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Hui Shao, Yang Yang, Ze Mi, Guang-Xi Zhu, Ai-Ping Qi, Wei-Gang Ji, Zhi-Ru Zhu
Rhynchophylline (RIN) is a significant active component isolated from the Chinese herbal medicine Uncaria rhynchophylla. Several studies have demonstrated that RIN has a significant anticonvulsant effect in many types of epilepsy models in vivo. However, the mechanisms of the anticonvulsant effect remain elusive. Using combined methods of behavioral testing, immunofluorescence and electrophysiological recordings, we characterized the anticonvulsant effect of RIN in a pilocarpine-induced status epilepticus (SE) rat model of temporal lobe epilepsy (TLE) and investigated the underlying cellular mechanisms...
September 23, 2016: Neuroscience
Dong-Hyun Kim, Su-Jin Lee, Sang June Hahn, Jin-Sung Choi
Trifluoperazine is a phenothiazine derivative which is mainly used in the management of schizophrenia and also acts as a calmodulin inhibitor. We used the whole-cell patch-clamp technique to study the effects of trifluoperazine on human Nav1.5 (hNav1.5) currents expressed in HEK293 cells. The 50% inhibitory concentration of trifluoperazine was 15.5 ± 0.3 μM and the Hill coefficient was 2.7 ± 0.1. The effects of trifluoperazine on hNav1.5 were completely and repeatedly reversible after washout. Trifluoperazine caused depolarizing shifts in the activation and hyperpolarizing shifts in the steady-state inactivation of hNav1...
October 21, 2016: Biochemical and Biophysical Research Communications
Qin Xu, Dakshesh Patel, Xian Zhang, Richard D Veenstra
Histone deacetylase (HDAC) inhibitors are small molecule anti-cancer therapeutics that exhibit limiting cardiotoxicities including QT interval prolongation and life-threatening cardiac arrhythmias. Because the molecular mechanisms for HDAC inhibitor-induced cardiotoxicity are poorly understood, we performed whole cell patch voltage clamp experiments to measure cardiac sodium currents (INa) from wild-type neonatal mouse ventricular or human induced pluripotent stem cell derived cardiomyocytes treated with trichostatin A (TSA), vorinostat (VOR), or romidepsin (FK228)...
September 16, 2016: American Journal of Physiology. Heart and Circulatory Physiology
Linlin Yang, Quanmin Li, Xinming Liu, Shiguang Liu
Diabetes mellitus (DM) is a common chronic medical problem worldwide; one of its complications is painful peripheral neuropathy, which can substantially erode quality of life and increase the cost of management. Despite its clinical importance, the pathogenesis of painful diabetic neuropathy (PDN) is complex and incompletely understood. Voltage-gated sodium channels (VGSCs) link many physiological processes to electrical activity by controlling action potentials in all types of excitable cells. Two isoforms of VGSCs, NaV1...
2016: International Journal of Molecular Sciences
Guangyou Duan, Chongyang Han, Qingli Wang, Shanna Guo, Yuhao Zhang, Ying Ying, Penghao Huang, Li Zhang, Lawrence Macala, Palak Shah, Mi Zhang, Ningbo Li, Sulayman D Dib-Hajj, Stephen G Waxman, Xianwei Zhang
BACKGROUND: Nav1.8 sodium channels, encoded by SCN10A, are preferentially expressed in nociceptive neurons and play an important role in human pain. Although rare gain-of-function variants in SCN10A have been identified in individuals with painful peripheral neuropathies, whether more common variants in SCN10A can have an effect at the channel level and at the dorsal root ganglion, neuronal level leading to a pain disorder or an altered normal pain threshold has not been determined. RESULTS: Candidate single nucleotide polymorphism association approach together with experimental pain testing in human subjects was used to explore possible common SCN10A missense variants that might affect human pain sensitivity...
2016: Molecular Pain
M Liu, K-C Yang, S C Dudley
The cardiac Na(+) channel (Nav1.5) conducts a depolarizing inward Na(+) current that is responsible for the generation of the upstroke Phase 0 of the action potential. In heart tissue, changes in Na(+) currents can affect conduction velocity and impulse propagation. The cardiac Nav1.5 is also involved in determination of the action potential duration, since some channels may reopen during the plateau phase, generating a persistent or late inward current. Mutations of cardiac Nav1.5 can induce gain or loss of channel function because of an increased late current or a decrease of peak current, respectively...
