An in vivo Biomarker to Characterize Ototoxic Compounds and Novel Protective Therapeutics

Joseph A Bellairs, Van A Redila, Patricia Wu, Ling Tong, Alyssa Webster, Julian A Simon, Edwin W Rubel, David W Raible, Joseph A Bellairs, Van A Redila, Patricia Wu, Ling Tong, Alyssa Webster, Julian A Simon, Edwin W Rubel, David W Raible

Abstract

There are no approved therapeutics for the prevention of hearing loss and vestibular dysfunction from drugs like aminoglycoside antibiotics. While the mechanisms underlying aminoglycoside ototoxicity remain unresolved, there is considerable evidence that aminoglycosides enter inner ear mechanosensory hair cells through the mechanoelectrical transduction (MET) channel. Inhibition of MET-dependent uptake with small molecules or modified aminoglycosides is a promising otoprotective strategy. To better characterize mammalian ototoxicity and aid in the translation of emerging therapeutics, a biomarker is needed. In the present study we propose that neonatal mice systemically injected with the aminoglycosides G418 conjugated to Texas Red (G418-TR) can be used as a histologic biomarker to characterize in vivo aminoglycoside toxicity. We demonstrate that postnatal day 5 mice, like older mice with functional hearing, show uptake and retention of G418-TR in cochlear hair cells following systemic injection. When we compare G418-TR uptake in other tissues, we find that kidney proximal tubule cells show similar retention. Using ORC-13661, an investigational hearing protection drug, we demonstrate in vivo inhibition of aminoglycoside uptake in mammalian hair cells. This work establishes how systemically administered fluorescently labeled ototoxins in the neonatal mouse can reveal important details about ototoxic drugs and protective therapeutics.

Keywords: aminoglycloside; biomarker; hair cell; mouse model; otoprotection; ototoxicity.

Conflict of interest statement

JAS, EWR, and DWR are cofounders of Oricula Therapeutics, which has licensed patents covering ORC-13661 from the University of Washington. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Bellairs, Redila, Wu, Tong, Webster, Simon, Rubel and Raible.

Figures

FIGURE 1
FIGURE 1
G418-TR is taken up by neonatal mammalian hair cells following systemic administration. (A) At 6 h after systemic injection with G418-TR, neonatal mice (P5) were sacrificed, cochlear sensory epithelia was dissected and fixed, and tissue was immunolabeled for myosin VIIa. Representative single z-plane images captured from the middle turn of the cochlea in the region between the cuticular plate and nucleus demonstrate dose-dependent uptake of G418-TR in OHCs. Scale bar = 10 μm. (B) 6 h after systemic administration of G418-TR, blood was collected from neonatal mice, serum was extracted, and fluorescence was quantified with a fluorescence plate reader. Increasing doses of G418-TR results in a dose-dependent increase in serum fluorescence [One-way ANOVA; F(3,16) = 25.02, P < 0.0001]. (C) Mean G418-TR fluorescence intensity of IHCs by tonotopic region 6 h after systemic treatment. IHCs demonstrate similar dose-dependent uptake of G418-TR in base, middle, and apex. (D) Mean G418-TR fluorescence intensity of OHCs by tonotopic region 6 h after systemic treatment. OHCs demonstrate significant dose-dependent and tonotopic G418-TR uptake [Mixed effects analysis; F(6,36) = 5.127, P = 0.0007]. ncochlea and nmice represent the number of cochlea and mice examined, respectively. When two cochlea from the same animal were analyzed, the animal mean was calculated and used for all statistics and graphs. Error bars are standard deviations. AU, arbitrary unit.
