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https://www.readbyqxmd.com/read/29783906/bulleyaconitine-a-attenuates-hyperexcitability-of-dorsal-root-ganglion-neurons-induced-by-spared-nerve-injury-the-role-of-preferably-blocking-nav1-7-and-nav1-3-channels
#1
Man-Xiu Xie, Jie Yang, Rui-Ping Pang, Wei-An Zeng, Han-Dong Ouyang, Yan-Qing Liu, Xian-Guo Liu
Background Oral administration of Bulleyaconitine A, an extracted diterpenoid alkaloid from Aconitum bulleyanum plants, is effective for treating chronic pain in rats and in human patients, but the underlying mechanisms are poorly understood. Results As the hyperexcitability of dorsal root ganglion neurons resulting from the upregulation of voltage-gated sodium (Nav) channels has been proved critical for development of chronic pain, we tested the effects of Bulleyaconitine A on Nav channels in rat spared nerve injury model of neuropathic pain...
January 2018: Molecular Pain
https://www.readbyqxmd.com/read/29780324/intercalated-disk-extracellular-nanodomain-expansion-in-patients-with-atrial-fibrillation
#2
Tristan B Raisch, Matthew S Yanoff, Timothy R Larsen, Mohammed A Farooqui, D Ryan King, Rengasayee Veeraraghavan, Robert G Gourdie, Joseph W Baker, William S Arnold, Soufian T AlMahameed, Steven Poelzing
Aims: Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous evidence in animal models suggests that the gap junction (GJ) adjacent nanodomain - perinexus - is a site capable of independent intercellular communication via ephaptic transmission. Perinexal expansion is associated with slowed conduction and increased ventricular arrhythmias in animal models, but has not been studied in human tissue. The purpose of this study was to characterize the perinexus in humans and determine if perinexal expansion associates with AF...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29752399/common-coding-variants-in-scn10a-are-associated-with-the-nav1-8-late-current-and-cardiac-conduction
#3
Vincenzo Macri, Jennifer A Brody, Dan E Arking, William J Hucker, Xiaoyan Yin, Honghuang Lin, Robert W Mills, Moritz F Sinner, Steven A Lubitz, Ching-Ti Liu, Alanna C Morrison, Alvaro Alonso, Ning Li, Vadim V Fedorov, Paul M Janssen, Joshua C Bis, Susan R Heckbert, Elena V Dolmatova, Thomas Lumley, Colleen M Sitlani, L Adrienne Cupples, Sara L Pulit, Christopher Newton-Cheh, John Barnard, Jonathan D Smith, David R Van Wagoner, Mina K Chung, Gus J Vlahakes, Christopher J O'Donnell, Jerome I Rotter, Kenneth B Margulies, Michael P Morley, Thomas P Cappola, Emelia J Benjamin, Donna Muzny, Richard A Gibbs, Rebecca D Jackson, Jared W Magnani, Caroline N Herndon, Stephen S Rich, Bruce M Psaty, David J Milan, Eric Boerwinkle, Peter J Mohler, Nona Sotoodehnia, Patrick T Ellinor
BACKGROUND: Genetic variants at the SCN5A / SCN10A locus are strongly associated with electrocardiographic PR and QRS intervals. While SCN5A is the canonical cardiac sodium channel gene, the role of SCN10A in cardiac conduction is less well characterized. METHODS: We sequenced the SCN10A locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue...
May 2018: Circulation. Genomic and precision medicine
https://www.readbyqxmd.com/read/29737846/design-of-conformationally-constrained-acyl-sulfonamide-isosteres-identification-of-n-1-2-4-triazolo-4-3-a-pyridin-3-yl-methane-sulfonamides-as-potent-and-selective-hnav1-7-inhibitors-for-the-treatment-of-pain
#4
Thilo Focken, Sultan Chowdhury, Alla Zenova, Michael E Grimwood, Christine Chabot, Tao Sheng, Ivan Hemeon, Shannon M Decker, Michael Wilson, Paul Bichler, Qi Jia, Shaoyi Sun, Clint Young, Sophia Lin, Samuel J Goodchild, Noah G Shuart, Elaine Chang, Zhiwei Xie, Bowen Li, Kuldip Khakh, Girish Bankar, Matthew Waldbrook, Rainbow Kwan, Karen Nelkenbrecher, Parisa Karimi Tari, Navjot Chahal, Luis Sojo, C Lee Robinette, Andrew D White, Chien-An Chen, Yi Zhang, Jodie Pang, Jae H Chang, David H Hackos, James P Johnson, Charles J Cohen, Daniel Fred Ortwine, Daniel P Sutherlin, Christoph M Dehnhardt, Brian Salvatore Safina
The sodium channel NaV1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of NaV1.7, with high selectivity over the cardiac isoform NaV1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)methanesulfonamides as selective NaV1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity...
