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amiloride, neuroprotection

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
Dorota L Stankowska, Brett H Mueller, Hidehiro Oku, Tsunehiko Ikeda, Adnan Dibas
PURPOSE: The purpose of the current study was to assess the potential involvement of acid-sensing ion channel 1 (ASIC1) in retinal ganglion cell (RGC) death and investigate the neuroprotective effects of inhibitors of ASICs in promoting RGC survival following optic nerve crush (ONC). RESULTS: ASIC1 protein was significantly increased in optic nerve extracts at day 7 following ONC in rats. Activated calpain-1 increased at 2 and 7 days following ONC as evidenced by increased degradation of α-fodrin, known substrate of calpain...
January 2018: Current Eye Research
Laís Silva Fernandes, Neife Aparecida G Dos Santos, Guilherme Luz Emerick, Antonio Cardozo Dos Santos
Some organophosphorus compounds (OP), including the pesticide mipafox, produce late onset distal axonal degeneration, known as organophosphorus-induced delayed neuropathy (OPIDN). The underlying mechanism involves irreversible inhibition of neuropathy target esterase (NTE) activity, elevated intracellular calcium levels, increased activity of calcium-activated proteases and impaired neuritogenesis. Voltage-gated calcium channels (VGCC) appear to play a role in several neurologic disorders, including OPIDN. Therefore, this study aimed to examine and compare the neuroprotective effects of T-type (amiloride) and L-type (nimodipine) VGCC blockers induced by the inhibitory actions of mipafox on neurite outgrowth and axonal proteins of retinoic-acid-stimulated SH-SY5Y human neuroblastoma cells, a neuronal model widely employed to determine the neurotoxicity attributed to OP...
2017: Journal of Toxicology and Environmental Health. Part A
Meneka Kanagaratnam, Christopher Pendleton, Danilo Almeida Souza, Joseph Pettit, James Howells, Mark D Baker
KEY POINTS: Optic nerve axons get less excitable with warming. F-fibre latency does not shorten at temperatures above 30°C. Action potential amplitude falls when the Na+ -pump is blocked, an effect speeded by warming. Diuretics reduce the rate of action potential fall in the presence of ouabain. Our data are consistent with electroneutral entry of Na+ occurring in axons and contributing to setting the resting potential. ABSTRACT: Raising the temperature of optic nerve from room temperature to near physiological has effects on the threshold, refractoriness and superexcitability of the shortest latency (fast, F) nerve fibres, consistent with hyperpolarization...
June 1, 2017: Journal of Physiology
Graciela L Mazzone, Priyadharishini Veeraraghavan, Carlota Gonzalez-Inchauspe, Andrea Nistri, Osvaldo D Uchitel
In the spinal cord high extracellular glutamate evokes excitotoxic damage with neuronal loss and severe locomotor impairment. During the cell dysfunction process, extracellular pH becomes acid and may activate acid-sensing ion channels (ASICs) which could be important contributors to neurodegenerative pathologies. Our previous studies have shown that transient application of the glutamate analog kainate (KA) evokes delayed excitotoxic death of spinal neurons, while white matter is mainly spared. The present goal was to enquire if ASIC channels modulated KA damage in relation to locomotor network function and cell death...
February 20, 2017: Neuroscience
Xiao-Su Gu, Fen Wang, Cai-Yi Zhang, Cheng-Jie Mao, Jing Yang, Ya-Ping Yang, Sha Liu, Li-Fang Hu, Chun-Feng Liu
Paeoniflorin (PF) is the main active component extracted from the roots of Paeonialactiflora, a traditional Chinese medicine used for the treatment of neurodegenerative disorders, especially Parkinson's disease (PD). The degeneration of dopaminergic (DA-) neurons in PD may be caused by pathological activation of acid-sensing ion channels (ASICs). Thus, we designed a series of experiments to evaluate the therapeutic effects of PF and to test whether its effects are related to its inhibitory effect on ASIC1a...