FIGURE 2
FIGURE 2
G418-TR is taken up by mature mammalian hair cells following systemic administration. (A) At 6 h after systemic injection with G418-TR, juvenile mice (P25-30) were sacrificed, cochlear sensory epithelia was dissected and fixed, and tissue was immunolabeled for myosin VIIa. Representative maximum projection images captured from the middle turn of the cochlea demonstrate dose-dependent uptake of G418-TR in inner and outer hair cells. Scale bar = 10 μm. (B) 6 h after systemic administration of G418-TR, blood was collected from juvenile mice, serum was extracted, and fluorescence was quantified with a fluorescence plate reader. Increasing doses of G418-TR results in a dose-dependent increase in serum fluorescence [One-way ANOVA; F(3,17) = 28.28, P < 0.0001]. (C) Mean G418-TR fluorescence intensity of IHCs by tonotopic region 6 h after systemic treatment. IHCs demonstrate low uptake at most doses of G418-TR with no significant tonotopic variation. (D) Mean G418-TR fluorescence intensity of OHCs by tonotopic region 6 h after systemic treatment. OHCs demonstrate dose-dependent uptake but not tonotopic variation in G418-TR uptake. ncochlea and nmice represent the number of cochlea and mice examined, respectively. When two cochlea from the same animal were analyzed, the animal mean was calculated and used for all statistics and graphs. Error bars are standard deviations. AU, arbitrary unit.
FIGURE 3
FIGURE 3
Characteristics of G418-TR uptake in neonatal and juvenile hair cells. (A) Pooled analysis of the ratio of OHC to IHC uptake (FOHC/FIHC) was calculated for all neonatal animals treated with G418-TR (2.5, 5, and 10 mg/kg) and sorted by tonotopic region. In neonatal hair cells, there is significant variation in FOHC/FIHC by region [Mixed-effects Analysis; F(2,52) = 11.81, P < 0.0001]. (B) Pooled analysis for all juvenile animals treated with G418-TR (5, 10, and 20 mg/kg) demonstrates no significant tonotopic variation in FOHC/FIHC [Mixed-effects Analysis; F(2,31) = 0.1442, P = 0.8662]. ncochlea and nmice represent the number of cochlea and mice examined, respectively. When two cochlea from the same animal were analyzed, the animal mean was calculated and used for all statistics and graphs. Error bars are standard deviations. **P < 0.01, ****P < 0.0001; P-values generated from multiple comparisons post hoc test (Tukey’s multiple comparison test).
FIGURE 4
FIGURE 4
Hair cells accumulate and retain G418-TR after systemic injection. (A) 30 min–72 h after systemic injection with 10 mg/kg G418-TR, neonatal mice (P5) were sacrificed, cochlear sensory epithelia was dissected and fixed, and tissue was immunolabeled for myosin VIIa. Representative images captured from the middle turn of the cochlea demonstrate uptake and retention of G418-TR. Images shown are single z-plane images capturing the region between the nucleus and cuticular plate. Arrowhead highlights transition from diffuse G418-TR distribution to accumulation in puncta with time. Scale bar = 10 μm. (B) Serum kinetics of G418-TR after systemic injection. After systemic injection with 10 mg/kg G418-TR, neonatal mice were sacrificed at different time points, serum was collected, and fluorescence was quantified. Fluorescence was converted to concentration in μg/mL utilizing a calibration curve of G418-TR diluted in fetal bovine serum. Quantification shows that serum levels of G418-TR peak at 3 h and are undetectable 24 h post-injection. (C) Mean hair cell fluorescence from the middle turn of the cochlea was calculated over 72 h. Both IHCs and OHCs show uptake and retention. Animals examined [t (hours), n] = (0,4), (0.5,4), (3,5), (6,6), (12,5), (24,5), (48,5), (72,5). Error bars are standard deviations. AU, arbitrary unit. Significant differences between IHC and OHCs denoted with: *P < 0.05, ***P < 0.001. P-values calculated from multiple comparisons post hoc test (Šídák’s multiple comparison test).
