek Poppe, Hongyan Li, Kristin L Andrews, Bryan D Moyer, Stefan I McDonough, Philippe Favreau, Reto Stöcklin, Les P Miranda
NaV1.7 is a voltage-gated sodium ion channel implicated by human genetic evidence as a therapeutic target for the treatment of pain. Screening fractionated venom from the tarantula Grammostola porteri led to the identification of a 34-residue peptide, termed GpTx-1, with potent activity on NaV1.7 (IC50 = 10 nM) and promising selectivity against key NaV subtypes (20× and 1000× over NaV1.4 and NaV1.5, respectively). NMR structural analysis of the chemically synthesized three disulfide peptide was consistent with an inhibitory cystine knot motif...
March 12, 2015: Journal of Medicinal Chemistry
Saad Javed, Ioannis N Petropoulos, Uazman Alam, Rayaz A Malik
Painful diabetic neuropathy (PDN) is a debilitating consequence of diabetes that may be present in as many as one in five patients with diabetes. The objective assessment of PDN is difficult, making it challenging to diagnose and assess in both clinical practice and clinical trials. No single treatment exists to prevent or reverse neuropathic changes or to provide total pain relief. Treatment of PDN is based on three major approaches: intensive glycaemic control and risk factor management, treatments based on pathogenetic mechanisms, and symptomatic pain management...
January 2015: Therapeutic Advances in Chronic Disease
Sudhish Mishra, Vitaliy Reznikov, Victor A Maltsev, Nidas A Undrovinas, Hani N Sabbah, Albertas Undrovinas
Late Na(+) current (INaL) contributes to action potential (AP) duration and Ca(2+) handling in cardiac cells. Augmented INaL was implicated in delayed repolarization and impaired Ca(2+) handling in heart failure (HF). We tested if Na(+) channel (Nav's) neuronal isoforms contribute to INaL and Ca(2+) cycling defects in HF in 17 dogs with HF achieved via sequential coronary artery embolizations. Six normal dogs served as control. Transient Na(+) current (INaT) and INaL in left ventricular cardiomyocytes (VCMs) were recorded by patch-clamp while Ca(2+) dynamics was monitored using fluo-4...
October 17, 2014: Journal of Physiology
Nikolaos Christidis, Isabell Kang, Brian E Cairns, Ujendra Kumar, Xudong Dong, Annika Rosén, Sigvard Kopp, Malin Ernberg
BACKGROUND: Previous studies have shown that 5-HT3-antagonists reduce muscle pain, but there are no studies that have investigated the expression of 5-HT3-receptors in human muscles. Also, tetrodotoxin resistant voltage gated sodium-channels (NaV) are involved in peripheral sensitization and found in trigeminal ganglion neurons innervating the rat masseter muscle. This study aimed to investigate the frequency of nerve fibers that express 5-HT3A-receptors alone and in combination with NaV1...
2014: Journal of Headache and Pain
R Cregg, J J Cox, D L H Bennett, J N Wood, R Werdehausen
BACKGROUND AND PURPOSE: The non-selective sodium channel inhibitor mexiletine has been found to be effective in several animal models of chronic pain and has become popular in the clinical setting as an orally available alternative to lidocaine. It remains unclear why patients with monogenic pain disorders secondary to gain-of-function SCN9a mutations benefit from a low systemic concentration of mexiletine, which does not usually induce adverse neurological side effects. The aim of this study was, therefore, to investigate the biophysical effects of mexiletine on the L858F primary erythromelalgia NaV 1...
October 2014: British Journal of Pharmacology
Nilufar Foadi, Christian Berger, Igor Pilawski, Carsten Stoetzer, Matthias Karst, Gertrud Haeseler, Florian Wegner, Andreas Leffler, Jörg Ahrens
BACKGROUND: The synthetic cannabinoid ajulemic acid has been demonstrated to alleviate pain in patients suffering from chronic neuropathic pain. Cannabinoids interact with several molecules within the pain circuit, including a potent inhibition of voltage-gated sodium channels. In this study, we closely characterized this property on neuronal and nonneuronal sodium channels. METHODS: The inhibition of sodium inward currents by ajulemic acid was studied in vitro...
