Endocytosis of aminoglycoside antibiotics in sensory hair cells

Hashino, Eri; Shero, Marlene

doi:10.1016/0006-8993(95)01198-6

Cited by 114 publications

(128 citation statements)

References 13 publications

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“…Development of aminoglycoside ototoxicity relates to the diffusion of aminoglycoside into the inner ear and its subsequent binding to cochlear tissues, followed by slow release into inner ear fluid. 9 Entry of aminoglycoside into cochlear cells includes the attachment of the cationic aminoglycoside molecule to negatively charged cell membrane and entering cochlear cells via endocytosis in vivo 43 or by permeating through nonselective cation channels such as mechanosensitive transduction channels at stereocilia tips. 44,27 A regulatable blood-labyrinthine barrier (BLB) for aminoglycoside entry exists at the interface between the perilymphatic and endolymphatic space.…”

Section: Discussionmentioning

confidence: 99%

Transient ischemia/hypoxia enhances gentamicin ototoxicity via caspase-dependent cell death pathway

Kao

Tsai

Lai

et al. 2011

Laboratory Investigation

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Aminoglycoside ototoxicity is a common cause of drug-induced hearing loss. Toxicity is dose related, but some patients may still develop hearing loss even under safe dosage. Apart for genetic idiosyncrasy, indirect evidences imply that ischemia may increase the aminoglycoside ototoxic sensitivity because common clinical situations associated with cochlear ischemia such as noise, sepsis, and shock are known to augment the development of aminoglycoside ototoxicity. At present, a direct interaction of cochlear ischemia and aminoglycoside ototoxicity is still lacking. This study demonstrated a direct evidence of increased gentamicin (GM) ototoxic sensitivity in chronic guinea pig models of transient cochlear ischemia. No permanent auditory changes were observed after a single dose of GM (125 mg/kg) or after transient cochlear ischemia for 30 min. Persistent and significant auditory threshold shift was detected when GM was given after transient cochlear ischemia. Cochlear hair cells and spiral ganglion neurons are the major regions affected. Apoptosis contributes to hair cell death during acute interaction of ischemia and GM ototoxicity. Increased apoptotic cell death was also depicted when GM crossreacted with hypoxia in vitro, using cochlear cell lines. Generation of reactive oxygen species, loss of mitochondrial membrane potential, calcium release, and caspase-dependent apoptotic cell death were shown during the interaction of hypoxia and GM ototoxicity in vitro. This synergistic ototoxicity may be critical to aminoglycoside-induced hearing loss in clinical scenarios. The results should improve our understanding of the interacting mechanism and potential preventive strategy to aminoglycoside ototoxicity.

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Section: Discussionmentioning

confidence: 99%

Transient ischemia/hypoxia enhances gentamicin ototoxicity via caspase-dependent cell death pathway

Kao

Tsai

Lai

et al. 2011

Laboratory Investigation

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“…The evidence that aminoglycosides enter hair cells from endolymph and induce cytotoxicity in vivo is based on in vitro studies demonstrating that the mechanoelectrical transduction channel is aminoglycoside-permissive (Gale et al, 2001;Marcotti et al, 2005), and the presence of aminoglycoside-laden endosomes at the apex of hair cells in vivo Hashino and Shero, 1995). In addition, aminoglycosides, GTTR, and fluorophores cross the apical membrane of hair cells in zebrafish lateral line neuromasts (Harris et al, 2003;Owens et al, 2007;Ton and Parng, 2005).…”