FIGURE 5
FIGURE 5
Selective aminoglycoside retention in proximal convoluted tubule cells of the kidney. (A) 0 min–72 h after systemic injection with G418-TR, neonatal mice (P5) were sacrificed, and kidneys were removed. Tissues were fixed, embedded and cryostat sectioned at a thickness of 12 μm. Tissue sections were stained with phalloidin and DAPI. Representative maximum projection images from the renal cortex show proximal convoluted tubule (p) uptake and retention, but minimal uptake in the distal convoluted tubule (d) and glomeruli (g). Like hair cells, PCT cells also show apical puncta (arrow) accumulation of G418-TR. Scale bar = 20 μm. (B) Mean fluorescence from proximal convoluted tubules (PCTs), distal convoluted tubules (DCTs), and glomeruli was calculated over 72 h. PCTs demonstrate G418-TR uptake and retention like that observed in cochlear hair cells. Animals examined n = 4 for each time point. Error bars are standard deviations. AU, arbitrary unit.
FIGURE 6
FIGURE 6
Differential aminoglycoside uptake and retention within the cochlea. Cochlea from neonatal mice treated with G418-TR were fixed, cryostat sectioned, and signed in order to analyze the organ of Corti, stria vascularis, and spiral ganglia neurons. In order to compare relative G418-TR uptake between specific tissue types, fluorescence was quantified for outer hair cells (OHCs), pillar cells, stria vascularis, and spiral ganglia neurons. Note that while OHCs take up and retain G418-TR fluorescence, stria vascularis tissue has an early peak but then declines while SGNs show consistent low level uptake. PCs display an intermediate level of uptake with some retention. Error bars are standard deviations. Animal numbers [time (hours), n] = (0,3), (6,4), (24,4), and (48,4).
FIGURE 7
FIGURE 7
ORC-13661 blocks G418-TR accumulation in mammalian hair cells. (A) Short (3 h) G418-TR exposure paradigm. Neonatal mice were pretreated with ORC-13661 or vehicle for 2 h, injected with 10 mg/kg G418-TR, and sacrificed 3 h after aminoglycoside injection. Basal turn OHC mean fluorescence for animals treated with either vehicle or ORC-13661 followed by 10 mg/kg G418-TR. OHC mean fluorescence was quantified and normalized to animals pre-treated with vehicle within each experimental replicate. [One-way ANOVA; F(3,20) = 23.55, P < 0.0001]. (B) Long (6 h) G418-TR exposure paradigm. Neonatal mice were pretreated with ORC-13661 or vehicle for 2 h, injected with 10 mg/kg G418-TR, and sacrificed 6 h after aminoglycoside injection. [One-way ANOVA; F(3,30) = 19.62, P < 0.0001]. (C) Booster dosing strategy with a single pretreatment injection of ORC-13661 followed by a second booster dose 3 h after G418-TR injection. Basal turn OHC mean fluorescence for animals treated with a pretreatment dose ORC-13661 (10–100 mg/kg) followed by 10 mg/kg G418-TR with an additional booster of ORC-13661 (same as pretreatment dose) 3 h after aminoglycoside administration. Note that data for single dose are non-normalized data from part B. Error bars are standard deviations. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; P-values generated from multiple comparisons post hoc test (A,B: Dunnett’s multiple comparison test; C: Šídák’s multiple comparison test).

References

    1. Abe T., Kakehata S., Kitani R., Maruya S., Navaratnam D., Santos-Sacchi J., et al. (2007). Developmental expression of the outer hair cell motor prestin in the mouse. J. Membr. Biol. 215 49–56. 10.1007/s00232-007-9004-5
    1. Alharazneh A., Luk L., Huth M., Monfared A., Steyger P. S., Cheng A. G., et al. (2011). Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. PLoS One 6:e22347. 10.1371/journal.pone.0022347
