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

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.

Exposure to Sodium Salicylate Disrupts VGLUT3 Expression in Cochlear Inner Hair Cells and Contributes to Tinnitus

“…Recent evidence has suggested that a moderate dose of salicylate may induce tinnitus via disruption of regular neural activity in the brain (Sun et al 2015). However, this assertion is not consistent with the results of our study, suggesting that changes in VGLUT3 expression in cochlear IHCs are likely to contribute to salicylate-induced tinnitus.…”

“…The main metabolites of salicylate, the active ingredient of SS, are salicylic acid and glucuronic acid. Tinnitus induced by high doses of SS was previously characterized as temporary hearing loss and shown to be reversible (Sun et al 2015). Tinnitus induced by SS was reported to be related to damage to cochlear hair cells and spiral ganglion cells (Norena 2015).…”

Loud noise exposure differentially affects subpopulations of auditory cortex pyramidal cells

“…For example, one hour of sound stimulation quickly increases high-threshold voltage dependent potassium channel expression (responsible for sustaining high frequency firing) in brain stem auditory neurons (Leão et al, 2010). Future studies should aim to investigate how specific outward currents are affected by noise trauma, especially as potassium channel modulators are used in tinnitus treatment (Sun et al, 2015).…”

Potassium channels as promising new targets for pharmacologic treatment of tinnitus: Can Internet-based ‘crowd sensing’ initiated by patients speed up the transition from bench to bedside?

“…[11] In another recent study ICA-105665, a novel small molecule that opens Kv7.2/3 and Kv7.3/5 channels, has been investigated in rats. [12] Hearing reduction after salicylate application could be prevented by ICA-105665 and it was hypothesized that it may also be effective in the prevention of salicylate-induced tinnitus. [12] …”

“…[12] Hearing reduction after salicylate application could be prevented by ICA-105665 and it was hypothesized that it may also be effective in the prevention of salicylate-induced tinnitus. [12] …”