Section: Discussionmentioning

confidence: 99%

A systemic gentamicin pathway across the stria vascularis

Dai

Steyger

2008

Hearing Research

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The mechanism(s) by which systemically-administered aminoglycosides enter the cochlea remain poorly understood. To elucidate which mechanisms may be involved, we co-administered different molar ratios of gentamicin and fluorescent gentamicin (GTTR) to mice in three different regimens:: (1) gentamicin (150, 300 or 600 mg/kg) containing a constant 300:1 molar ratio of gentamicin:GTTR; (2): 300 mg/kg gentamicin containing a variable molar ratio of gentamicin:GTTR (150:1-600:1), or (3): an increasing dose of gentamicin (150-900 mg/kg), each dose containing 1.7 mg/kg GTTR. Three hours later, cochleae were fixed and examined by confocal microscopy.First, increasing doses of a constant molar ratio of gentamicin:GTTR, resulted in increasing intensities of GTTR fluorescence in hair cells and strial tissues. Second, a fixed gentamicin dose with increasing molar dilution of GTTR led to decreasing GTTR fluorescence in hair cells and strial tissues. Third, a fixed GTTR dose with increasing molar dilution by gentamicin led to decreased GTTR uptake in hair cells and marginal cells, but not intra-strial tissues and capillaries. Thus, only hair cell and marginal cell uptake of GTTR is competitively inhibited by gentamicin, suggesting that a regulatable barrier for gentamicin entry into endolymph exists at the interface between marginal cells, the intra-strial space and intermediate cells.

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“…Accumulation of aminoglycoside drugs in sensory cells of the inner ear has been documented by many investigators (Balogh et al 1970;Portmann et al 1974;Hayashida et al 1985;Veldman et al 1985;Hayashida 1989;DeGroot et al 1990;Hiel et al 1992aHiel et al ,b, 1993Iwamori et al 1994;Hashino and Shero 1995;Hashino et al 1997;Aran et al, 1999). Due to sensitivity limitations of the previously utilized assays, most studies of the distribution of accumulated aminoglycoside were performed in the chronically treated animals, an experimental design which complicates interpretation of uptake kinetics.…”

Section: Discussionmentioning

confidence: 99%

Distribution of Gentamicin in the Guinea Pig Inner Ear after Local or Systemic Application

Imamura

Adams

2003

JARO - Journal of the Association for Research in Otolaryngolog

110

112

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Uptake and retention of gentamicin by cells in the guinea pig inner ear after a single peritoneal injection or local application on the round window were investigated using immunocytochemistry to localize the drug. The cells that accumulated the drug under the two conditions were the same, but staining for the drug was more intense and was often accompanied by widespread cochlear degeneration following local application. Soon after drug administration by either route, there was diffuse staining for the drug throughout all tissue within the labyrinth, including bone. At later times when distinct cell staining became evident, virtually all cell types were found to be positive, with several cell types staining more darkly for the drug than hair cells, indicating that hair cells were not the most avid in accumulating gentamicin. The infracuticular portion of auditory and vestibular hair cells as well as type III fibrocytes of the spiral ligament were positively stained in almost all cases and these sites were found to be positive for as long as six months post administration. In animals with loss of the organ of Corti, there was unusually intense staining for gentamicin in root cells of the spiral ligament, in marginal cells of the stria vascularis, and in cells of the spiral limbus. Dark staining of surviving cells in cases with overt tissue destruction suggests that variability in the extent of damage caused by the drug was determined more by the degree of its local uptake than by differences in animals' capacities to metabolize the drug systemically. The present results show that gentamicin may damage or destroy all cochlear cells following a single round window application. The findings broaden the scope of our knowledge of cochlear gentamicin uptake and damage and have implications for treatment of patients with vestibular disorders by infusion of aminoglycosides into the middle ear, as well as implications for prospects of rehabilitating patients that have been deafened by aminoglycosides.

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Endocytosis of aminoglycoside antibiotics in sensory hair cells

Cited by 114 publications

References 13 publications

Transient ischemia/hypoxia enhances gentamicin ototoxicity via caspase-dependent cell death pathway

Transient ischemia/hypoxia enhances gentamicin ototoxicity via caspase-dependent cell death pathway

A systemic gentamicin pathway across the stria vascularis

Distribution of Gentamicin in the Guinea Pig Inner Ear after Local or Systemic Application

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