    1. Aminoglycosides (2012). LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases.
    1. Bailey T. C., Little J. R., Littenberg B., Reichley R. M., Dunagan W. C. (1997). A meta-analysis of extended-interval dosing versus multiple daily dosing of aminoglycosides. Clin. Infect. Dis. 24 786–795. 10.1093/clinids/24.5.786
    1. Bareggi R., Narducci P., Grill V., Mallardi F., Zweyer M., Fusaroli P. (1986). Localization of an aminoglycoside (streptomycin) in the inner ear after its systemic administration. Histochemistry 84 237–240. 10.1007/BF00495788
    1. Barza M., Ioannidis J. P., Cappelleri J. C., Lau J. (1996). Single or multiple daily doses of aminoglycosides: a meta- analysis. BMJ 312 338–344. 10.1136/bmj.312.7027.338
    1. Beurg M., Evans M. G., Hackney C. M., Fettiplace R. (2006). A large-conductance calcium-selective mechanotransducer channel in mammalian cochlear hair cells. J. Neurosci. 26 10992–11000. 10.1523/JNEUROSCI.2188-06.2006
    1. Chen C.-S., Saunders J. C. (1983). The sensitive period for ototoxicity of kanamycin in mice: morphological evidence. Arch. Otorhinolaryngol. 238 217–223. 10.1007/BF00453932
    1. Cheng A. G., Cunningham L. L., Rubel E. W. (2003). Hair cell death in the avian basilar papilla: characterization of the in vitro model and caspase activation. J. Assoc. Res. Otolaryngol. 4 91–105. 10.1007/s10162-002-3016-8
    1. Cheng A. G., Cunningham L. L., Rubel E. W. (2005). Mechanisms of hair cell death and protection. Curr. Opin. Otolaryngol. Head Neck Surg. 13 343–348. 10.1097/01.moo.0000186799.45377.63
    1. Chowdhury S., Owens K. N., Herr R. J., Jiang Q., Chen X., Johnson G., et al. (2018). Phenotypic optimization of urea-thiophene carboxamides to yield potent, well tolerated and orally active protective agents against aminoglycoside-induced hearing loss. J. Med. Chem. 61 84–97. 10.1021/acs.jmedchem.7b00932
    1. Coffin A. B., Williamson K. L., Mamiya A., Raible D. W., Rubel E. W. (2013). Profiling drug-induced cell death pathways in the zebrafish lateral line. Apoptosis 18 393–408. 10.1007/s10495-013-0816-8
    1. Contopoulos-Ioannidis D. G., Giotis N. D., Baliatsa D. V., Ioannidis J. P. A. (2004). Extended-interval aminoglycoside administration for children: a meta-analysis. Pediatrics 114 e111–e118. 10.1542/peds.114.1.e111
    1. Dai C. F., Mangiardi D., Cotanche D. A., Steyger P. S. (2006). Uptake of fluorescent gentamicin by vertebrate sensory cells in vivo. Hear. Res. 213 64–78. 10.1016/j.heares.2005.11.011
    1. de Groot J. C. M. J., Meeuwsen F., Ruizendaal W. E., Veldman J. E. (1990). Ultrastructural localization of gentamicin in the cochlea. Hear. Res. 50 35–42. 10.1016/0378-5955(90)90031-J
    1. Ding D., Liu H., Qi W., Jiang H., Li Y., Wu X., et al. (2016). Ototoxic effects and mechanisms of loop diuretics. J. Otol. 11 145–156. 10.1016/j.joto.2016.10.001
    1. Dunn K. W., Sandoval R. M., Kelly K. J., Dagher P. C., Tanner G. A., Atkinson S. J., et al. (2002). Functional studies of the kidney of living animals using multicolor two-photon microscopy. Am. J. Physiol. Cell Physiol. 283 C905–C916. 10.1152/ajpcell.00159.2002
    1. Durante-Mangoni E., Grammatikos A., Utili R., Falagas M. E. (2009). Do we still need the aminoglycosides? Int. J. Antimicrob. Agents 33 201–205. 10.1016/j.ijantimicag.2008.09.001
    1. Esterberg R., Hailey D. W., Rubel E. W., Raible D. W. (2014). ER–mitochondrial calcium flow underlies vulnerability of mechanosensory hair cells to damage. J. Neurosci. 34 9703–9719. 10.1523/JNEUROSCI.0281-14.2014
    1. Esterberg R., Linbo T., Pickett S. B., Wu P., Ou H. C., Rubel E. W., et al. (2016). Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death. J. Clin. Invest. 126 3556–3566. 10.1172/JCI84939
    1. FDA-NIH Biomarker Working Group (2016). BEST (Biomarkers, Endpoints, and other Tools) Resource. Silver Spring, MD: Food and Drug Administration.
