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https://www.readbyqxmd.com/read/28804613/novel-derivatives-of-phthalimide-with-potent-anticonvulsant-activity-in-ptz-and-mes-seizure-models
#1
Asghar Davood, Maryam Iman, Hanieh Pouriaiee, Hamed Shafaroodi, Sepideh Akhbari, Leila Azimidoost, Erfan Imani, Somaieh Rahmatpour
OBJECTIVES: Phthalimide-based derivatives have anticonvulsant activity like as phenytoin by inhibition of sodium channel. In our previously research we mentioned about some phthalimide derivatives as potent anticonvulsant agents. MATERIALS AND METHODS: Fourteen analogs of 2-substituted phthalimide pharmacophore were synthesized and then were evaluated for the anticonvulsant activities in pentylenetetrazole-induced seizures (PTZ) and maximal electroshock seizure (MES) models...
April 2017: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28775062/de-novo-fgf12-fibroblast-growth-factor-12-functional-variation-is-potentially-associated-with-idiopathic-ventricular-tachycardia
#2
Qianqian Li, Yuanyuan Zhao, Gang Wu, Shanshan Chen, Yingchao Zhou, Sisi Li, Mengchen Zhou, Qian Fan, Jielin Pu, Kui Hong, Xiang Cheng, Qing Kenneth Wang, Xin Tu
BACKGROUND: Idiopathic ventricular tachycardia (VT) is a type of cardiac arrhythmia occurring in structurally normal hearts. The heritability of idiopathic VT remains to be clarified, and numerous genetic factors responsible for development of idiopathic VT are as yet unclear. Variations in FGF12 (fibroblast growth factor 12), which is expressed in the human ventricle and modulates the cardiac Na(+) channel NaV1.5, may play an important role in the genetic pathogenesis of VT. METHODS AND RESULTS: We tested the hypothesis that genetic variations in FGF12 are associated with VT in 2 independent Chinese cohorts and resequenced all the exons and exon-intron boundaries and the 5' and 3' untranslated regions of FGF12 in 320 unrelated participants with idiopathic VT...
August 3, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28751508/between-fire-and-ice-refractory-hypothermia-and-warmth-induced-pain-in-inherited-erythromelalgia
#3
See Wan Tham, Li Li, Philip Effraim, Stephen Waxman
Inherited erythromelalgia (IEM) is a well-described pain disorder caused by mutations of sodium channel Nav1.7, a peripheral channel expressed within dorsal root ganglion and the sympathetic ganglion neurons. Clinically, IEM is characterised by paroxysmal attacks of severe pain, usually in the distal extremities, triggered by warmth or exercise. Pain is not adequately treated by existing pharmacological agents. Individuals with IEM classically cool their limbs for relief, in some cases resulting in tissue injury...
July 26, 2017: BMJ Case Reports
https://www.readbyqxmd.com/read/28727712/intervertebral-foramen-injection-of-ozone-relieves-mechanical-allodynia-and-enhances-analgesic-effect-of-gabapentin-in-animal-model-of-neuropathic-pain
#4
Wen-Jun Luo, Fan Yang, Fei Yang, Wei Sun, Wei Zheng, Xiao-Liang Wang, Fang-Fang Wu, Jiang-Lin Wang, Jia-Shuang Wang, Su-Min Guan, Jun Chen
BACKGROUND: In a 5-year follow-up study in a hospital in southern China, it was shown that intervertebral foramen (IVF) injection of ozone at the involved segmental levels could significantly alleviate paroxysmal spontaneous pain and mechanical allodynia in patients with chronic, intractable postherpetic neuralgia (PHN) and improve the quality of life. However, so far no proof-of-concept studies in animals have been available. OBJECTIVE: This study was designed to investigate whether IVF ozone has an analgesic effect on animal models of neuropathic and inflammatory pain...
July 2017: Pain Physician
https://www.readbyqxmd.com/read/28710467/human-ipsc-derived-cardiomyocytes-cultured-in-3d-engineered-heart-tissue-show-physiological-upstroke-velocity-and-sodium-current-density
#5
Marc D Lemoine, Ingra Mannhardt, Kaja Breckwoldt, Maksymilian Prondzynski, Frederik Flenner, Bärbel Ulmer, Marc N Hirt, Christiane Neuber, András Horváth, Benjamin Kloth, Hermann Reichenspurner, Stephan Willems, Arne Hansen, Thomas Eschenhagen, Torsten Christ
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a promising tool for drug testing and modelling genetic disorders. Abnormally low upstroke velocity is a current limitation. Here we investigated the use of 3D engineered heart tissue (EHT) as a culture method with greater resemblance to human heart tissue in comparison to standard technique of 2D monolayer (ML) format. INa was measured in ML or EHT using the standard patch-clamp technique. INa density was ~1.8 fold larger in EHT (-18...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28683073/high-throughput-electrophysiological-assays-for-voltage-gated-ion-channels-using-syncropatch-768pe
#6
Tianbo Li, Gang Lu, Eugene Y Chiang, Tania Chernov-Rogan, Jane L Grogan, Jun Chen
Ion channels regulate a variety of physiological processes and represent an important class of drug target. Among the many methods of studying ion channel function, patch clamp electrophysiology is considered the gold standard by providing the ultimate precision and flexibility. However, its utility in ion channel drug discovery is impeded by low throughput. Additionally, characterization of endogenous ion channels in primary cells remains technical challenging. In recent years, many automated patch clamp (APC) platforms have been developed to overcome these challenges, albeit with varying throughput, data quality and success rate...
