Protection of the cochlear hair cells in adult C57BL/6J mice by T-type calcium channel blockers

Abstract

Abstract. The aim of the present study was to investigate the protective effect of T-type calcium channel blockers against presbycusis, using a C57BL/6J mice model. The expression of three T-type calcium channel receptor subunits in the cochlea of 6-8-week-old C57BL/6J mice was evaluated using reverse transcription-quantitative polymerase chain reaction. The results confirmed that the three subunits were expressed in the cochlea. In addition, the capacity of T-type calcium channel blockers to protect the cochlear hair cells of 24-26-week-old C57BL/6J mice was investigated in mice treated with mibefradil, benidipine or saline for 4 weeks. Differences in hearing threshold were detected using auditory brainstem recording (ABR), while differences in amplitudes were measured using a distortion product otoacoustic emission (DPOAE) test. The ABR test results showed that the hearing threshold significantly decreased at 24 kHz in the mibefradil-treated and benidipine-treated groups compared with the saline-treated group. The DPOAE amplitudes in the mibefradil-treated group were increased compared with those in the saline-treated group at the F2 frequencies of 11.3 and 13.4 kHz. Furthermore, the DPOAE amplitudes in the benidipine-treated group were increased compared with those in the saline-treated group at an F2 frequency of 13.4 kHz. The loss of outer hair cells (OHCs) was not evident in the mibefradil-treated group; however, the stereocilia of the inner hair cells (IHCs) were disorganised and sparse. In summary, these results indicate that the administration of a T-type calcium channel blocker for four consecutive weeks may improve the hearing at 24 kHz of 24-26-week-old C57BL/6J mice. The function and morphology of the OHCs of the C57BL/6J mice were significantly altered by the administration of a T-type calcium channel blocker; however, the IHCs were unaffected.

Altered Outer Hair Cell Mitochondrial and Subsurface Cisternae Connectomics Are Candidate Mechanisms for Hearing Loss in Mice

“…Cytoplasmic and mitochondrial Ca 21 levels and responsiveness to high K 1 stimulation were reduced in aged CBA/CaJ OHCs Based on the DPOAE findings and because blocking Ca 21 entry into OHCs affects the DPOAE (Kujawa et al, 1996), we tested whether perturbed Ca 21 flux in OHCs contributes to OHC dysfunction. Overactivation of T-type Ca v in OHCs plays a role in ARHL (Sang et al, 2017), and channel suppression may confer a protective effect (Yu et al, 2016). We used confocal microscopy to image cytoplasmic Ca 21 levels in OHCs in semi-intact, viable cochleae from the apical aspects of the sensory epithelia harvested from young and old (Fig.…”

Age-Dependent Changes in the Cochlea

“…To date, there is no pharmaceutical therapy that can prevent or reduce ARHL. Many different therapeutic strategies such as calcium channel blockers, statins, natural micronutrients like the antioxidant vitamins A, C, and E, melatonin, polyphenols, vasodilators like magnesium, and caloric restriction have been studied, but the positive effect on hearing has been inconsistent [44][45][46][47][48][49][50][51]. Modern approaches to hearing restoration focus on regeneration of hair cells and auditory neurons via stem cell therapies, gene therapies, and molecular therapies by manipulating endogenous signaling pathways in supporting cells [52].…”

Age-related hearing loss and its potential drug candidates: a systematic review

“…Numerous Ca 2+ channel blockers have also demonstrated protective effects against ARHL. For instance, T-type Ca 2+ channel blockers were able to significantly preserve SGN [ 138 , 139 ] while also affecting the function and morphology of OHCs in C57BL/6J mice [ 140 ].…”