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amiloride and multiple sclerosis

Heather Y Yong, Kyla A McKay, Cole G J Daley, Helen Tremlett
BACKGROUND: Several environmental and lifestyle factors have been associated with multiple sclerosis (MS) risk, including some pharmacological treatments. We systematically reviewed the literature on prescription drug exposure and MS risk. METHODS: Six databases were searched for original observational studies reporting drug exposure and MS risk published before 2017. RESULTS: Thirteen articles fulfilled inclusion criteria. Exposure to neither amiloride nor valproic acid was associated with MS (adjusted hazard ratio (adj...
February 2018: Pharmacoepidemiology and Drug Safety
Justin B McKee, Charles L Cottriall, John Elston, Simon Epps, Nikos Evangelou, Stephen Gerry, Christopher Kennard, Yazhuo Kong, Abigail Koelewyn, Wilhelm Kueker, Maria Isabel Leite, Jacqueline Palace, Matthew Craner
BACKGROUND: Recent basic and clinical evidence suggests amiloride may be neuroprotective in multiple sclerosis (MS) through the blockade of the acid sensing ion channel (ASIC). OBJECTIVE: To examine the neuroprotective efficacy of amiloride in acute optic neuritis (ON). METHODS: A total of 48 patients were recruited to a phase 2, double blind, single site, randomised controlled trial. Scanning laser polarimetry (GDx) at 6 months was the primary outcome measure and optical coherence tomography (OCT) and visual and electrophysiological measures were secondary outcome measures...
November 1, 2017: Multiple Sclerosis: Clinical and Laboratory Research
Audrey Ortega-Ramírez, Rosario Vega, Enrique Soto
Acid-sensing ion channels (ASICs) are a family of proton-sensing channels that are voltage insensitive, cation selective (mostly permeable to Na+ ), and nonspecifically blocked by amiloride. Derived from 5 genes ( ACCN1-5 ), 7 subunits have been identified, 1a, 1b, 2a, 2b, 3, 4, and 5, that are widely expressed in the peripheral and central nervous system as well as other tissues. Over the years, different studies have shown that activation of these channels is linked to various physiological and pathological processes, such as memory, learning, fear, anxiety, ischemia, and multiple sclerosis to name a few, so their potential as therapeutic targets is increasing...
2017: Mediators of Inflammation
Teresa Maria Creanza, Maria Liguori, Sabino Liuni, Nicoletta Nuzziello, Nicola Ancona
Differential gene expression analyses to investigate multiple sclerosis (MS) molecular pathogenesis cannot detect genes harboring genetic and/or epigenetic modifications that change the gene functions without affecting their expression. Differential co-expression network approaches may capture changes in functional interactions resulting from these alterations. We re-analyzed 595 mRNA arrays from publicly available datasets by studying changes in gene co-expression networks in MS and in response to interferon (IFN)-β treatment...
June 15, 2016: International Journal of Molecular Sciences
Justin B McKee, John Elston, Nikos Evangelou, Stephen Gerry, Lars Fugger, Christopher Kennard, Yazhuo Kong, Jacqueline Palace, Matthew Craner
INTRODUCTION: Neurodegeneration is a widely accepted contributor to the development of long-term disability in multiple sclerosis (MS). While current therapies in MS predominantly target inflammation and reduce relapse rate they have been less effective at preventing long-term disability. The identification and evaluation of effective neuroprotective therapies within a trial paradigm are key unmet needs. Emerging evidence supports amiloride, a licenced diuretic, as a neuroprotective agent in MS through acid sensing ion channel blockade...
November 9, 2015: BMJ Open
Hanna M Vesterinen, Peter Connick, Cadi M J Irvine, Emily S Sena, Kieren J Egan, Gary G Carmichael, Afiyah Tariq, Sue Pavitt, Jeremy Chataway, Malcolm R Macleod, Siddharthan Chandran
OBJECTIVE: To develop and implement an evidence based framework to select, from drugs already licenced, candidate oral neuroprotective drugs to be tested in secondary progressive multiple sclerosis. DESIGN: Systematic review of clinical studies of oral putative neuroprotective therapies in MS and four other neurodegenerative diseases with shared pathological features, followed by systematic review and meta-analyses of the in vivo experimental data for those interventions...
2015: PloS One
Tarunya Arun, Valentina Tomassini, Emilia Sbardella, Michiel B de Ruiter, Lucy Matthews, Maria Isabel Leite, Rose Gelineau-Morel, Ana Cavey, Sandra Vergo, Matt Craner, Lars Fugger, Alex Rovira, Mark Jenkinson, Jacqueline Palace
Neurodegeneration is the main cause for permanent disability in multiple sclerosis. The effect of current immunomodulatory treatments on neurodegeneration is insufficient. Therefore, direct neuroprotection and myeloprotection remain an important therapeutic goal. Targeting acid-sensing ion channel 1 (encoded by the ASIC1 gene), which contributes to the excessive intracellular accumulation of injurious Na(+) and Ca(2+) and is over-expressed in acute multiple sclerosis lesions, appears to be a viable strategy to limit cellular injury that is the substrate of neurodegeneration...
