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      Potassium Channel Activator Attenuates Salicylate-Induced Cochlear Hearing Loss Potentially Ameliorating Tinnitus

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          Abstract

          High dose sodium salicylate causes moderate, reversible hearing loss and tinnitus. Salicylate-induced hearing loss is believed to arise from a reduction in the electromotile response of outer hair cells (OHCs) and/or reduction of KCNQ4 potassium currents in OHCs, which decreases the driving force for the transduction current. Therefore, enhancing OHC potassium currents could potentially prevent salicylate-induced temporary hearing loss. In this study, we tested whether opening voltage-gated potassium channels using ICA-105665, a novel small molecule that opens KCNQ2/3 and KCNQ3/5 channels, can reduce salicylate-induced hearing loss. We found that systemic application of ICA-105665 at 10 mg/kg prevented the salicylate-induced amplitude reduction and threshold shift in the compound action potentials recorded at the round window of the cochlea. ICA-105665 also prevented the salicylate-induced reduction of distortion-product otoacoustic emission. These results suggest that ICA-105665 partially compensates for salicylate-induced cochlear hearing loss by enhancing KCNQ2/3 and KCNQ3/5 potassium currents and the motility of OHCs.

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          KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway.

          Rena Schweizer, J Hardelin, S Safieddine … (2000)
          Mutations in the potassium channel gene KCNQ4 underlie DFNA2, an autosomal dominant form of progressive hearing loss in humans. In the mouse cochlea, the transcript has been found exclusively in the outer hair cells. By using specific antibodies, we now show that KCNQ4 is situated at the basal membrane of these sensory cells. In the vestibular organs, KCNQ4 is restricted to the type I hair cells and the afferent calyx-like nerve endings ensheathing these sensory cells. Several lines of evidence suggest that KCNQ4 underlies the I(K,n) and g(K,L) currents that have been described in the outer and type I hair cells, respectively, and that are already open at resting potentials. KCNQ4 is also expressed in neurons of many, but not all, nuclei of the central auditory pathway, and is absent from most other brain regions. It is present, e.g., in the cochlear nuclei, the nuclei of the lateral lemniscus, and the inferior colliculus. This is the first ion channel shown to be specifically expressed in a sensory pathway. Moreover, the expression pattern of KCNQ4 in the mouse auditory system raises the possibility of a central component in the DFNA2 hearing loss.
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            Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI).

            Emilio Perucca, Meir Bialer, Torbjörn Tomson … (2012)
            The Eleventh Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT XI, took place in Eilat, Israel from the 6th to 10th of May 2012. About 100 basic scientists, clinical pharmacologists and neurologists from 20 countries attended the conference, whose main themes included "Indications overlapping with epilepsy" and "Securing the successful development of an investigational antiepileptic drug in the current environment". Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 1994. Like the EILAT X report, the current manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, 2-deoxy-glucose, ganaxolone, ICA-105665, imepitoin, NAX 801-2, perampanel and other AMPA receptor antagonists, tonabersat, valnoctamide and its homologue sec-propylbutylacetamide (SPD), VX-765 and YK3089. Since the previous Eilat conference, retigabine (ezogabine) has been marketed and four newer AEDs in development (NAX 810-2, SPD, tonabersat and VX-765) are included in this manuscript. Copyright © 2012 Elsevier B.V. All rights reserved.
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              Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness.

              R. Nouvian, T Kharkovets, Thomas Jentsch … (2006)
              KCNQ4 is an M-type K+ channel expressed in sensory hair cells of the inner ear and in the central auditory pathway. KCNQ4 mutations underlie human DFNA2 dominant progressive hearing loss. We now generated mice in which the KCNQ4 gene was disrupted or carried a dominant negative DFNA2 mutation. Although KCNQ4 is strongly expressed in vestibular hair cells, vestibular function appeared normal. Auditory function was only slightly impaired initially. It then declined over several weeks in Kcnq4-/- mice and over several months in mice carrying the dominant negative allele. This progressive hearing loss was paralleled by a selective degeneration of outer hair cells (OHCs). KCNQ4 disruption abolished the I(K,n) current of OHCs. The ensuing depolarization of OHCs impaired sound amplification. Inner hair cells and their afferent synapses remained mostly intact. These cells were only slightly depolarized and showed near-normal presynaptic function. We conclude that the hearing loss in DFNA2 is predominantly caused by a slow degeneration of OHCs resulting from chronic depolarization.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Neurol
                Journal ID (iso-abbrev): Front Neurol
                Journal ID (publisher-id): Front. Neurol.
                Title: Frontiers in Neurology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1664-2295
                Publication date (Electronic): 07 April 2015
                Publication date Collection: 2015
                Volume: 6
                Electronic Location Identifier: 77
                Affiliations
                [1] 1Center for Hearing and Deafness, State University of New York at Buffalo , Buffalo, NY, USA
                [2] 2Department of Otolaryngology, General Hospital of PLA , Beijing, China
                [3] 3Department of Otolaryngology, Peking University Third Hospital , Beijing, China
                [4] 4Neusentis Research Unit, Pfizer , Cambridge, UK
                Author notes

                Edited by: Jinsheng Zhang, Wayne State University, USA

                Reviewed by: Huiming Zhang, University of Windsor, Canada; Jian Wang, Dalhousie University, Canada

                *Correspondence: Wei Sun, Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, Buffalo, NY 14214, USA e-mail: weisun@ 123456buffalo.edu

                This article was submitted to Neuro-otology, a section of the journal Frontiers in Neurology.

                Article
                DOI: 10.3389/fneur.2015.00077
                PMC ID: 4387930
                PubMed ID: 25904892
                SO-VID: c9326fa5-b16f-4582-9640-8d1a49a5b138
                Copyright © Copyright © 2015 Sun, Liu, Zhang, Zhou, Manohar, Winchester, Miranda and Salvi.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 19 December 2014
                Date accepted : 20 March 2015
                Page count
                Figures: 5, Tables: 2, Equations: 0, References: 34, Pages: 6, Words: 4768
                Categories
                Subject: Neuroscience
                Subject: Original Research

                ScienceOpen disciplines: Neurology
                Keywords: salicylate,kcnq,hearing loss,compound action potential,otoacoustic emission
                Data availability:
                ScienceOpen disciplines: Neurology
                Keywords: salicylate, kcnq, hearing loss, compound action potential, otoacoustic emission

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