Protective Role of Trimetazidine Against Neomycin-induced Hair Cell Damage in Zebrafish
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Objectives. Trimetazidine (TMZ) is known to reduce the generation of oxygen-derived free radicals. The objective of the present study was to evaluate the effects of TMZ on neomycin-induced ototoxicity in transgenic zebrafish (Brn3C: EGFP). Methods. Five-day, postfertilization zebrafish larvae were exposed to 125 μM neomycin and one of the following TMZ concentrations for 1 hour: 10 μM, 100 μM, 500 μM, 1,000 μM, 1,500 μM, or 2,000 μM. Hair cells within the neuromasts of the supraorbital (SO1 and SO2), otic (O1), and occipital (OC1) lateral lines were analyzed using fluorescence microscopy and confocal microscopy (n=10). Hair cell survival was calculated as a percentage of hair cells in the control group that were not exposed to neomycin. Ultrastructural changes were evaluated using scanning electron microscopy. Results. TMZ protected against neomycin-induced hair cell loss in the neuromasts (TMZ 1,000 μM, 11.2±0.4 cells; 125 μM neomycin only, 4.2±0.5 cells; n=10; P<0.05) and decreased the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) reaction. In the ultrastructural analysis, structures of mitochondria and hair cells within the neuromasts were preserved in zebrafish exposed to 125 μM neomycin and 1,000 μM TMZ. Conclusion. TMZ attenuated neomycin-induced hair cell loss in zebrafish. The results of this study suggest that neomycin induces apoptosis, and that apoptotic cell death can be prevented by treatment with tremetazidine.
Abstract
Objectives. Trimetazidine (TMZ) is known to reduce the generation of oxygen-derived free radicals. The objective of the present study was to evaluate the effects of TMZ on neomycin-induced ototoxicity in transgenic zebrafish (Brn3C: EGFP). Methods. Five-day, postfertilization zebrafish larvae were exposed to 125 μM neomycin and one of the following TMZ concentrations for 1 hour: 10 μM, 100 μM, 500 μM, 1,000 μM, 1,500 μM, or 2,000 μM. Hair cells within the neuromasts of the supraorbital (SO1 and SO2), otic (O1), and occipital (OC1) lateral lines were analyzed using fluorescence microscopy and confocal microscopy (n=10). Hair cell survival was calculated as a percentage of hair cells in the control group that were not exposed to neomycin. Ultrastructural changes were evaluated using scanning electron microscopy. Results. TMZ protected against neomycin-induced hair cell loss in the neuromasts (TMZ 1,000 μM, 11.2±0.4 cells; 125 μM neomycin only, 4.2±0.5 cells; n=10; P<0.05) and decreased the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) reaction. In the ultrastructural analysis, structures of mitochondria and hair cells within the neuromasts were preserved in zebrafish exposed to 125 μM neomycin and 1,000 μM TMZ. Conclusion. TMZ attenuated neomycin-induced hair cell loss in zebrafish. The results of this study suggest that neomycin induces apoptosis, and that apoptotic cell death can be prevented by treatment with tremetazidine.
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