June 2014: Anesthesia and Analgesia
Joanna Gajewiak, Layla Azam, Julita Imperial, Aleksandra Walewska, Brad R Green, Pradip K Bandyopadhyay, Shrinivasan Raghuraman, Beatrix Ueberheide, Marshall Bern, H Mimi Zhou, Natali A Minassian, Rebecca H Hagan, Mack Flinspach, Yi Liu, Grzegorz Bulaj, Alan D Wickenden, Baldomero M Olivera, Doju Yoshikami, Min-Min Zhang
A cone snail venom peptide, μO§-conotoxin GVIIJ from Conus geographus, has a unique posttranslational modification, S-cysteinylated cysteine, which makes possible formation of a covalent tether of peptide to its target Na channels at a distinct ligand-binding site. μO§-conotoxin GVIIJ is a 35-aa peptide, with 7 cysteine residues; six of the cysteines form 3 disulfide cross-links, and one (Cys24) is S-cysteinylated. Due to limited availability of native GVIIJ, we primarily used a synthetic analog whose Cys24 was S-glutathionylated (abbreviated GVIIJSSG)...
February 18, 2014: Proceedings of the National Academy of Sciences of the United States of America
Botond Borcsa, László Fodor, Dezső Csupor, Peter Forgo, Attila Molnár, Judit Hohmann
A new aconitane alkaloid, 1-O-demethylswatinine (1), was isolated from the root of Aconitum moldavicum together with the known compounds cammaconine (2), columbianine (3), swatinine (4), gigactonine (5), delcosine (6), lycoctonine (7), and ajacine (8). The structures were established by means of HRESIMS, 1D and 2D NMR spectroscopy, including 1H-1H COSY, NOESY, HSQC, and HMBC experiments, resulting in complete 1H-NMR chemical shift assignments for 1-4. The effects of the isolated compounds 4-8, together with eighteen other Aconitum diterpene and norditerpene alkaloids with different skeletal types and substitution patterns, were studied on Nav 1...
February 2014: Planta Medica
Yukiko Muroi, Bradley J Undem
Recent advances in our understanding of voltage-gated sodium channels (NaVs) lead to the rational hypothesis that drugs capable of selective blockade of NaV subtypes may be a safe and effective strategy for the treatment of unwanted cough. Among the nine NaV subtypes (NaV1.1-NaV1.9), the afferent nerves involved in initiating cough, in common with nociceptive neurons in the somatosensory system, express mainly NaV1.7, NaV1.8, and NaV1.9. Although knowledge about the effect of selectively blocking these channels on the cough reflex is limited, their biophysical properties indicate that each may contribute to the hypertussive and allotussive state that typifies subacute and chronic nonproductive cough...
February 2014: Lung
Ken McCormack, Sonia Santos, Mark L Chapman, Douglas S Krafte, Brian E Marron, Christopher W West, Michael J Krambis, Brett M Antonio, Shannon G Zellmer, David Printzenhoff, Karen M Padilla, Zhixin Lin, P Kay Wagoner, Nigel A Swain, Paul A Stupple, Marcel de Groot, Richard P Butt, Neil A Castle
Voltage-gated sodium (Nav) channels play a fundamental role in the generation and propagation of electrical impulses in excitable cells. Here we describe two unique structurally related nanomolar potent small molecule Nav channel inhibitors that exhibit up to 1,000-fold selectivity for human Nav1.3/Nav1.1 (ICA-121431, IC50, 19 nM) or Nav1.7 (PF-04856264, IC50, 28 nM) vs. other TTX-sensitive or resistant (i.e., Nav1.5) sodium channels. Using both chimeras and single point mutations, we demonstrate that this unique class of sodium channel inhibitor interacts with the S1-S4 voltage sensor segment of homologous Domain 4...
July 16, 2013: Proceedings of the National Academy of Sciences of the United States of America
Shai Sandalon, Birte Könnecke, Hani Levkovitch-Verbin, Mikael Simons, Katharina Hein, Muriel B Sättler, Mathias Bähr, Ron Ofri
Voltage gated sodium channels (Nav), are proposed mediators of neuronal damage in ischemic and excitotoxicity disease models. We evaluated the neuroprotective effects of lamotrigine, a Nav blocker, in the acute and chronic rat ocular hypertension models. Additionally, expression of the main Nav subtypes in the optic nerve (ON) was assessed to test whether their upregulation plays a role in the pathogenesis of ocular hypertension induced optic neuropathy. Unilateral intraocular pressure (IOP) elevation was induced for 60 min (80 mmHg) and 14-21 days (670-859 mmHg*day) in the acute and chronic models, respectively...