May 8, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29723257/pharmacological-characterization-of-potent-and-selective-nav1-7-inhibitors-engineered-from-chilobrachys-jingzhao-tarantula-venom-peptide-jztx-v
#5
Bryan D Moyer, Justin K Murray, Joseph Ligutti, Kristin Andrews, Philippe Favreau, John B Jordan, Josie H Lee, Dong Liu, Jason Long, Kelvin Sham, Licheng Shi, Reto Stöcklin, Bin Wu, Ruoyuan Yin, Violeta Yu, Anruo Zou, Kaustav Biswas, Les P Miranda
Identification of voltage-gated sodium channel NaV1.7 inhibitors for chronic pain therapeutic development is an area of vigorous pursuit. In an effort to identify more potent leads compared to our previously reported GpTx-1 peptide series, electrophysiology screening of fractionated tarantula venom discovered the NaV1.7 inhibitory peptide JzTx-V from the Chinese earth tiger tarantula Chilobrachys jingzhao. The parent peptide displayed nominal selectivity over the skeletal muscle NaV1.4 channel. Attribute-based positional scan analoging identified a key Ile28Glu mutation that improved NaV1...
2018: PloS One
https://www.readbyqxmd.com/read/29722437/the-opioid-oxycodone-use-dependently-inhibits-the-cardiac-sodium-channel-nav1-5
#6
Jannis E Meents, Krisztina Juhasz, Sonja Stölzle-Feix, Vera Peuckmann-Post, Roman Rolke, Angelika Lampert
BACKGROUND AND PURPOSE: Oxycodone is a potent semi-synthetic opioid that is commonly used for the treatment of severe acute and chronic pain. However, treatment with oxycodone can lead to cardiac electrical changes, such as long-QT syndrome, potentially inducing sudden cardiac arrest. Here, we investigate whether the cardiac side effects of oxycodone can be explained by modulation of the cardiac sodium channel Nav1.5. EXPERIMENTAL APPROACH: Heterologously expressed Nav1...
May 3, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29719455/preemptive-application-of-qx-314-attenuates-trigeminal-neuropathic-mechanical-allodynia-in-rats
#7
Jeong-Ho Yoon, Jo-Young Son, Min-Ji Kim, Song-Hee Kang, Jin-Sook Ju, Yong-Chul Bae, Dong-Kuk Ahn
The aim of the present study was to examine the effects of preemptive analgesia on the development of trigeminal neuropathic pain. For this purpose, mechanical allodynia was evaluated in male Sprague-Dawley rats using chronic constriction injury of the infraorbital nerve (CCI-ION) and perineural application of 2% QX-314 to the infraorbital nerve. CCI-ION produced severe mechanical allodynia, which was maintained until postoperative day (POD) 30. An immediate single application of 2% QX-314 to the infraorbital nerve following CCI-ION significantly reduced neuropathic mechanical allodynia...
May 2018: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/29718319/characterization-of-the-nile-grass-rat-as-a-unique-model-for-type-2-diabetic-polyneuropathy
#8
Jyoti Singh, Muhammad Saad Yousuf, Kelvin E Jones, Paige T M Shelemey, Twinkle Joy, Haecy Macandili, Bradley J Kerr, Douglas W Zochodne, Yves Sauvé, Klaus Ballanyi, Christine A Webber
Type 2 diabetes (T2D) has reached pandemic proportions worldwide. Almost half of T2D patients suffer from polyneuropathy that can present as paresthesia, hyperalgesia, allodynia, or hypoesthesia. Therapeutic treatment options are largely incomplete, suggesting new avenues of research are needed. Herein, we introduce the African Nile Grass rat (NGR), which develops T2D solely by diet manipulation, as a novel T2D polyneuropathy model. The purpose of this study was to first characterize T2D-induced polyneuropathy in the NGRs before highlighting their strength as a potential prediabetic model of T2D...
April 28, 2018: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/29712513/-express-prenatal-maternal-stress-induces-visceral-hypersensitivity-of-adult-rat-offspring-through-activation-of-cystathionine-%C3%AE-synthase-signaling-in-primary-sensory-neurons
#9
Hong-Jun Wang, Xue Xu, Rui-Hua Xie, Yun-Yun Rui, Ping-An Zhang, Xiao-Jue Zhu, Guang-Yin Xu
Irritable bowel syndrome (IBS) is a disorder of unknown etiology characterized by widespread, chronic abdominal pain associated with altered bowel movements. Increasing amounts of evidence indicate that stressors presented during gestational periods could have long-term effects on the offspring's tissue structure and function, which may predispose to gastrointestinal diseases. The aim of the present study is designed to determine whether prenatal maternal stress (PMS) is a adverse factor affecting gastrointestinal sensitivity and to investigate possible mechanisms underlying PMS-induced visceral hypersensitivity in adult offspring...
