Effects of Methionine and Glutathione on Acute Ototoxicity Induced by Amikacin and Furosemide in an Animal Model of Hearing Threshold Decrease

Abstract

Background/Objectives: Aminoglycoside antibiotics and loop diuretics are still the main causes of hearing loss in patients, and no specific prevention is available for this drug-induced ototoxicity. The aim of this study was to compare the protective effects of methionine (MET) and glutathione (GLUT) in terms of the reduction in ototoxicity induced by mixtures of amikacin (AMI, an aminoglycoside antibiotic) and furosemide (FUR, a loop diuretic) in a mouse model in which the hearing threshold decreased by 20% and 50%, respectively. Methods: To compare the otoprotective effects of MET and GLUT on AMI- and FUR-induced ototoxicity in mice, an isobolographic transformation of interactions was applied. Results: MET, but not GLUT, mitigated the AMI- and FUR-induced hearing threshold changes in mice. Additionally, MET exerted an antagonistic interaction with a combination of FUR+AMI, as the hearing threshold decreased by 50%, and an additive interaction, with a tendency toward antagonism in the model of hearing threshold decreased by 20%. In contrast, GLUT exerted only additive interactions when combined with FUR+AMI for both variant hearing thresholds decreased by 20% and 50%, respectively. Only MET could be a potential otoprotective drug in further prevention of hearing loss induced by AMI and FUR. Conclusions: MET is superior to GLUT in mitigating AMI- and FUR-induced hearing threshold decreases in mice. MET could be recommended as an otoprotectant in the prevention of hearing loss in patients receiving AMI and FUR.

Keywords: amikacin; furosemide; glutathione; hearing loss; hearing threshold decrease; methionine; ototoxicity.

Figure 1

Timeline for induction of anesthesia, Auditory Brainstem Response (ABR) measurements, MET or GLUT administration, and AMI and FUR injections in mice. All the drugs used in this study were administered i.p.

Figure 2

Dose-response relationship lines for MET on AMI- (a), FUR- (b), (AMI+FUR)- (c), and (FUR+AMI)- (d) induced hearing threshold decreases by 20% and 50% in experimental animals. Each point on the graphs represents a mean value of 6 animals. To calculate each HTDD₂₀ or HTDD₅₀ value, 18 mice (3 groups of 6 animals per group) underwent ABR measurements.

Figure 3

Dose-response relationship lines for GLUT on AMI- (a), FUR- (b), (AMI+FUR)- (c) and (FUR+AMI)- (d) induced hearing threshold decreases by 20% and 50% in the experimental animals. Each point on the graphs represents a mean value of 6 animals. To calculate each HTDD₂₀ or HTDD₅₀ value, 18 mice (3 groups of 6 animals per group) underwent ABR measurements.

Figure 4

Isobolographic transformation of interactions between AMI, FUR, MET and GLUT in drug-induced hearing threshold decreases by 20% and 50% in mice. The doses of AMI and FUR are plotted on the X- and Y-axes, respectively. The dotted line parallel to the Y-axis represents a constant dose of AMI (a,b) or FUR (c,d), which was added to increasing doses of FUR or AMI in the mouse model of hearing threshold decreases by 20% and 50%, respectively. Point A (on each graph) illustrates the theoretically additive dose of the two-drug mixture (AMI+FUR) that could produce a hearing threshold decrease of 20% or 50%, respectively. Point M indicates the dose of AMI+FUR+MET that experimentally induced hearing threshold decreases by 20% and 50%, respectively. Point G illustrates the dose of AMI+FUR+GLUT that experimentally induced hearing threshold decreases of 20% and 50%, respectively. * p < 0.05 vs. the respective additive value. AMI—amikacin; FUR—furosemide; GLUT—glutathione; MET—methionine; NS—not significant.