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Benjamin E Blass
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March 8, 2018: ACS Medicinal Chemistry Letters
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
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
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
César Mattei
Tetrodotoxin (TTX), the mode of action of which has been known since the 1960s, is widely used in pharmacology as a specific inhibitor of voltage-gated sodium channels (Nav channels). This toxin has contributed to the characterization of the allosteric model of the Nav channel, and to discriminating TTX-sensitive and TTX-resistant subtypes. In addition to its role as a pharmacological tool, TTX is now considered a therapeutic molecule, and its development should lead to its use in certain pathologies involving Nav channels, particularly in the field of pain...
February 22, 2018: Marine Drugs
Iris M de Lange, Marco J Koudijs, Ruben van 't Slot, Boudewijn Gunning, Anja C M Sonsma, Lisette J J M van Gemert, Flip Mulder, Ellen C Carbo, Marjan J A van Kempen, Nienke E Verbeek, Isaac J Nijman, Robert F Ernst, Sanne M C Savelberg, Nine V A M Knoers, Eva H Brilstra, Bobby P C Koeleman
OBJECTIVE: Phenotypes caused by de novo SCN1A pathogenic variants are very variable, ranging from severely affected patients with Dravet syndrome to much milder genetic epilepsy febrile seizures plus cases. The most important determinant of disease severity is the type of variant, with variants that cause a complete loss of function of the SCN1A protein (α-subunit of the neuronal sodium channel Nav1.1) being detected almost exclusively in Dravet syndrome patients. However, even within Dravet syndrome disease severity ranges greatly, and consequently other disease modifiers must exist...
February 20, 2018: Epilepsia
Didier Bouhassira, Nadine Attal
Neuropathic pain represents a highly unmet medical need because most of the available treatments have a modest efficacy or dose-limiting side effects. Hence, novel therapeutic perspectives are warranted. Many compounds acting on new pain targets are in preclinical or early clinical development. Only few clinical trials have suggested their clinical relevance in neuropathic pain. This concerns in particular NaV1.7 antagonists and angiotensin type II inhibitors. Another type of emerging drug therapy in neuropathic pain is represented by drugs largely used for other indications, such as botulinum toxin A and the antiepileptic oxcarbazepine, which have recently found to be effective in peripheral neuropathic pain...
March 2018: Pain
Fernanda C Cardoso, Mahadhi Hasan, Tianjiao Zhao, Richard J Lewis
PURPOSE OF REVIEW: Pain is a distressing protective sensory experience warning of actual or potential tissue damage. Natural toxins have evolved to exploit pain and related neuronal pathways to facilitate prey capture and for defence, often producing either numbness, paralysis or intense pain by selectively modulating ion channels and receptors in pain pathways. Understanding how toxins modulate pain pathways can enhance our understanding of the physiological and pathological basis of pain...
February 12, 2018: Current Opinion in Supportive and Palliative Care
M Kollarik, H Sun, R A Herbstsomer, F Ru, M Kocmalova, S N Meeker, B J Undem
The action potential (AP) initiation in the nerve terminals and AP conduction along the axons do not necessarily depend on the same subtypes of Na V 1s. We evaluated the role of tetrodotoxin(TTX)-sensitive and TTX-resistant Na V 1s in vagal afferent nociceptor nerves derived from jugular and nodose ganglia innervating the respiratory system. Single cell RT-PCR was performed on vagal afferent neurons retrogradely labelled from the guinea pig trachea. Virtually all the jugular neurons expressed the TTX-sensitive channel Na V 1...
February 12, 2018: Journal of Physiology
Xiongzhi Zeng, Pengpeng Li, Bo Chen, Juan Huang, Ren Lai, Jingze Liu, Mingqiang Rong
Jingzhaotoxin-34 (JZTX-34) is a selective inhibitor of tetrodotoxin-sensitive (TTX-S) sodium channels. In this study, we found that JZTX-34 selectively acted on Nav1.7 with little effect on other sodium channel subtypes including Nav1.5. If the DIIS3-S4 linker of Nav1.5 is substituted by the correspond linker of Nav1.7, the sensitivity of Nav1.5 to JZTX-34 extremely increases to 1.05 µM. Meanwhile, a mutant D816R in the DIIS3-S4 linker of Nav1.7 decreases binding affinity of Nav1.7 to JZTX-34 about 32-fold...
February 2, 2018: Toxins
Ao Ri-Ge-le, Zhuang-Li Guo, Qi Wang, Bao-Jian Zhang, Da-Wei Kong, Wen-Qiang Yang, Yan-Bing Yu, Li Zhang
Painful diabetic neuropathy (PDN) is one of the intractable complications of diabetes mellitus, which manifest as exaggerated pain perception. Previous studies showed that Tanshinone IIA (TIIA), one of the major bioactive extracts of Salvia miltiorrhiza Bunge, have obvious analgesic effect on different types of pain process, and the underlying analgesic mechanisms are not fully understood. The present study combined the behavioral, electrophysiological and biochemical methods to elucidate the analgesic mechanism of TIIA, using streptozotocin (STZ)-induced PDN rat models...
January 31, 2018: Experimental and Clinical Endocrinology & Diabetes
Jianying Huang, Malgorzata A Mis, Brian Tanaka, Talia Adi, Mark Estacion, Shujun Liu, Suellen Walker, Sulayman D Dib-Hajj, Stephen G Waxman
Sodium channel Nav1.7 plays a central role in pain-signaling: gain-of-function Nav1.7 mutations usually cause severe pain and loss-of-function mutations produce insensitivity to pain. The Nav1.7 I234T gain-of-function mutation, however, is linked to a dual clinical presentation of episodic pain, together with absence of pain following fractures, and corneal anesthesia. How a Nav1.7 mutation that produces gain-of-function at the channel level causes clinical loss-of-function has remained enigmatic. We show by current-clamp that expression of I234T in dorsal root ganglion (DRG) neurons produces a range of membrane depolarizations including a massive shift to >-40 mV that reduces excitability in a small number of neurons...
January 29, 2018: Scientific Reports
Katrin Schrenk-Siemens, Corinna Rösseler, Angelika Lampert
Chronic pain patients are often left with insufficient treatment as the pathophysiology especially of neuropathic pain remains enigmatic. Recently, genetic variations in the genes of the voltage-gated sodium channels (Navs) were linked to inherited neuropathic pain syndromes, opening a research pathway to foster our understanding of the pathophysiology of neuropathic pain. More than 10 years ago, the rare, inherited pain syndrome erythromelalgia was linked to mutations in the subtype Nav1.7, and since then a plethora of mutations and genetic variations in this and other Nav genes were identified...
January 28, 2018: Handbook of Experimental Pharmacology
Yang Yang, Malgorzata A Mis, Mark Estacion, Sulayman D Dib-Hajj, Stephen G Waxman
Chronic pain is a global unmet medical need. Most existing treatments are only partially effective or have side effects that limit their use. Rapid progress in elucidating the contribution of specific genes, including those that encode peripheral voltage-gated sodium channels, to the pathobiology of chronic pain suggests that it may be possible to advance pain pharmacotherapy. Focusing on voltage-gated sodium channel NaV1.7 as an example, this article reviews recent progress in developing patient-specific induced pluripotent stem cells (iPSCs) and their differentiation into sensory neurons, together with advances in structural modeling, that have provided a basis for first-in-human translational studies...
January 19, 2018: Trends in Pharmacological Sciences
Liang-Ta Yen, Yu-Chan Hsu, Jaung-Geng Lin, Ching-Liang Hsieh, Yi-Wen Lin
BACKGROUND: The mechanisms underlying fibromyalgia (FM) pain are not understood. The US Food and Drug Administration has recommended three drugs for treating FM-namely, pregabalin, duloxetine and milnacipran; however, these medications are associated with severe side effects. OBJECTIVE: To create a mouse model of FM pain using dual injections of acidic saline to cause mechanical hyperalgesia and test whether ASIC3, Nav1.7 and Nav1.8 are involved in this process and whether electroacupuncture (EA) can reverse these phenomena...
January 17, 2018: Acupuncture in Medicine: Journal of the British Medical Acupuncture Society
Alexandros H Kanellopoulos, Jennifer Koenig, Honglei Huang, Martina Pyrski, Queensta Millet, Stéphane Lolignier, Toru Morohashi, Samuel J Gossage, Maude Jay, John E Linley, Georgios Baskozos, Benedikt M Kessler, James J Cox, Annette C Dolphin, Frank Zufall, John N Wood, Jing Zhao
The voltage-gated sodium channel NaV1.7 plays a critical role in pain pathways. We generated an epitope-tagged NaV1.7 mouse that showed normal pain behaviours to identify channel-interacting proteins. Analysis of NaV1.7 complexes affinity-purified under native conditions by mass spectrometry revealed 267 proteins associated with Nav1.7 in vivo The sodium channel β3 (Scn3b), rather than the β1 subunit, complexes with Nav1.7, and we demonstrate an interaction between collapsing-response mediator protein (Crmp2) and Nav1...
January 15, 2018: EMBO Journal
Sangsu Bang, Jiho Yoo, Xingrui Gong, Di Liu, Qingjian Han, Xin Luo, Wonseok Chang, Gang Chen, Sang-Taek Im, Yong Ho Kim, Judith A Strong, Ma-Zhong Zhang, Jun-Ming Zhang, Seok-Yong Lee, Ru-Rong Ji
The voltage-gated Na+ channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody (SVmab) reduces Na+ currents and pain and itch responses in mice. Here, we investigated whether recombinant SVmab (rSVmab) binds to and blocks Nav1.7 similar to SVmab. ELISA tests revealed that SVmab was capable of binding to Nav1.7-expressing HEK293 cells, mouse DRG neurons, human nerve tissue, and the voltage-sensor domain II of Nav1.7. In contrast, rSVmab showed no or weak binding to Nav1...
January 15, 2018: Neuroscience Bulletin
Leigh A Nattkemper, Hong Liang Tey, Rodrigo Valdes-Rodriguez, Helen Lee, Nicholas K Mollanazar, Christian Albornoz, Kristen M Sanders, Gil Yosipovitch
To identify itch-related mediators and receptors that are differentially expressed in pruritic skin, we used RNA sequencing to analyze the complete transcriptome in skin from paired itchy, lesional and non-itchy, non-lesional skin biopsies from 25 atopic dermatitis (AD) and 25 psoriasis patients and site-matched biopsies from 30 healthy controls. This analysis identified 18,000 differentially expressed genes common between itchy atopic and psoriatic skin compared to healthy skin. Of those, almost 2,000 genes were differentially expressed between itchy and non-itchy skin in atopic and psoriatic subjects...
January 6, 2018: Journal of Investigative Dermatology
Tania Chernov-Rogan, Tianbo Li, Gang Lu, Henry Verschoof, Kuldip Khakh, Steven W Jones, Maureen H Beresini, Chang Liu, Daniel F Ortwine, Steven J McKerrall, David H Hackos, Daniel Sutherlin, Charles J Cohen, Jun Chen
Many ion channels, including Nav1.7, Cav1.3, and Kv1.3, are linked to human pathologies and are important therapeutic targets. To develop efficacious and safe drugs, subtype-selective modulation is essential, but has been extremely difficult to achieve. We postulate that this challenge is caused by the poor assay design, and investigate the Nav1.7 membrane potential assay, one of the most extensively employed screening assays in modern drug discovery. The assay uses veratridine to activate channels, and compounds are identified based on the inhibition of veratridine-evoked activities...
January 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
Peter Franz Klein-Weigel, Theresa Sophie Volz, Jutta Gisela Richter
Erythromelalgia is a rare syndrome characterized by the intermittent or, less commonly, by the permanent occurrence of extremely painful hyperperfused skin areas mainly located in the distal extremities. Primary erythromelalgia is nowadays considered to be a genetically determined neuropathic disorder affecting SCN9A, SCN10A, and SCN11A coding for NaV1.7, NaV1.8, and NaV1.9 neuronal sodium channels. Secondary forms might be associated with myeloproliferative disorders, connective tissue disease, cancer, infections, and poisoning...
January 4, 2018: VASA. Zeitschrift Für Gefässkrankheiten
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