2017: PloS One
https://www.readbyqxmd.com/read/28682065/discovery-of-clinical-candidate-4-2-5-amino-1h-pyrazol-4-yl-4-chlorophenoxy-5-chloro-2-fluoro-n-1-3-thiazol-4-ylbenzenesulfonamide-pf-05089771-design-and-optimization-of-diaryl-ether-aryl-sulfonamides-as-selective-inhibitors-of-nav1-7
#7
Nigel A Swain, Dave Batchelor, Serge Beaudoin, Bruce M Bechle, Paul A Bradley, Alan D Brown, Bruce Brown, Ken J Butcher, Richard P Butt, Mark L Chapman, Stephen Denton, David Ellis, Sebastien R G Galan, Steven M Gaulier, Ben S Greener, Marcel J de Groot, Mel S Glossop, Ian K Gurrell, Jo Hannam, Matthew S Johnson, Zhixin Lin, Christopher J Markworth, Brian E Marron, David S Millan, Shoko Nakagawa, Andy Pike, David Printzenhoff, David J Rawson, Sarah J Ransley, Steven M Reister, Kosuke Sasaki, R Ian Storer, Paul A Stupple, Christopher W West
A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics...
August 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28676574/aberrant-sodium-channel-currents-and-hyperexcitability-of-medial-entorhinal-cortex-neurons-in-a-mouse-model-of-scn8a-encephalopathy
#8
Matteo Ottolini, Bryan S Barker, Ronald P Gaykema, Miriam H Meisler, Manoj K Patel
SCN8A encephalopathy, or early infantile epileptic encephalopathy 13 (EIEE13), is caused predominantly by de novo gain-of-function mutations in the voltage-gated sodium (Na) channel Nav1.6. Affected individuals suffer from refractory seizures, developmental delay, cognitive disability and elevated risk of sudden unexpected death in epilepsy (SUDEP). A knock-in mouse model carrying the patient mutation p.Asn1768Asp (N1768D) reproduces many features of the disorder including spontaneous seizures and SUDEP. We used the mouse model to examine the effects of the mutation on layer II stellate neurons of the medial entorhinal cortex (mEC), which transmit excitatory input to the hippocampus...
July 4, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28675424/predicting-qrs-and-pr-interval-prolongations-in-humans-using-nonclinical-data
#9
L Bergenholm, J Parkinson, J Mettetal, N D Evans, M J Chappell, T Collins
BACKGROUND AND PURPOSE: Risk of cardiac conduction slowing (QRS/PR prolongations) is assessed prior to clinical trials using in vitro and in vivo studies. Understanding the quantitative translation of these studies to the clinical situation enables improved risk assessment in the nonclinical phase. EXPERIMENTAL APPROACH: Four compounds that prolong QRS and/or PR (AZD1305, flecainide, quinidine and verapamil) were characterised using in vitro (sodium/calcium channels), in vivo (guinea pigs/dogs) and clinical data...
July 3, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28620319/vascular-endothelial-growth-factor-b-induces-a-distinct-electrophysiological-phenotype-in-mouse-heart
#10
Nikolay Naumenko, Jenni Huusko, Tomi Tuomainen, Jussi T Koivumäki, Mari Merentie, Erika Gurzeler, Kari Alitalo, Riikka Kivelä, Seppo Ylä-Herttuala, Pasi Tavi
Vascular endothelial growth factor B (VEGF-B) is a potent mediator of vascular, metabolic, growth, and stress responses in the heart, but the effects on cardiac muscle and cardiomyocyte function are not known. The purpose of this study was to assess the effects of VEGF-B on the energy metabolism, contractile, and electrophysiological properties of mouse cardiac muscle and cardiac muscle cells. In vivo and ex vivo analysis of cardiac-specific VEGF-B TG mice indicated that the contractile function of the TG hearts was normal...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28609318/biochemical-and-pharmacological-characterization-of-a-mice-model-of-complex-regional-pain-syndrome
#11
Vaskar Das, Jeffrey S Kroin, Mario Moric, Asokumar Buvanendran
BACKGROUND AND OBJECTIVES: Complex regional pain syndrome is a challenging disease to treat. Recently, a mouse fracture model of complex regional pain syndrome has been developed that has many signs of the clinical syndrome. However, many aspects of the sensory neuron biochemistry and behavioral and pharmacological characterization of this model remain to be clarified. METHODS: Mice were randomly assigned to fracture/cast or control (naive) groups. Fracture/cast mice underwent a closed distal tibia facture, with hindlimb wrapped in casting tape for 3 weeks...