January 1, 2018: Molecular Pain
https://www.readbyqxmd.com/read/29703751/gating-modifier-toxins-isolated-from-spider-venom-modulation-of-voltage-gated-sodium-channels-and-the-role-of-lipid-membranes
#10
Akello J Agwa, Steve Peigneur, Chun Yuen Chow, Nicole Lawrence, David J Craik, Jan Tytgat, Glenn F King, Sonia Troeira Henriques, Christina I Schroeder
Gating modifier toxins (GMTs) are venom-derived peptides isolated from spiders and other venomous creatures that modulate activity of disease-relevant voltage-gated ion channels and are therefore being pursued as therapeutic leads. The amphipathic surface profile of GMTs has prompted the proposal that some GMTs simultaneously bind to the cell membrane and voltage-gated ion channels in a trimolecular complex. Here we examined whether there is a relationship among spider GMT amphipathicity, membrane binding and potency or selectivity for voltage-gated sodium (NaV) channels...
April 27, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29686617/a-chimeric-nav1-8-channel-expression-system-based-on-hek293t-cell-line
#11
Xi Zhou, Yunxiao Zhang, Dongfang Tang, Songping Liang, Ping Chen, Cheng Tang, Zhonghua Liu
Among the nine voltage-gated sodium channel (NaV) subtypes, NaV1.8 is an attractive therapeutic target for pain. The heterologous expression of recombinant NaV1.8 currents is of particular importance for its electrophysiological and pharmacological studies. However, NaV1.8 expresses no or low-level functional currents when transiently transfected into non-neuronal cell lines. The present study aims to explore the molecular determinants limiting its functional expression and accordingly establish a functional NaV1...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29678208/glial-interleukin-1%C3%AE-upregulates-neuronal-sodium-channel-1-7-in-trigeminal-ganglion-contributing-to-temporomandibular-joint-inflammatory-hypernociception-in-rats
#12
Peng Zhang, Rui-Yun Bi, Ye-Hua Gan
BACKGROUND: The proinflammatory cytokine interleukin-1β (IL-1β) drives pain by inducing the expression of inflammatory mediators; however, its ability to regulate sodium channel 1.7 (Nav1.7), a key driver of temporomandibular joint (TMJ) hypernociception, remains unknown. IL-1β induces cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). We previously showed that PGE2 upregulated trigeminal ganglionic Nav1.7 expression. Satellite glial cells (SGCs) involve in inflammatory pain through glial cytokines...
April 20, 2018: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/29659026/%C3%AE-1-subunit-stabilises-sodium-channel-nav1-7-against-mechanical-stress
#13
Jannis Körner, Jannis Meents, Jan-Philipp Machtens, Angelika Lampert
Voltage-gated sodium channels are key players in neuronal excitability and pain signalling. Precise gating of these channels is crucial as small alterations can already lead to pathologic phenotypes like pain or heart failure. Mechanical stress has been shown to affect sodium channel activation and inactivation. This suggests that stabilising components are necessary to ensure precise channel gating in living organisms. Here, we show that mechanical shear stress affects voltage dependence of activation and fast inactivation of the Nav1...
April 16, 2018: Journal of Physiology
https://www.readbyqxmd.com/read/29655575/crmp2-neurofibromin-interface-drives-nf1-related-pain
#14
Aubin Moutal, Li Sun, Xiaofang Yang, Wennan Li, Song Cai, Shizhen Luo, Rajesh Khanna
An understudied symptom of the genetic disorder Neurofibromatosis type 1 (NF1) is chronic idiopathic pain. We used targeted editing of Nf1 in rats to provide direct evidence of a causal relationship between neurofibromin, the protein product of the Nf1 gene, and pain responses. Our study data identified a protein-interaction network with collapsin response meditator protein 2 (CRMP2) as a node and neurofibromin, syntaxin 1A, and the N-type voltage-gated calcium (CaV2.2) channel as interaction edges. Neurofibromin uncouples CRMP2 from syntaxin 1A...
April 12, 2018: Neuroscience
https://www.readbyqxmd.com/read/29578944/efficacy-of-the-nav1-7-blocker-pf-05089771-in-a-randomised-placebo-controlled-double-blind-clinical-study-in-subjects-with-painful-diabetic-peripheral-neuropathy
#15
Aoibhinn Mc Donnell, Susie Collins, Zahid Ali, Laura Iavarone, Raulin Surujbally, Simon Kirby, Richard P Butt
The effect of PF-05089771, a selective, peripherally restricted Nav1.7 sodium channel blocker on pain due diabetic peripheral neuropathy was investigated in a randomised, placebo and active-controlled parallel group clinical trial (NCT02215252). A 1-week placebo-run in period was followed by a 4-week treatment period and a 1-week placebo run-out/taper down period. Single-blind placebo was administered throughout run-in and run-out periods. Subjects were randomised to receive either PF-05089771 150 mg BID, pregabalin 150 mg BID or placebo during the 4-week treatment period...