    1. Fettiplace R. (2009). Defining features of the hair cell mechanoelectrical transducer channel. Pflugers Arch. 458 1115–1123. 10.1007/s00424-009-0683-x
    1. Forge A., Schacht J. (2000). Aminoglycoside antibiotics. Audiol. Neurootol. 5 3–22. 10.1159/000013861
    1. UpToDate (2021). Furosemide: Drug Information. Available online at: [accessed November 22, 2021].
    1. Guo X., Nzerue C. (2002). How to prevent, recognize, and treat drug-induced nephrotoxicity. Cleve. Clin. J. Med. 69 289–290, 293,–294, 296–297 passim. 10.3949/ccjm.69.4.289
    1. Hailey D. W., Esterberg R., Linbo T. H., Rubel E. W., Raible D. W. (2017). Fluorescent aminoglycosides reveal intracellular trafficking routes in mechanosensory hair cells. J. Clin. Invest. 127 472–486. 10.1172/JCI85052
    1. Hashino E., Shero M., Salvi R. J. (1997). Lysosomal targeting and accumulation of aminoglycoside antibiotics in sensory hair cells. Brain Res. 777 75–85. 10.1016/S0006-8993(97)00977-3
    1. Hatala R., Dinh T., Cook D. J. (1996). Once-daily aminoglycoside dosing in immunocompetent adults. Ann. Intern. Med. 124 717–725. 10.7326/0003-4819-124-8-199604150-00003
    1. He D. Z., Evans B. N., Dallos P. (1994). First appearance and development of electromotility in neonatal gerbil outer hair cells. Hear. Res. 78 77–90. 10.1016/0378-5955(94)90046-9
    1. Hiel H., Erre J.-P., Aurousseau C., Bouali R., Dulon D., Aran J.-M. (1993). Gentamicin uptake by cochlear hair cells precedes hearing impairment during chronic treatment. Audiology 32 78–87. 10.3109/00206099309072930
    1. Hirose K., Hockenbery D. M., Rubel E. W. (1997). Reactive oxygen species in chick hair cells after gentamicin exposure in vitro. Hear. Res. 104 1–14. 10.1016/S0378-5955(96)00169-4
    1. Horvath L., Bächinger D., Honegger T., Bodmer D., Monge Naldi A. (2019). Functional and morphological analysis of different aminoglycoside treatment regimens inducing hearing loss in mice. Exp. Ther. Med. 18 1123–1130. 10.3892/etm.2019.7687
    1. Huth M. E., Ricci A. J., Cheng A. G. (2011). Mechanisms of aminoglycoside ototoxicity and targets of hair cell protection. Int. J. Otolaryngol. 2011:e937861. 10.1155/2011/937861
    1. Huxel C., Raja A., Ollivierre-Lawrence M. D. (eds). (2021). “Loop diuretics,” in StatPearls (Treasure Island, FL: StatPearls Publishing; ).