July 2017: Regional Anesthesia and Pain Medicine
https://www.readbyqxmd.com/read/28560448/multiple-nav1-5-isoforms-are-functionally-expressed-in-the-brain-and-present-distinct-expression-patterns-compared-with-cardiac-nav1-5
#12
Jun Wang, Shao-Wu Ou, Yun-Fei Bai, Yun-Jie Wang, Zhi-Qing David Xu, Guo-Ming Luan
It has previously been demonstrated that there are various voltage gated sodium channel (Nav) 1.5 splice variants expressed in brain tissue. A total of nine Nav1.5 isoforms have been identified, however, the potential presence of further Nav1.5 variants expressed in brain neurons remains to be elucidated. The present study systematically investigated the expression of various Nav1.5 splice variants and their associated electrophysiological properties in the rat brain tissue, via biochemical analyses and whole‑cell patch clamp recording...
July 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28554967/basal-late-sodium-current-is-a-significant-contributor-to-the-duration-of-action-potential-of-guinea-pig-ventricular-myocytes
#13
Yejia Song, Luiz Belardinelli
In cardiac myocytes, an enhancement of late sodium current (INaL) under pathological conditions is known to cause prolongation of action potential duration (APD). This study investigated the contribution of INaL under basal, physiological conditions to the APD Whole-cell INaL and the APD of ventricular myocytes isolated from healthy adult guinea pigs were measured at 36°C. The INaL inhibitor GS967 or TTX was applied to block INaL The amplitude of basal INaL and the APD at 50% repolarization in myocytes stimulated at a frequency of 0...
May 2017: Physiological Reports
https://www.readbyqxmd.com/read/28552773/voltage-gated-ion-channels-blockade-is-the-underlying-mechanism-of-bimu8-induced-cardiotoxicity
#14
Shahid Muhammad Iqbal, Rosa Lemmens-Gruber
BIMU8 is a 5-HT4a receptor agonist and used as an experimental drug to counteract opioid induced respiratory depression. In preliminary experiments serious disturbances in ECG were observed in anesthetized rabbits which prompted us to explore the underlying cause of BIMU8 induced abnormal changes in ECG recordings. Electrophysiological experiments were performed on HEK-293 cells expressing hERG, CaV1.2 and NaV1.5 ion channels. In whole-cell recordings BIMU8 effectively blocked these three channels, with IC50 values of 0...
August 5, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28544933/cardiotoxic-effect-of-levofloxacin-and-ciprofloxacin-in-rats-with-without-acute-myocardial-infarction-impact-on-cardiac-rhythm-and-cardiac-expression-of-kv4-3-kv1-2-and-nav1-5-channels
#15
Ahmed M Abdelrady, Sawsan A Zaitone, Noha E Farag, Manal S Fawzy, Yasser M Moustafa
Prolongation of QT interval is possible with fluoroquinolones, yet the underlying contributing factors have not been elucidated. Two widely used fluoroquinolone drugs were at the focus of this study in rats with/without acute myocardial dysfunction (AMI) induced by isoproterenol. The effects of levofloxacin and ciprofloxacin on the cardiac mRNA expression of rat Kv4.3, Kv1.2 and Nav1.5 mRNAs were determined. Administration of the two antibiotics produced dose-dependent changes in ECG parameters that were more prominent in rats with AMI than healthy rats; this was accompanied by elevations in serum lactate dehydrogenase and creatine kinase-MB...