2016: Current Topics in Membranes
Yiyun Lou, Fan Zhang, Yuqin Luo, Liya Wang, Shisi Huang, Fan Jin
The ubiquitously expressed serum and glucocorticoid regulated kinase 1 (SGK1) is tightly regulated by osmotic and hormonal signals, including glucocorticoids and mineralocorticoids. Recently, SGK1 has been implicated as a signal hub for the regulation of sodium transport. SGK1 modulates the activities of multiple ion channels and carriers, such as epithelial sodium channel (ENaC), voltage-gated sodium channel (Nav1.5), sodium hydrogen exchangers 1 and 3 (NHE1 and NHE3), sodium-chloride symporter (NCC), and sodium-potassium-chloride cotransporter 2 (NKCC2); as well as the sodium-potassium adenosine triphosphatase (Na⁺/K⁺-ATPase) and type A natriuretic peptide receptor (NPR-A)...
2016: International Journal of Molecular Sciences
Weihua Cai, Jing Cao, Xiuhua Ren, Liang Qiao, Xuemei Chen, Ming Li, Weidong Zang
BACKGROUND: Abnormal acute pain after burn injury still torments patients severely. In this study, we investigated that one voltage gated sodium channel Nav1.7 plays a vital role in lowering heat pain threshold after burn injury, and the hypothesis that knockdown of Nav1.7 attenuates pain following burn injury. METHODS: Sixty eight adult male Sprague-Dawley rats were divided into 4 treatment groups: (1) sham, which hind paw was put on the room temperature metal plate for 15 s (2) burn model, which hind paw was put on the 85 °C metal plate for 15 s...
2016: BMC Anesthesiology
Nicola Price, Rostam Namdari, Judith Neville, Katie J W Proctor, Samer Kaber, Jeffery Vest, Michael Fetell, Richard Malamut, Robin Sherrington, Simon N Pimstone, Yigal P Goldberg
OBJECTIVES: To evaluate the safety and efficacy of TV-45070 ointment, as a treatment for PHN, and to explore the response in patients with the Nav1.7 R1150W gain-of-function polymorphism. METHODS: This was a randomized, placebo-controlled, 2-period, 2-treatment crossover trial. Patients with PHN with moderate or greater pain received TV-45070 and Placebo ointments, each applied twice daily for 3 weeks. The primary efficacy measure was the difference in change in mean daily pain score from baseline compared to the last week of placebo and active treatment...
July 15, 2016: Clinical Journal of Pain
K Y Yang, M J Kim, J S Ju, S K Park, C G Lee, S T Kim, Y C Bae, D K Ahn
Previous studies have demonstrated that botulinum toxin type A (BoNT-A) attenuates orofacial nociception. However, there has been no evidence of the participation of the voltage-gated sodium channels (Navs) in the antinociceptive mechanisms of BoNT-A. This study investigated the cellular mechanisms underlying the antinociceptive effects of BoNT-A in a male Sprague-Dawley rat model of trigeminal neuropathic pain produced by malpositioned dental implants. The left mandibular second molar was extracted under anesthesia, followed by a miniature dental implant placement to induce injury to the inferior alveolar nerve...
September 2016: Journal of Dental Research
Mariet P Van't Klooster, Nilufar Foadi, Axel Hage, Carsten Stoetzer, Florian Wegner, Mirjam Eberhardt, Andreas Leffler
5-hydroxytryptamine 3 receptor (5-HT3 receptor) antagonists are administered for prevention and therapy of nausea and vomiting. Although regarded as safe therapeutics, they can also provoke arrhythmias by prolonging the QRS interval. However, the mechanisms mediating this cardiotoxicity are poorly understood. Here we investigated effects of 5-HT3 receptor antagonists on the cardiac Na(+) channel Nav1.5. We explored the interaction of dolasetron, tropisetron, granisetron and ondansetron on the human α-subunit Nav1...
October 15, 2016: European Journal of Pharmacology
Bianca T A de Greef, Ingemar S J Merkies, Margot Geerts, Catharina G Faber, Janneke G J Hoeijmakers
BACKGROUND: Small fiber neuropathy generally leads to considerable pain and autonomic symptoms. Gain-of-function mutations in the SCN9A- gene, which codes for the Nav1.7 voltage-gated sodium channel, have been reported in small fiber neuropathy, suggesting an underlying genetic basis in a subset of patients. Currently available sodium channel blockers lack selectivity, leading to cardiac and central nervous system side effects. Lacosamide is an anticonvulsant, which blocks Nav1.3, Nav1...
2016: Trials
Wenhua Xu, Jun Zhang, Yuanyin Wang, Liecheng Wang, Xuxia Wang
Voltage-gated sodium channels (VGSCs), especially the tetrodotoxin-sensitive Nav1.3 and Nav1.7, and the tetrodotoxin-resistant Nav1.8 and Nav1.9, have been implicated in acute and chronic neuropathic pain. The aim of this study was to investigate the expression of VGSC Nav1.3, Nav1.7, Nav1.8, and Nav1.9 after nerve injury and their roles in the development of trigeminal neuralgia (TN). We used the infraorbital nerve-chronic constriction injury model of TN in the rat. The time course of changes in the mechanical pain threshold was examined...