November 2016: Neurochemical Research
F Beisse, R Diem
BACKGROUND: To date, high-dose corticosteroids constitute the only established treatment of acute optic neuritis (ON); however, steroids cannot prevent the loss of retinal nerve fibers. New acute therapeutic drugs are therefore being sought for a reduction of ganglion cell death. METHODS: Literature search comprising clinical studies on treatment of ON with immunomodulatory and neuroprotective drugs. RESULTS: For the immunomodulatory drug simvastatin some evidence for long-term benefits was shown, particularly regarding visual evoked potentials...
May 2016: Der Ophthalmologe: Zeitschrift der Deutschen Ophthalmologischen Gesellschaft
Tang-Peng Ou-Yang, Ge-Min Zhu, Yin-Xiu Ding, Feng Yang, Xiao-Long Sun, Wen Jiang
Accumulating data suggest that sodium-hydrogen exchangers (NHEs) play a key role in modulating seizure activity by regulating neuronal pH in the brain. Amiloride, an inhibitor of NHEs, has been demonstrated to be effective in many seizure models, although its efficacy for prolonged febrile seizures (FS) remains unclear. In this study, we investigated whether amiloride could produce neuroprotective effects in a prolonged FS model in which FS were induced in rat pups at postnatal day 10 using a heated air approach...
April 2016: Neurochemical Research
Priscila L Santos, Adriana G Guimarães, Rosana S S Barreto, Mairim R Serafini, Jullyana S S Quintans, Lucindo J Quintans-Júnior
Acid-sensing ion channels (ASICs) are scattered various cells of human body. Drugs like amiloride has demonstrated nonspecific antagonism ASICs. Toxins, such as Psalmotoxin-1, have been used in animal models. There are no drugs available in the market whose action mechanism acts through these channels. We revised all patents relating to pharmaceutical formulations of applicability in ASICs. Drugs acting as antagonist in ASIC1 or ASIC3 channels seem to be the most promising targets. Patent data have suggested a variety of approaches for selective ASICs drugs, such as neuroprotective and analgesic...
2015: Recent Patents on Biotechnology
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
Xue Sun, Jun Jin, Ji-Gang Zhang, Lin Qi, Frank Karl Braun, Xing-Ding Zhang, Feng Xu
Non-steroid anti-inflammatory drugs (NSAIDs) are generally used in the treatment of inflammation and pain through cyclooxygenase (COX) inhibition. Mounting evidence has indicated additional COX-independent targets for NSAIDs including acid-sensing ion channels (ASICs) 1a and 3. However, detailed function and mechanism of ASICs still remain largely elusive. In this study, the impact of NSAIDs on ASICs in nucleus pulposus cells of the human intervertebral disk was investigated. Nucleus pulposus cells were isolated and cultured from protruded disk tissues of 40 patients...
September 2014: Acta Biochimica et Biophysica Sinica
Masahiro Kuroiwa, Masahiko Watanabe, Hiroyuki Katoh, Kaori Suyama, Daisuke Matsuyama, Takeshi Imai, Joji Mochida
After traumatic spinal cord injury (SCI), endoplasmic reticulum (ER) stress exacerbates secondary injury, leading to expansion of demyelination and reduced remyelination due to oligodendrocyte precursor cell (OPC) apoptosis. Although recent studies have revealed that amiloride controls ER stress and leads to improvement in several neurological disorders including SCI, its mechanism is not completely understood. Here, we used a rat SCI model to assess the effects of amiloride on functional recovery, secondary damage expansion, ER stress-induced cell death and OPC survival...
October 2014: European Journal of Neuroscience
Chun-xiao Pan, Fan-rong Wu, Xiao-yu Wang, Jie Tang, Wen-fan Gao, Jin-fang Ge, Fei-hu Chen
Hepatic fibrosis is a chronic inflammation-associated disease, which is involved in the infiltration of inflammatory cells and releasing of proinflammatory cytokines. In the pathological process, protons are released by damaged cells and acidosis is considered to play a critical role in cell injury. Although the underlying mechanism (s) remain ill-defined, ASICs (acid-sensing ion channels) are assumed to be involved in this process. The diuretic, amiloride, is neuroprotective in models of cerebral ischemia, a property attributable to the inhibition of central ASICs by the drug...
September 2014: Cell Biology International
Meg A Younger, Martin Müller, Amy Tong, Edward C Pym, Graeme W Davis
An electrophysiology-based forward genetic screen has identified two genes, pickpocket11 (ppk11) and pickpocket16 (ppk16), as being necessary for the homeostatic modulation of presynaptic neurotransmitter release at the Drosophila neuromuscular junction (NMJ). Pickpocket genes encode Degenerin/Epithelial Sodium channel subunits (DEG/ENaC). We demonstrate that ppk11 and ppk16 are necessary in presynaptic motoneurons for both the acute induction and long-term maintenance of synaptic homeostasis. We show that ppk11 and ppk16 are cotranscribed as a single mRNA that is upregulated during homeostatic plasticity...
September 18, 2013: Neuron
Kwok Keung Tai, Daniel D Truong
It has been reported that both activation of N-methyl-D-aspartate receptors and acid-sensing ion channels during cerebral ischemic insult contributed to brain injury. But which of these two molecular targets plays a more pivotal role in hypoxia-induced brain injury during ischemia is not known. In this study, the neuroprotective effects of an acid-sensing cation channel blocker and an N-methyl-D-aspartate receptor blocker were evaluated in a rat model of cardiac arrest-induced cerebral hypoxia. We found that intracisternal injection of amiloride, an acid-sensing ion channel blocker, dose-dependently reduced cerebral hypoxia-induced neurodegeneration, seizures, and audiogenic myoclonic jerks...
2013: PloS One
Janusz K Rybakowski
Mood stabilizers form a cornerstone in the long-term treatment of bipolar disorder. The first representative of their family was lithium, still considered a prototype drug for the prevention of manic and depressive recurrences in bipolar disorder. Along with carbamazepine and valproates, lithium belongs to the first generation of mood stabilizers, which appeared in psychiatric treatment in the 1960s. Atypical antipsychotics with mood-stabilizing properties and lamotrigine, which were introduced in the mid-1990 s, form the second generation of such drugs...
March 2013: CNS Drugs
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
Dietrich E Lorke, Mohamed Y Hasan, Syed M Nurulain, Mohamed Shafiullah, Kamil Kuča, Georg A Petroianu
Prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors can protect against the lethal effects of organophosphorus compounds (OPCs). The usefulness of pyridostigmine, the only compound approved by the Food and Drug Administration (FDA) for such pretreatment, has been questioned. In search for more efficacious alternatives, we have examined in vivo the efficacy of a group of ten compounds with known anti-AChE activity (pyridostigmine, metoclopramide, tiapride, ranitidine, physostigmine, tacrine, amiloride, methylene blue, 7- methoxytacrine and K-27) to reduce mortality induced by the OPC methyl-paraoxon...
December 2012: CNS & Neurological Disorders Drug Targets
Nicola J Robertson, Takenori Kato, Alan Bainbridge, Manigandan Chandrasekaran, Osuke Iwata, Andrew Kapetanakis, Stuart Faulkner, Jeanie Cheong, Sachiko Iwata, Mariya Hristova, Ernest Cady, Gennadij Raivich
Na⁺/H⁺ exchanger (NHE) blockade attenuates the detrimental consequences of ischaemia and reperfusion in myocardium and brain in adult and neonatal animal studies. Our aim was to use magnetic resonance spectroscopy (MRS) biomarkers and immunohistochemistry to investigate the cerebral effects of the NHE inhibitor, methyl isobutyl amiloride (MIA) given after severe perinatal asphyxia in the piglet. Eighteen male piglets (aged < 24 h) underwent transient global cerebral hypoxia-ischaemia and were randomized to (i) saline placebo; or (ii) 3 mg/kg intravenous MIA administered 10 min post-insult and 8 hourly thereafter...
March 2013: Journal of Neurochemistry
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