Evaluation of Mitoquinone for Protecting Against Amikacin-Induced Ototoxicity in Guinea Pigs

Abstract

Hypothesis: Mitoquinone (MitoQ) attenuates amikacin ototoxicity in guinea pigs.

Background: MitoQ, a mitochondria-targeted derivative of the antioxidant ubiquinone, has improved bioavailability and demonstrated safety in humans. Thus, MitoQ is a promising therapeutic approach for protecting against amikacin-induced ototoxicity.

Methods: Both oral and subcutaneous administrations of MitoQ were tested. Amikacin-treated guinea pigs (n = 12-18 per group) received water alone (control) or MitoQ 30 mg/l-supplemented drinking water; or injected subcutaneously with 3 to 5 mg/kg MitoQ or saline (control). Auditory brainstem responses and distortion product otoacoustic emissions were measured before MitoQ or control solution administration and after amikacin injections. Cochlear hair cell damage was assessed using scanning electron microscopy and Western blotting.

Results: With oral administration, animals that received 30 mg/l MitoQ had better hearing than controls at only 24 kHz at 3-week (p = 0.017) and 6-week (p = 0.027) post-amikacin. With subcutaneous administration, MitoQ-injected guinea pigs had better hearing than controls at only 24 kHz, 2-week post-amikacin (p = 0.013). Distortion product otoacoustic emission (DPOAE) amplitudes were decreased after amikacin injections, but were not different between treatments (p > 0.05). Electron microscopy showed minor difference in outer hair cell loss between treatments. Western blotting demonstrated limited attenuation of oxidative stress in the cochlea of MitoQ-supplemented guinea pigs.

Conclusions: Oral or subcutaneous MitoQ provided limited protection against amikacin-induced hearing loss and cochlear damage in guinea pigs. Other strategies for attenuating aminoglycoside-induced ototoxicity should be explored.

Figure 1

ABR threshold at 4, 8, 16, and 24 kHz at 3-weeks (A) and 6-weeks (B) after amikacin 200mg/kg and oral MitoQ treatment. Data represent mean ± SEM of control (n=18) and MitoQ (n=16) guinea pigs.

Figure 2

DPOAE amplitudes at 4, 8, 16, and 24 kHz at 3-weeks (A) and 6-weeks (B) after amikacin 200mg/kg treatment and oral MitoQ treatment. Values are means ± SEM control (n=18) and MitoQ 30mg/L-supplemented guinea pigs (n = 16).

Figure 3

Electron micrographs of the basal, middle and apical turn of cochleas from control and oral MitoQ-supplemented guinea pigs.

Figure 4

Protein expression of mitochondrial proteins (A), antioxidants (B), and apoptotic proteins (C) in the cochlea of amikacin-treated guinea pigs with and without oral MitoQ. *p <0.05 compared to control.

Figure 4

Protein expression of mitochondrial proteins (A), antioxidants (B), and apoptotic proteins (C) in the cochlea of amikacin-treated guinea pigs with and without oral MitoQ. *p <0.05 compared to control.

Figure 5

ABR threshold at 4, 8, 16, and 24 kHz at 2-weeks (A) and 4-weeks (B) after amikacin 200mg/kg and subcutaneous MitoQ treatment. Data represent mean ± SEM of control (n=11) and MitoQ (n=12) guinea pigs.

Figure 6

Electron micrographs of the basal, middle and apical turn of cochleas from control and MitoQ-injected guinea pigs.