August 17, 2016: Neuroreport
Elif Kubat Öktem, Karen Mruk, Joshua Chang, Ata Akin, William R Kobertz, Robert H Brown
No abstract text is available yet for this article.
June 7, 2016: Journal of Biological Physics
Bhawana Gupta, Sabyasachi Chakraborty, Soumya Saha, Sunita Gulabsingh Chandel, Atul Kumar Baranwal, Manish Banerjee, Mousumi Chatterjee, Ashok Chaudhury
Shikonin possess a diverse spectrum of pharmacological properties in multiple therapeutic areas. However, the nociceptive effect of shikonin is not largely known. To investigate the antinociceptive potential of shikonin, panel of GPCRs, ion channels, and enzymes involved in pain pathogenesis were studied. To evaluate the translation of shikonin efficacy in vivo, it was tested in 3 established rat pain models. Our study reveals that shikonin has significant inhibitory effect on pan sodium channel/N1E115 and NaV1...
July 2016: Canadian Journal of Physiology and Pharmacology
Haoyu Zeng, Maria I Roman, Edward Lis, Armando Lagrutta, Frederick Sannajust
FDSS/μCell is a high-speed acquisition imaging platform (Hamamatsu Ltd., Hamamatsu, Japan) that allows for simultaneous high-throughput reading under controlled conditions. We evaluated the Ca(2+) transients or optical membrane potential changes of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) (iCells) in the presence or absence of 44 pharmacological agents known to interfere with cardiac ion channels (e.g., hERG, IKs, NaV1.5, CaV1.2). We tested two Ca(2+)-sensitive fluorescence dyes (Codex ACTOne® and EarlyTox®) and a membrane potential dye (FLIPR® membrane potential dye)...
September 2016: Journal of Pharmacological and Toxicological Methods
Mette R Rosberg, Susana Alvarez, Dennis Klein, Finn Cilius Nielsen, Rudolf Martini, S Rock Levinson, Christian Krarup, Mihai Moldovan
Mice heterozygously deficient for the myelin protein P0 gene (P0+/-) develop a slowly progressing neuropathy modeling demyelinating Charcot-Marie-Tooth disease (CMT1B). The aim of the study was to investigate the long-term progression of motor dysfunction in P0+/- mice at 3, 7, 12 and 20months. By comparison with WT littermates, P0+/- showed a decreasing motor performance with age. This was associated with a progressive reduction in amplitude and increase in latency of the plantar compound muscle action potential (CMAP) evoked by stimulation of the tibial nerve at ankle...
September 2016: Neurobiology of Disease
John V Mulcahy, James R Walker, Jeffrey E Merit, Alan Whitehead, J Du Bois
The paralytic shellfish poisons are a collection of guanidine-containing natural products that are biosynthesized by prokaryote and eukaryote marine organisms. These compounds bind and inhibit isoforms of the mammalian voltage-gated Na(+) ion channel at concentrations ranging from 10(-11) to 10(-5) M. Here, we describe the de novo synthesis of three paralytic shellfish poisons, gonyautoxin 2, gonyautoxin 3, and 11,11-dihydroxysaxitoxin. Key steps include a diastereoselective Pictet-Spengler reaction and an intramolecular amination of an N-guanidyl pyrrole by a sulfonyl guanidine...
May 11, 2016: Journal of the American Chemical Society
Hugo R Arias, Federica Ravazzini, Katarzyna M Targowska-Duda, Agnieszka A Kaczor, Dominik Feuerbach, Juan C Boffi, Piotr Draczkowski, Dirk Montag, Brandon M Brown, Ana Belén Elgoyhen, Krzysztof Jozwiak, Giulia Puia
The activity of positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (AChRs), including 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), 3-furan-2-yl-N-o-tolylacrylamide (PAM-3), and 3-furan-2-yl-N-phenylacrylamide (PAM-4), was tested on a variety of ligand- [i.e., human (h) α7, rat (r) α9α10, hα3-containing AChRs, mouse (m) 5-HT3AR, and several glutamate receptors (GluRs)] and voltage-gated (i.e., sodium and potassium) ion channels, as well as on acetylcholinesterase (AChE) and β-amyloid (Aβ) content...
July 2016: International Journal of Biochemistry & Cell Biology
Jan Kubanek, Jingyi Shi, Jon Marsh, Di Chen, Cheri Deng, Jianmin Cui
Transcranial focused ultrasound (US) has been demonstrated to stimulate neurons in animals and humans, but the mechanism of this effect is unknown. It has been hypothesized that US, a mechanical stimulus, may mediate cellular discharge by activating mechanosensitive ion channels embedded within cellular membranes. To test this hypothesis, we expressed potassium and sodium mechanosensitive ion channels (channels of the two-pore-domain potassium family (K2P) including TREK-1, TREK-2, TRAAK; NaV1.5) in the Xenopus oocyte system...
2016: Scientific Reports
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