Potassium ion channel openers, Maxipost and Retigabine, protect against peripheral salicylate ototoxicity in rats

Abstract

Sodium Salicylate (SS) reliably induces a sensorineural hearing loss and tinnitus when administered in high doses. Recent animal modeled studies indicate that potassium channel openers such as Maxipost and Retigabine (RTG) can block SS- or noise-induced tinnitus respectively; however, the origins and mechanisms are poorly understood. Since SS blocks the same potassium channels that Maxipost and RTG open, we postulated that these drugs might influence peripheral auditory function. To test this hypothesis Maxipost or RTG were administered alone or in combination with SS in rats. When administered alone, Maxipost and RTG had no effect on distortion product otoacoustic emissions (DPOAE) or compound action potentials (CAPs). However when Maxipost or RTG were administered with SS, Maxipost prevented the SS-reduced CAP amplitudes at high frequencies (≥20 kHz) and RTG prevented SS-reduced CAP amplitudes at low frequencies (≤8 kHz). These results suggest that Maxipost and RTG can protect against peripheral damage and therefore reduce the incidence of tinnitus.

Noise-induced plasticity of KCNQ2/3 and HCN channels underlies vulnerability and resilience to tinnitus

“…Moreover, application of KCNQ channel activators did not affect ABR thresholds, wave I amplitude, or PPI ratios ( Figure 7B–D , Figure 7—figure supplement 1B ), suggesting that these activators do not affect either noise-induced hearing threshold shifts or auditory nerve damage. These results are consistent with recent studies showing that application of retigabine does not have any effect on hearing thresholds ( Sheppard et al, 2015 ). However, application of retigabine reduced hearing loss in an animal model of sodium salicylate-induced sensorineural hearing loss and tinnitus ( Sheppard et al, 2015 ).…”

Prolonged low-level noise-induced plasticity in the peripheral and central auditory system of rats

“…Immediately after acquiring the IC data, the CAP and SP were collected from the cochlea as described previously (Chen, Stolzberg et al 2013, Sheppard, Chen et al 2015). The animal was placed in a customized head-holder, the right bulla was exposed and a small fistula made to access the cochlear round window.…”

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?

“…[10] A comparison of Maxipost and retigabine in rats with salicylate-induced hearing loss revealed that Maxipost prevented hearing loss at high frequencies, whereas retigabine prevented hearing loss at low frequencies. [11] These effects seem to be mediated by potassium channels in the cochlea, since Maxipost and retigabine have a differential effect on Kv7 and BK potassium channels and since the expression of these channels varies on the cochlear hair cells along the tonotopic gradient. [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.…”

“…[11] These effects seem to be mediated by potassium channels in the cochlea, since Maxipost and retigabine have a differential effect on Kv7 and BK potassium channels and since the expression of these channels varies on the cochlear hair cells along the tonotopic gradient. [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.…”