March 23, 2018: Pain
https://www.readbyqxmd.com/read/29572558/modulation-of-sodium-channels-as-pharmacological-tool-for-pain-therapy-highlights-and-gaps
#16
REVIEW
Nilufar Foadi
Voltage-gated sodium channels are crucially involved in the transduction and transmission of nociceptive signals and pathological pain states. In the past decades, a lot of effort has been spent examining and characterizing biophysical properties of the different sodium channels and their role in signaling pathways. Several gains of function mutations of the sodium channels Nav1.7, Nav1.8, and Nav1.9 are associated with pain disorders. Due to their critical role in nociceptive pathways voltage-gated sodium channels are regarded interesting targets for pharmacological pain treatment...
March 23, 2018: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/29541350/acyl-sulfonamides-nav1-7-blockers-useful-for-the-treatment-of-pain
#17
EDITORIAL
Benjamin E Blass
No abstract text is available yet for this article.
March 8, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29532179/selective-ligands-and-drug-discovery-targeting-the-voltage-gated-sodium-channel-nav1-7
#18
Jian Payandeh, David H Hackos
The voltage-gated sodium (Nav) channel Nav1.7 has been the focus of intense investigation in recent years. Human genetics studies of individuals with gain-of-function and loss-of-function mutations in the Nav1.7 channel have implicated Nav1.7 as playing a critical role in pain. Therefore, selective inhibition of Nav1.7 represents a potentially new analgesic strategy that is expected to be devoid of the significant liabilities associated with available treatment options. Although the identification and development of selective Nav channel modulators have historically been challenging, a number of recent publications has demonstrated progression of increasingly subtype-selective small molecules and peptides toward potential use in preclinical or clinical studies...
March 13, 2018: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29500686/variable-epilepsy-phenotypes-associated-with-heterozygous-mutation-in-the-scn9a-gene-report-of-two-cases
#19
Cuiwei Yang, Yi Hua, Weiqin Zhang, Jialu Xu, Lu Xu, Feng Gao, Peifang Jiang
Up to now, SCN9A mutations encoding Nav1.7 have been limited to inherited pain syndromes. A few of pathogenic SCN9A mutations with or without SCN1A mutations have been identified in epileptic patients. Here, we report two heterozygous SCN9A mutations with no SCN1A mutations, which are associated with variable epilepsy phenotypes and explored the possibility of SCN9A contributing to a multifactorial etiology for epilepsy. Our findings suggest that the two SCN9A mutations (c.980G>A chr2:167149868 p.G327E; c...
March 2, 2018: Neurological Sciences
https://www.readbyqxmd.com/read/29495239/-homocysteine-induces-calcium-overload-in-neonatal-rat-atrial-cells-through-activation-of-sodium-current-and-camk%C3%A2-%C3%AE
#20
L Han, Q B Dong, Y C Wei, A C Zheng, J X Li, K Hong, Y Q Wu, X S Cheng
Objective: To investigate the effect and related mechanism of homocysteine (Hcy) on calcium overload in neonatal rat atrial cells (NRICs). Methods: NRICs were assigned to 9 groups after culture for 3 days: (1) control group; (2) Hcy group (0, 50, 100, 200, 500 μmol/L for 48 hours); (3) antioxidant group (NAC, 10 μmol/L for 24 hours); (4) Hcy+NAC group (500 μmol/L Hcy for 48 hours, then treated with 10 μmol/L NAC for 24 hours); (5) calcium/calmodulin dependent protein kinase Ⅱδ (CaMKⅡδ) inhibitor group (KN-93, 3 μmol/L KN-93 for 5 hours); (6) specific sodium current inhibitor group (ELE, 1 μmol/L ELE for 5 hours); (7) Hcy+KN-93 group (500 μmol/L Hcy for 48 hours, then treated with 3 μmol/L KN-93 for 5 hours); (8) Hcy+ELE group (500 μmol/L Hcy for 48 hours, then treated with 1 μmol/L ELE for 5 hours; (9) Hcy+KN-93+ELE group (500 μmol/L Hcy for 48 hours, then treated with 3 μmol/L KN-93 and 1 μmol/L ELE for 5 hours)...
February 24, 2018: Zhonghua Xin Xue Guan Bing za Zhi
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