    1. Huy P. T. B., Bernard P., Schacht J. (1986). Kinetics of gentamicin uptake and release in the rat. Comparison of inner ear tissues and fluids with other organs. J. Clin. Invest. 77 1492–1500. 10.1172/JCI112463
    1. Imamura S., Adams J. C. (2003). Distribution of gentamicin in the guinea pig inner ear after local or systemic application. J. Assoc. Res. Otolaryngol. 4 176–195. 10.1007/s10162-002-2036-8
    1. Jeng J., Ceriani F., Hendry A., Johnson S. L., Yen P., Simmons D. D., et al. (2020). Hair cell maturation is differentially regulated along the tonotopic axis of the mammalian cochlea. J. Physiol. 598 151–170. 10.1113/JP279012
    1. Jiang H., Sha S.-H., Forge A., Schacht J. (2006). Caspase-independent pathways of hair cell death induced by kanamycin in vivo. Cell Death Differ. 13 20–30. 10.1038/sj.cdd.4401706
    1. Jiang M., Karasawa T., Steyger P. S. (2017). Aminoglycoside-induced cochleotoxicity: a review. Front. Cell. Neurosci. 11:308. 10.3389/fncel.2017.00308
    1. Kalinec G. M., Webster P., Lim D. J., Kalinec F. (2003). A cochlear cell line as an in vitro system for drug ototoxicity screening. Audiol. Neurootol. 8 177–189. 10.1159/000071059
    1. Kenyon E. J., Kirkwood N. K., Kitcher S. R., Goodyear R. J., Derudas M., Cantillon D. M., et al. (2021). Identification of a series of hair-cell MET channel blockers that protect against aminoglycoside-induced ototoxicity. JCI Insight 6:e145704. 10.1172/jci.insight.145704
    1. Kim J., Ricci A. J. (2022). In vivo real-time imaging reveals megalin as the aminoglycoside gentamicin transporter into cochlea whose inhibition is otoprotective. Proc. Natl. Acad. Sci. U.S.A. 119:e2117946119. 10.1073/pnas.2117946119
    1. Kirkwood N. K., O’Reilly M., Derudas M., Kenyon E. J., Huckvale R., van Netten S. M., et al. (2017). d-Tubocurarine and berbamine: alkaloids that are permeant blockers of the hair cell’s mechano-electrical transducer channel and protect from aminoglycoside toxicity. Front. Cell. Neurosci. 11:262. 10.3389/fncel.2017.00262
    1. Kitahara T., Li H.-S., Balaban C. D. (2005). Changes in transient receptor potential cation channel superfamily V (TRPV) mRNA expression in the mouse inner ear ganglia after kanamycin challenge. Hear. Res. 201 132–144. 10.1016/j.heares.2004.09.007
    1. Kitcher S. R., Kirkwood N. K., Camci E. D., Wu P., Gibson R. M., Redila V. A., et al. (2019). ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity. JCI Insight 4:e126764. 10.1172/jci.insight.126764
    1. Kros C. J., Ruppersberg J. P., Rüsch A. (1998). Expression of a potassium current in inner hair cells during development of hearing in mice. Nature 394 281–284. 10.1038/28401
    1. Kruger M., Boney R., Ordoobadi A. J., Sommers T. F., Trapani J. G., Coffin A. B. (2016). Natural bizbenzoquinoline derivatives protect zebrafish lateral line sensory hair cells from aminoglycoside toxicity. Front. Cell. Neurosci. 10:83. 10.3389/fncel.2016.00083
    1. Lee S. H., Ju H. M., Choi J. S., Ahn Y., Lee S., Seo Y. J. (2018). Circulating serum miRNA-205 as a diagnostic biomarker for ototoxicity in mice treated with aminoglycoside antibiotics. Int. J. Mol. Sci. 19:2836. 10.3390/ijms19092836
    1. Lim D. J. (1986). Effects of noise and ototoxic drugs at the cellular level in the cochlea: a review. Am. J. Otolaryngol. 7 73–99. 10.1016/S0196-0709(86)80037-0
    1. Liu J., Kachelmeier A., Dai C., Li H., Steyger P. S. (2015). Uptake of fluorescent gentamicin by peripheral vestibular cells after systemic administration. PLoS One 10:e0120612. 10.1371/journal.pone.0120612
    1. Lopez-Novoa J. M., Quiros Y., Vicente L., Morales A. I., Lopez-Hernandez F. J. (2011). New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view. Kidney Int. 79 33–45. 10.1038/ki.2010.337
    1. Makabe A., Kawashima Y., Sakamaki Y., Maruyama A., Fujikawa T., Ito T., et al. (2020). Systemic fluorescent gentamicin enters neonatal mouse hair cells predominantly through sensory mechanoelectrical transduction channels. J. Assoc. Res. Otolaryngol. 21 137–149. 10.1007/s10162-020-00746-3
    1. Marche P., Koutouzov S., Girard A. (1983). Impairment of membrane phosphoinositide metabolism by aminoglycoside antibiotics: streptomycin, amikacin, kanamycin, dibekacin, gentamicin and neomycin. J. Pharmacol. Exp. Ther. 227 415–420.