January 2013: Brain: a Journal of Neurology
Xiang-Ping Chu, Zhi-Gang Xiong
Acid-sensing ion channels (ASICs), a novel family of proton-gated amiloride-sensitive cation channels, are expressed primarily in neurons of peripheral sensory and central nervous systems. Recent studies have shown that activation of ASICs, particularly the ASIC1a channels, plays a critical role in neuronal injury associated with neurological disorders such as brain ischemia, multiple sclerosis, and spinal cord injury. In normal conditions in vitro, ASIC1a channels desensitize rapidly in the presence of a continuous acidosis or following a preexposure to minor pH drop, raising doubt for their contributions to the acidosis-mediated neuronal injury...
2013: Advances in Experimental Medicine and Biology
Björn Pasternak, Henrik Svanström, Nete M Nielsen, Mads Melbye, Anders Hviid
PURPOSE: Amiloride reduces functional neurological deficits and neuronal damage in animal models of multiple sclerosis (MS). We investigated whether amiloride use was associated with reduced risk of incident MS and of MS hospitalization and death in humans. METHODS: We conducted two propensity score-matched cohort studies, linking nationwide registry data on filled drug prescriptions, diagnostic information, and covariates. First, we compared rates of incident MS in new users of amiloride and new users of an active control treatment, thiazide diuretics...
August 2012: Pharmacoepidemiology and Drug Safety
Sandra Vergo, Matthew J Craner, Ruth Etzensperger, Kathrine Attfield, Manuel A Friese, Jia Newcombe, Margaret Esiri, Lars Fugger
Although there is growing evidence for a role of excess intracellular cations, particularly calcium ions, in neuronal and glial cell injury in multiple sclerosis, as well as in non-inflammatory neurological conditions, the molecular mechanisms involved are not fully determined. We previously showed that the acid-sensing ion channel 1 which, when activated under the acidotic tissue conditions found in inflammatory lesions opens to allow influx of sodium and calcium ions, contributes to axonal injury in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis...
February 2011: Brain: a Journal of Neurology
Xuanmao Chen, Liyan Qiu, Minghua Li, Stefan Dürrnagel, Beverley A Orser, Zhi-Gang Xiong, John F MacDonald
Acid-sensing ion channels (ASICs) are proton-gated cation channels that are predominantly expressed in the nervous system. ASICs are involved in a number of neurological diseases such as pain, ischemic stroke and multiple sclerosis but limited tools are available to target these channels and provide probes for their physiological functions. Here we report that the anti-protozoal diarylamidines, 4',6-diamidino-2-phenylindole (DAPI), diminazene, hydroxystilbamidine (HSB) and pentamidine potently inhibit ASIC currents in primary cultured hippocampal neurons with apparent affinities of 2...
June 2010: Neuropharmacology
Manuel A Friese, Matthew J Craner, Ruth Etzensperger, Sandra Vergo, John A Wemmie, Michael J Welsh, Angela Vincent, Lars Fugger
Multiple sclerosis is a neuroinflammatory disease associated with axonal degeneration. The neuronally expressed, proton-gated acid-sensing ion channel-1 (ASIC1) is permeable to Na+ and Ca2+, and excessive accumulation of these ions is associated with axonal degeneration. We tested the hypothesis that ASIC1 contributes to axonal degeneration in inflammatory lesions of the central nervous system (CNS). After induction of experimental autoimmune encephalomyelitis (EAE), Asic1-/- mice showed both a markedly reduced clinical deficit and reduced axonal degeneration compared to wild-type mice...
December 2007: Nature Medicine
Luisa Bernardinelli, Salvatore Bruno Murgia, Pier Paolo Bitti, Luisa Foco, Raffaela Ferrai, Luigina Musu, Inga Prokopenko, Roberta Pastorino, Valeria Saddi, Anna Ticca, Maria Luisa Piras, David Roxbee Cox, Carlo Berzuini
Multiple genome screens have been performed to identify regions in linkage or association with Multiple Sclerosis (MS, OMIM 126200), but little overlap has been found among them. This may be, in part, due to a low statistical power to detect small genetic effects and to genetic heterogeneity within and among the studied populations. Motivated by these considerations, we studied a very special population, namely that of Nuoro, Sardinia, Italy. This is an isolated, old, and genetically homogeneous population with high prevalence of MS...
May 30, 2007: PloS One
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