October 2013: Experimental Eye Research
Nicholas J Hargus, Aradhya Nigam, Edward H Bertram, Manoj K Patel
During epileptogenesis a series of molecular and cellular events occur, culminating in an increase in neuronal excitability, leading to seizure initiation. The entorhinal cortex has been implicated in the generation of epileptic seizures in both humans and animal models of temporal lobe epilepsy. This hyperexcitability is due, in part, to proexcitatory changes in ion channel activity. Sodium channels play an important role in controlling neuronal excitability, and alterations in their activity could facilitate seizure initiation...
September 2013: Journal of Neurophysiology
Najwa Abbas, Christelle Gaudioso-Tyzra, Caroline Bonnet, Mélanie Gabriac, Muriel Amsalem, Aurélie Lonigro, Françoise Padilla, Marcel Crest, Marie-France Martin-Eauclaire, Patrick Delmas
Voltage-gated Na(+) channels (Nav) are the targets of a variety of scorpion toxins. Here, we investigated the effects of Amm VIII, a toxin isolated from the venom of the scorpion Androctonus mauretanicus mauretanicus, on pain-related behaviours in mice. The effects of Amm VIII were compared with the classic scorpion α-toxin AaH II from Androctonus australis. Contrary to AaH II, intraplantar injection of Amm VIII at relatively high concentrations caused little nocifensive behaviours. However, Amm VIII induced rapid mechanical and thermal pain hypersensitivities...
August 2013: Pain
Mena Abdelsayed, Stanislav Sokolov
Epilepsy is a brain disorder characterized by seizures and convulsions. The basis of epilepsy is an increase in neuronal excitability that, in some cases, may be caused by functional defects in neuronal voltage gated sodium channels, Nav1.1 and Nav1.2. The effects of antiepileptic drugs (AEDs) as effective therapies for epilepsy have been characterized by extensive research. Most of the classic AEDs targeting Nav share a common mechanism of action by stabilizing the channel's fast-inactivated state. In contrast, novel AEDs, such as lacosamide, stabilize the slow-inactivated state in neuronal Nav1...
May 2013: Channels
Audrey J Stone, Joyce S Kim, Katsuya Yamauchi, Victor Ruiz-Velasco, Marc P Kaufman
In decerebrated rats, we determined the dose of A803467, a NaV 1.8 antagonist, needed to attenuate the reflex pressor responses to femoral arterial injections of lactic acid (24 mM; ~0.1 ml) and capsaicin (0.1 μg), agents which stimulate thin fiber afferents having NaV 1.8 channels. We also determined whether the dose of A803467 needed to attenuate these reflex responses affected the responses of muscle spindle afferents to tendon stretch and succinylcholine (200 μg). Spindle afferents are not supplied with NaV 1...
May 24, 2013: Neuroscience Letters
W-S Vanessa Ho, Alison J Davis, Preet S Chadha, Iain A Greenwood
This study investigated the molecular identity and impact of enhancing voltage-gated Na(+) (Na(V)) channels in the control of vascular tone. In rat isolated mesenteric and femoral arteries mounted for isometric tension recording, the vascular actions of the Na(V) channel activator veratridine were examined. Na(V) channel expression was probed by molecular techniques and immunocytochemistry. In mesenteric arteries, veratridine induced potent contractions (pEC(50) = 5.19 ± 0.20, E(max) = 12.0 ± 2.7 mN), which were inhibited by 1 μM TTX (a blocker of all Na(V) channel isoforms, except Na(V)1...
April 15, 2013: American Journal of Physiology. Cell Physiology
T Hagenacker, N Schäfer, D Büsselberg, M Schäfers
BACKGROUND: Lacosamide is a novel anti-epileptic drug that enhances the slow- and not fast-inactivating state of voltage-gated sodium channels. Lacosamide has demonstrated analgesic efficacy in several animal studies but preclinical studies on neuropathic pain models are rare, and recent clinical trials showed no superior analgesic effects. METHODS: Here, we examine whether an acute or chronic administration of lacosamide (3-60 mg/kg, i.p.) attenuates pain behaviour induced by spinal nerve ligation (SNL)...
July 2013: European Journal of Pain: EJP
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