    1. Marcotti W., Johnson S. L., Holley M. C., Kros C. J. (2003). Developmental changes in the expression of potassium currents of embryonic, neonatal and mature mouse inner hair cells. J. Physiol. 548 383–400. 10.1113/jphysiol.2002.034801
    1. Marcotti W., Kros C. J. (1999). Developmental expression of the potassium current IK, n contributes to maturation of mouse outer hair cells. J. Physiol. 520 653–660. 10.1111/j.1469-7793.1999.00653.x
    1. Marcotti W., Netten S. M. V., Kros C. J. (2005). The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano -electrical transducer channels. J. Physiol. 567 505–521. 10.1113/jphysiol.2005.085951
    1. Mingeot-Leclercq M.-P., Tulkens P. M. (1999). Aminoglycosides: nephrotoxicity. Antimicrob. Agents Chemother. 43 1003–1012.
    1. Munckhof W. J., Grayson M. L., Turnidge J. D. (1996). A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses. J. Antimicrob. Chemother. 37 645–663. 10.1093/jac/37.4.645
    1. Nakai Y., Chang K. C., Ohashi K., Morisaki N. (1983). Ototoxic effect of an aminoglycoside drug on an immature inner ear. Acta Otolaryngol. Suppl. 393 1–5. 10.3109/00016488309129570
    1. Naples J., Cox R., Bonaiuto G., Parham K. (2018). Prestin as an otologic biomarker of cisplatin ototoxicity in a guinea pig model. Otolaryngol. Head Neck Surg. 158 541–546. 10.1177/0194599817742093
    1. O’Sullivan M. E., Song Y., Greenhouse R., Lin R., Perez A., Atkinson P. J., et al. (2020). Dissociating antibacterial from ototoxic effects of gentamicin C-subtypes. Proc. Natl. Acad. Sci. U.S.A. 117 32423–32432. 10.1073/pnas.2013065117
    1. Owens K. N., Santos F., Roberts B., Linbo T., Coffin A. B., Knisely A. J., et al. (2008). Identification of genetic and chemical modulators of zebrafish mechanosensory hair cell death. PLoS Genet. 4:e1000020. 10.1371/journal.pgen.1000020
    1. Pickett S. B., Raible D. W. (2019). Water waves to sound waves: using zebrafish to explore hair cell biology. J. Assoc. Res. Otolaryngol. 20 1–19. 10.1007/s10162-018-00711-1
