{"id":1832,"date":"2019-12-13T10:26:06","date_gmt":"2019-12-13T01:26:06","guid":{"rendered":"http:\/\/misterx95.myds.me\/?p=1832"},"modified":"2019-12-13T10:26:08","modified_gmt":"2019-12-13T01:26:08","slug":"2019-12-13-journal-club","status":"publish","type":"post","link":"https:\/\/misterx95.myds.me\/wordpress\/?p=1832","title":{"rendered":"2019.12.13. Journal club"},"content":{"rendered":"\n<p><strong>3\u2019-O-Methylorobol Inhibits the Voltage-Gated Sodium Channel Nav1.7 with Anti-Itch E<\/strong>ffi<strong>cacy in A Histamine-Dependent Itch Mouse Model<\/strong><\/p>\n\n\n\n<p><strong>Fan Zhang&nbsp;<\/strong>\u2020<strong>, Ying Wu&nbsp;<\/strong>\u2020<strong>, Shuwen Xue, Shuangyan Wang, Chunlei Zhang * and Zhengyu Cao *<\/strong><\/p>\n\n\n\n<p>State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China; zhangfan20111112@126.com (F.Z.); wingwycpu@126.com (Y.W.); xsw19850856166@163.com (S.X.); shuangyanwcpu@163.com (S.W.)<\/p>\n\n\n\n<p><strong>*&nbsp;<\/strong>Correspondence: zhangchunlei11@sina.com (C.Z.); zycao1999@hotmail.com (Z.C.); Tel.:&nbsp;+86-25-8618-5955 (C.Z.);&nbsp;+86-25-8618-5955 (Z.C.)<\/p>\n\n\n\n<p>\u2020&nbsp;These authors contributed equally to this work.<br>Received: 15 November 2019; Accepted: 29 November 2019; Published: 1 December 2019<\/p>\n\n\n\n<p>\udbff\udc00\udbff\udc01\udbff\udc02\udbff\udc00\udbff\udc03 \udbff\udc05\udbff\udc06\udbff\udc07<\/p>\n\n\n\n<div class=\"wp-block-file\"><a href=\"http:\/\/misterx95.myds.me\/wordpress\/wp-content\/uploads\/2019\/12\/3\u2019-O-Methylorobol-Inhibits-the-Voltage-Gated-Sodium-Channel-Nav1.7-with-Anti-Itch-Efficacy-in-A-Histamine-Dependent-Itch-Mouse-Model.pdf\">3\u2019-O-Methylorobol-Inhibits-the-Voltage-Gated-Sodium-Channel-Nav1.7-with-Anti-Itch-Efficacy-in-A-Histamine-Dependent-Itch-Mouse-Model<\/a><a href=\"http:\/\/misterx95.myds.me\/wordpress\/wp-content\/uploads\/2019\/12\/3\u2019-O-Methylorobol-Inhibits-the-Voltage-Gated-Sodium-Channel-Nav1.7-with-Anti-Itch-Efficacy-in-A-Histamine-Dependent-Itch-Mouse-Model.pdf\" class=\"wp-block-file__button\" download>Download<\/a><\/div>\n\n\n\n<p><strong>\udbff\udc08\udbff\udc09\udbff\udc0a\udbff\udc0b\udbff\udc0c\udbff\udc02\udbff\udc0d<\/strong><\/p>\n\n\n\n<p><strong>Abstract:&nbsp;<\/strong>An itch is a clinical complication that affects millions of patients. However, few treatment options are available. The voltage-gated sodium channel Nav1.7 is predominantly expressed in peripheral sensory neurons and is responsible for the rising phase of action potentials, thereby mediating nociceptive conduction. A gain-of-function mutation of Nav1.7 results in the hyperexcitability of sensory neurons and causes the inherited paroxysmal itch. Conversely, a monoclonal antibody that selectively inhibits Nav1.7 is able to effectively suppress the histamine-dependent itch in mice. Therefore, Nav1.7 inhibitors may possess the potential to relieve the itch. In the present study, using whole-cell voltage-clamp recordings, we demonstrated that 3\u2019-O-methylorobol inhibited Na+&nbsp;currents in Nav1.7-CHO cells and tetrodotoxin-sensitive Na+&nbsp;currents in mouse dorsal root ganglion (DRG) neurons with IC50&nbsp;(half-maximal inhibitory concentration) values of 3.46 and 6.60&nbsp;\u03bcM, respectively. 3\u2019-O-methylorobol also suppressed the tetrodotoxin-resistant Na+&nbsp;currents in DRG neurons, though with reduced potency (~43% inhibition at 30&nbsp;\u03bcM). 3\u2019-O-methylorobol (10&nbsp;\u03bcM) affected the Nav1.7 by shifting the half-maximal voltage (V1\/2) of activation to a depolarizing direction by ~6.76 mV, and it shifted the V1\/2&nbsp;of inactivation to a hyperpolarizing direction by ~16.79 mV. An analysis of 3\u2019-O-methylorobol activity toward an array of itch targets revealed that 3\u2019-O-methylorobol was without effect on histamine H1&nbsp;receptor, TRPV1, TRPV3, TRPV4, TRPC4 and TRPM8. The intrathecal administration of 3\u2019-O-methylorobol significantly attenuated compound 48\/80-induced histamine-dependent spontaneous scratching bouts and the expression level of&nbsp;<em>c-fos&nbsp;<\/em>in the nuclei of spinal dorsal horn neurons with a comparable efficacy to that of cyproheptadine. Our data illustrated the therapeutic potential for 3\u2019-O-methylorobol for histamine-dependent itching, and the small molecule inhibition of Nav1.7 may represent a useful strategy to develop novel therapeutics for itching.<\/p>\n\n\n\n<p><strong>Keywords:&nbsp;<\/strong>Nav1.7; 3\u2019-O-methylorobol; gating modifier; itch relief; lead compound<\/p>\n","protected":false},"excerpt":{"rendered":"<p>3\u2019-O-Methylorobol Inhibits the Voltage-Gated Sodium Channel Nav1.7 with Anti-Itch Efficacy in A Histamine-Dependent Itch Mouse Model Fan Zhang&nbsp;\u2020, Ying Wu&nbsp;\u2020, Shuwen Xue, Shuangyan Wang, Chunlei Zhang * and Zhengyu Cao * State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, School of Traditional Chinese Pharmacy, China Pharmaceutical [&hellip;]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center 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