Prevention of gentamicin-induced apoptosis with the mitochondria-targeted antioxidant mitoquinone

• Published in: The Laryngoscope 2012-11, Vol.122 (11), p.2543-2548
• Main Authors: Ojano-Dirain, Carolyn P., Antonelli, Patrick J.
• Format: Article
• Language: English
• Subjects: aminoglycoside; Analysis of Variance; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; antioxidant; Apoptosis - drug effects; Biological and medical sciences; Caspase 3 - metabolism; Cell Survival; Drug toxicity and drugs side effects treatment; Gentamicin; Gentamicins - toxicity; Haemophilus influenzae - drug effects; Medical sciences; Microbial Sensitivity Tests; Mitochondria - drug effects; Mitochondria - enzymology; mitoquinone; Organophosphorus Compounds - pharmacology; Otorhinolaryngology. Stomatology; ototoxicity; Pharmacology. Drug treatments; Prospective Studies; Pseudomonas aeruginosa - drug effects; Staphylococcus aureus - drug effects; Toxicity: respiratory system, ent, stomatology; Ubiquinone - analogs & derivatives; Ubiquinone - pharmacology
• ISSN: 0023-852X; 1531-4995
• DOI: 10.1002/lary.23593

Objectives/Hypothesis: Antioxidants have been shown to protect against aminoglycoside‐induced hearing loss. Mitoquinone (MitoQ) is a mitochondria‐targeted derivative of the antioxidant ubiquinone. MitoQ is attached to a lipophilic triphenylphosphonium (TPP) cation, which enables its accumulation inside the mitochondria several hundred‐fold over the untargeted antioxidant. The goals of this study were to determine if MitoQ attenuates gentamicin‐induced activation of caspase‐3/7 activity as a marker of apoptosis and to determine if MitoQ impacts aminoglycoside antimicrobial efficacy. Study Design: Prospective and controlled. Methods: Antibiotic efficacy and minimum inhibitory concentrations (MICs) of gentamicin against three strains each of Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa were evaluated with and without MitoQ using broth dilution methods. Apoptosis was assessed by caspase‐3/7 activity in untreated HEI‐OC1 cells and cells exposed to 2 mM gentamicin for 24 hours, with and without a 24‐hour preincubation with 0.5 μM each of MitoQ, idebenone (an untargeted ubiquinone), or decylTPP (positive control). Results: Gentamicin MICs for P aeruginosa and H influenzae were not affected by MitoQ at pharmacological levels. MICs for S aureus were enhanced by MitoQ. Cell viability was significantly lower in the gentamicin‐treated cells. A significant increase in caspase‐3/7 activity was observed in cells treated with gentamicin or with idebenone + gentamicin (P = .005). Preincubation with MitoQ decreased the gentamicin‐induced apoptosis of HEI‐OC1 cells to a greater extent compared to idebenone (P = .002). Conclusions: MitoQ attenuates gentamicin‐induced apoptosis in HEI‐OC1 cells and does not compromise gentamicin antibiotic efficacy. MitoQ holds promise as a means of preventing aminoglycoside ototoxicity. Laryngoscope, 2012