    1. Pickles J. (1998). An Introduction to the Physiology of Hearing, 4th Edn. Leiden: Brill.
    1. Portmann M., Darrouzet J., Coste C. (1974). Distribution within the cochlea of dihydrostreptomycin injected into the circulation. An autoradiographic and electron microscopic study. Arch. Otolaryngol. 100 473–475. 10.1001/archotol.1974.00780040487014
    1. Prieve B. A., Yanz J. L. (1984). Age-dependent changes in susceptibility to ototoxic hearing loss. Acta Otolaryngol. 98 428–438. 10.3109/00016488409107584
    1. Priuska E. M., Schacht J. (1995). Formation of free radicals by gentamicin and iron and evidence for an iron/gentamicin complex. Biochem. Pharmacol. 50 1749–1752. 10.1016/0006-2952(95)02160-4
    1. Qian X., He Z., Wang Y., Chen B., Hetrick A., Dai C., et al. (2021). Hair cell uptake of gentamicin in the developing mouse utricle. J. Cell. Physiol. 236 5235–5252. 10.1002/jcp.30228
    1. Qian Y., Guan M.-X. (2009). Interaction of aminoglycosides with human mitochondrial 12S rRNA carrying the deafness-associated mutation. Antimicrob. Agents Chemother. 53 4612–4618. 10.1128/AAC.00965-08
    1. Richardson G. P., Russell I. J. (1991). Cochlear cultures as a model system for studying aminoglycoside induced ototoxicity. Hear. Res. 53 293–311. 10.1016/0378-5955(91)90062-e
    1. Rizzi M. D., Hirose K. (2007). Aminoglycoside ototoxicity. Curr. Opin. Otolaryngol. Head Neck Surg. 15 352–357. 10.1097/MOO.0b013e3282ef772d
    1. Rubel E. W. (1978). “Ontogeny of structure and function in the vertebrate auditory system,” in Development of Sensory Systems Handbook of Sensory Physiology, eds Bate C. M., Carr V. M. C. M., Graziadei P. P. C., Hirsch H. V. B., Hughes A., Ingle D., et al. (Berlin: Springer; ), 135–237. 10.1007/978-3-642-66880-7_5
    1. Rubel E. W., Fay R. R. (2012). Development of the Auditory System. Berlin: Springer Science & Business Media.
    1. Rybak L. P. (1993). Ototoxicity of Loop Diuretics#. Otolaryngol. Clin. North Am. 26 829–844. 10.1016/S0030-6665(20)30770-2
    1. Rybak L. P., Talaska A. E., Schacht J. (2008). “Drug-induced hearing loss,” in Auditory Trauma, Protection, and Repair Springer Handbook of Auditory Research, eds Schacht J., Popper A. N., Fay R. R. (Boston, MA: Springer; ), 219–256. 10.1007/978-0-387-72561-1_8
    1. Rybak M. J., Abate B. J., Kang S. L., Ruffing M. J., Lerner S. A., Drusano G. L. (1999). Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob. Agents Chemother. 43 1549–1555. 10.1128/AAC.43.7.1549
    1. Schmitz C., Hilpert J., Jacobsen C., Boensch C., Christensen E. I., Luft F. C., et al. (2002). Megalin deficiency offers protection from renal aminoglycoside accumulation *. J. Biol. Chem. 277 618–622. 10.1074/jbc.M109959200
    1. Seyhan A. A. (2019). Lost in translation: the valley of death across preclinical and clinical divide – identification of problems and overcoming obstacles. Transl. Med. Commun. 4:18. 10.1186/s41231-019-0050-7
    1. Silverblatt F. J., Kuehn C. (1979). Autoradiography of gentamicin uptake by the rat proximal tubule cell. Kidney Int. 15 335–345. 10.1038/ki.1979.45
    1. Taylor R. R., Nevill G., Forge A. (2008). Rapid hair cell loss: a mouse model for cochlear lesions. J. Assoc. Res. Otolaryngol. 9 44–64. 10.1007/s10162-007-0105-8
    1. Van Boeckel T. P., Gandra S., Ashok A., Caudron Q., Grenfell B. T., Levin S. A., et al. (2014). Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect. Dis. 14 742–750. 10.1016/S1473-3099(14)70780-7
    1. Vu A. A., Nadaraja G. S., Huth M. E., Luk L., Kim J., Chai R., et al. (2013). Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death. PLoS One 8:e54794. 10.1371/journal.pone.0054794
    1. Wang Q., Steyger P. S. (2009). Trafficking of systemic fluorescent gentamicin into the cochlea and hair cells. J. Assoc. Res. Otolaryngol. 10 205–219. 10.1007/s10162-009-0160-4
    1. Wu W.-J., Sha S.-H., McLaren J. D., Kawamoto K., Raphael Y., Schacht J. (2001). Aminoglycoside ototoxicity in adult CBA, C57BL and BALB mice and the Sprague–Dawley rat. Hear. Res. 158 165–178. 10.1016/S0378-5955(01)00303-3

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel