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.
Highlights
Aspirin, with sodium salicylate as an active ingredient, is one of the most widely used analgesic, anti-inflammatory, and antipyretic drugs [1]
Salicylate-induced sensorineural hearing loss is mainly caused by down regulation of the electromotile response of outer hair cells (OHCs), which decreases the neural output of cochlea [4,5,6,7,8,9]
We found that the activation of cochlear potassium channels using ICA-105665, an activator of KCNQ2/3 and KCNQ3/5 channels, can decrease salicylate-induced Compound action potentials (CAPs) amplitude reduction and threshold shifts
Summary
With sodium salicylate as an active ingredient, is one of the most widely used analgesic, anti-inflammatory, and antipyretic drugs [1]. Sodium salicylate at a high dose (1–10 mM) can induce a moderate, reversible cochlear hearing loss (~20–40 dB threshold elevation), tinnitus, and suppression of otoacoustic emissions (OAEs) [2, 3] These perceptual changes have generally been attributed to functional impairments in the cochlea such as a down regulation of the electromotile response of outer hair cells (OHCs) and a decrease in neural output of the cochlea [4,5,6,7,8,9]. A more recent study found that at moderate concentrations (0.1–1 mM), salicylate causes a concentration-dependent reversible reduction of a voltage-gated potassium channel, which is encoded by KCNQ4 gene of OHCs [10] This subsequently may depolarize the OHC, which would reduce the net driving force of the transduction current thereby diminishing OHC electromotility. We tested the effects of ICA105665, a novel small molecule that selectively opens KCNQ2/3 and KCNQ3/5 channels (Kv7.2/7.3 and Kv7.3/7.5) [25, 26] to determine its effects on salicylate-induced hearing loss
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