August 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28529474/mir-30b-attenuates-neuropathic-pain-by-regulating-voltage-gated-sodium-channel-nav1-3-in-rats
#16
Songxue Su, Jinping Shao, Qingzan Zhao, Xiuhua Ren, Weihua Cai, Lei Li, Qian Bai, Xuemei Chen, Bo Xu, Jian Wang, Jing Cao, Weidong Zang
Nav1.3 is a tetrodotoxin-sensitive isoform among voltage-gated sodium channels that are closely associated with neuropathic pain. It can be up-regulated following nerve injury, but its biological function remains uncertain. MicroRNAs (miRNAs) are endogenous non-coding RNAs that can regulate post-transcriptional gene expression by binding with their target mRNAs. Using Target Scan software, we discovered that SCN3A is the major target of miR-30b, and we then determined whether miR-30b regulated the expression of Nav1...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28522250/ppargamma-agonists-rescue-increased-phosphorylation-of-fgf14-at-s226-in-the-tg2576-mouse-model-of-alzheimer-s-disease
#17
Wei-Chun J Hsu, Norelle C Wildburger, Sigmund J Haidacher, Miroslav N Nenov, Oluwarotimi Folorunso, Aditya K Singh, Brent C Chesson, Whitney F Franklin, Ibdanelo Cortez, Rovshan G Sadygov, Kelly T Dineley, Jay S Rudra, Giulio Taglialatela, Cheryl F Lichti, Larry Denner, Fernanda Laezza
BACKGROUND: Cognitive impairment in humans with Alzheimer's disease (AD) and in animal models of Aβ-pathology can be ameliorated by treatments with the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ) agonists, such as rosiglitazone (RSG). Previously, we demonstrated that in the Tg2576 animal model of AD, RSG treatment rescued cognitive deficits and reduced aberrant activity of granule neurons in the dentate gyrus (DG), an area critical for memory formation...
September 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28503166/inhibition-of-ectopic-arginine-vasopressin-production-by-phenytoin-in-the-small-cell-lung-cancer-cell-line-lu-165
#18
Takahiro Ohta, Mitsuo Mita, Shigeru Hishinuma, Reiko Ishii-Nozawa, Kazuhisa Takahashi, Masaru Shoji
Phenytoin, a voltage-gated sodium channel (NaV channel) antagonist, reportedly inhibits arginine vasopressin (AVP) release from an isolated rat neurohypophysis. So far, it is uncertain whether phenytoin has a direct action on ectopic AVP-producing neuroendocrine tumors. We studied the effect of phenytoin on the release of copeptin, the C-terminal fragment of pro-AVP, and expression of AVP gene in the human small cell lung cancer cell line Lu-165. Cells were maintained in RPMI1640 medium with 10% fetal bovine serum and were used within the fifth passage...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28473457/pharmacologic-characterization-of-amg8379-a-potent-and-selective-small-molecule-sulfonamide-antagonist-of-the-voltage-gated-sodium-channel-nav1-7
#19
Thomas J Kornecook, Ruoyuan Yin, Stephen Altmann, Xuhai Be, Virginia Berry, Christopher P Ilch, Michael Jarosh, Danielle Johnson, Josie H Lee, Sonya G Lehto, Joseph Ligutti, Dong Liu, Jason Luther, David Matson, Danny Ortuno, John Roberts, Kristin Taborn, Jinti Wang, Matthew M Weiss, Violeta Yu, Dawn X D Zhu, Robert T Fremeau, Bryan D Moyer
Potent and selective antagonists of the voltage-gated sodium channel NaV1.7 represent a promising avenue for the development of new chronic pain therapies. We generated a small molecule atropisomer quinolone sulfonamide antagonist AMG8379 and a less active enantiomer AMG8380. Here we show that AMG8379 potently blocks human NaV1.7 channels with an IC50 of 8.5 nM and endogenous tetrodotoxin (TTX)-sensitive sodium channels in dorsal root ganglion (DRG) neurons with an IC50 of 3.1 nM in whole-cell patch clamp electrophysiology assays using a voltage protocol that interrogates channels in a partially inactivated state...
July 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28428547/the-tarantula-toxin-%C3%AE-%C3%AE-trtx-pre1a-highlights-the-importance-of-the-s1-s2-voltage-sensor-region-for-sodium-channel-subtype-selectivity
#20
Joshua S Wingerd, Christine A Mozar, Christine A Ussing, Swetha S Murali, Yanni K-Y Chin, Ben Cristofori-Armstrong, Thomas Durek, John Gilchrist, Christopher W Vaughan, Frank Bosmans, David J Adams, Richard J Lewis, Paul F Alewood, Mehdi Mobli, Macdonald J Christie, Lachlan D Rash
Voltage-gated sodium (NaV) channels are essential for the transmission of pain signals in humans making them prime targets for the development of new analgesics. Spider venoms are a rich source of peptide modulators useful to study ion channel structure and function. Here we describe β/δ-TRTX-Pre1a, a 35-residue tarantula peptide that selectively interacts with neuronal NaV channels inhibiting peak current of hNaV1.1, rNaV1.2, hNaV1.6, and hNaV1.7 while concurrently inhibiting fast inactivation of hNaV1.1 and rNaV1...
April 20, 2017: Scientific Reports
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