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Nerissa K Kirkwood, Molly O'Reilly, Marco Derudas, Emma J Kenyon, Rosemary Huckvale, Sietse M van Netten, Simon E Ward, Guy P Richardson, Corné J Kros
Aminoglycoside antibiotics are widely used for the treatment of life-threatening bacterial infections, but cause permanent hearing loss in a substantial proportion of treated patients. The sensory hair cells of the inner ear are damaged following entry of these antibiotics via the mechano-electrical transducer (MET) channels located at the tips of the hair cell's stereocilia. d-Tubocurarine (dTC) is a MET channel blocker that reduces the loading of gentamicin-Texas Red (GTTR) into rat cochlear hair cells and protects them from gentamicin treatment...
2017: Frontiers in Cellular Neuroscience
Hongzhe Li, Allan Kachelmeier, David N Furness, Peter S Steyger
Loud sound exposure exacerbates aminoglycoside ototoxicity, increasing the risk of permanent hearing loss and degrading the quality of life in affected individuals. We previously reported that loud sound exposure induces temporary threshold shifts (TTS) and enhances uptake of aminoglycosides, like gentamicin, by cochlear outer hair cells (OHCs). Here, we explore mechanisms by which loud sound exposure and TTS could increase aminoglycoside uptake by OHCs that may underlie this form of ototoxic synergy. Mice were exposed to loud sound levels to induce TTS, and received fluorescently-tagged gentamicin (GTTR) for 30 min prior to fixation...
2015: Frontiers in Cellular Neuroscience
Jianping Liu, Allan Kachelmeier, Chunfu Dai, Hongzhe Li, Peter S Steyger
OBJECTIVE: In addition to cochleotoxicity, systemic aminoglycoside pharmacotherapy causes vestibulotoxicity resulting in imbalance and visual dysfunction. The underlying trafficking routes of systemically-administered aminoglycosides from the vasculature to the vestibular sensory hair cells are largely unknown. We investigated the trafficking of systemically-administered gentamicin into the peripheral vestibular system in C56Bl/6 mice using fluorescence-tagged gentamicin (gentamicin-Texas-Red, GTTR) imaged by scanning laser confocal microscopy to determine the cellular distribution and intensity of GTTR fluorescence in the three semicircular canal cristae, utricular, and saccular maculae at 5 time points over 4 hours...
2015: PloS One
Meiyan Jiang, Qi Wang, Takatoshi Karasawa, Ja-Won Koo, Hongzhe Li, Peter S Steyger
Aminoglycoside antibiotics, like gentamicin, continue to be clinically essential worldwide to treat life-threatening bacterial infections. Yet, the ototoxic and nephrotoxic side-effects of these drugs remain serious complications. A major site of gentamicin uptake and toxicity resides within kidney proximal tubules that also heavily express electrogenic sodium-glucose transporter-2 (SGLT2; SLC5A2) in vivo. We hypothesized that SGLT2 traffics gentamicin, and promotes cellular toxicity. We confirmed in vitro expression of SGLT2 in proximal tubule-derived KPT2 cells, and absence in distal tubule-derived KDT3 cells...
2014: PloS One
Feng Zhai, Ru Zhang, Ting Zhang, Peter S Steyger, Chun-Fu Dai
OBJECTIVE: To clarify whether gentamicin affects vestibular dark cells in guinea pigs and relieves patients of aural fullness with intractable Ménière's disease following intratympanic administration. MATERIALS AND METHODS: Purified gentamicin-Texas Red (GTTR) was injected intratympanically in guinea pigs that were sacrificed at 1, 3, 7, 14 and 28 days. GTTR uptake was examined in hair cells, and transitional cells and dark cells in vestibular end-organs were examined...
2013: Audiology & Neuro-otology
Phillip M Uribe, Huifang Sun, Kevin Wang, James D Asuncion, Qi Wang, Chien-Wei Chen, Peter S Steyger, Michael E Smith, Jonathan I Matsui
Aminoglycoside antibiotics, like gentamicin, kill inner ear sensory hair cells in a variety of species including chickens, mice, and humans. The zebrafish (Danio rerio) has been used to study hair cell cytotoxicity in the lateral line organs of larval and adult animals. Little is known about whether aminoglycosides kill the hair cells within the inner ear of adult zebrafish. We report here the ototoxic effects of gentamicin on hair cells in the saccule, the putative hearing organ, and utricle of zebrafish. First, adult zebrafish received a single 30 mg/kg intraperitoneal injection of fluorescently-tagged gentamicin (GTTR) to determine the distribution of gentamicin within inner ear sensory epithelia...
2013: PloS One
Jeong-Han Lee, Channy Park, Se-Jin Kim, Hyung-Jin Kim, Gi-Su Oh, AiHua Shen, Hong-Seob So, Raekil Park
Hair cells at the base of the cochlea appear to be more susceptible to damage by the aminoglycoside gentamicin than those at the apex. However, the mechanism of base-to-apex gradient ototoxicity by gentamicin remains to be elucidated. We report here that gentamicin caused rodent cochlear hair cell damages in a time- and dose-dependent manner. Hair cells at the basal turn were more vulnerable to gentamicin than those at the apical turn. Gentamicin-conjugated Texas Red (GTTR) uptake was predominant in basal turn hair cells in neonatal rats...
2013: Experimental & Molecular Medicine
Ru Zhang, Yi-Bo Zhang, Chun-Fu Dai, Peter S Steyger
BACKGROUND AND OBJECTIVE: Transtympanic administration of gentamicin is effective for treating patients with intractable vertigo. This study explored the spatial and temporal distribution of gentamicin in vestibular end-organs after transtympanic administration. METHODS: Thirty guinea pigs were transtympanically injected with gentamicin conjugated to Texas Red (GTTR) and their vestibular end-organs examined after various survival periods. Another 9 guinea pigs received GTTR at different doses...
April 2013: Hearing Research
Andrew A Vu, Garani S Nadaraja, Markus E Huth, Lauren Luk, John Kim, Renjie Chai, Anthony J Ricci, Alan G Cheng
Sound perception requires functional hair cell mechanotransduction (MET) machinery, including the MET channels and tip-link proteins. Prior work showed that uptake of ototoxic aminoglycosides (AG) into hair cells requires functional MET channels. In this study, we examined whether tip-link proteins, including Cadherin 23 (Cdh23), regulate AG entry into hair cells. Using time-lapse microscopy on cochlear explants, we found rapid uptake of gentamicin-conjugated Texas Red (GTTR) into hair cells from three-day-old Cdh23(+/+) and Cdh23(v2J/+) mice, but failed to detect GTTR uptake in Cdh23(v2J/v2J) hair cells...
2013: PloS One
Shayanne A Lajud, Zhao Han, Fang-Lu Chi, Rende Gu, Danish A Nagda, Orysia Bezpalko, Samudra Sanyal, Andres Bur, Ziying Han, Bert W O'Malley, Daqing Li
OBJECTIVE: We have recently developed a novel inner ear drug delivery system using chitosan glycerophosphate (CGP) hydrogel loaded with drugs commonly used for treatment of inner ear diseases, significantly improving the drugs' sustained delivery. The goal of this study is to evaluate the effectiveness of chitosanase as a "switch off" mechanism for this drug delivery system when side effects and potential ototoxicities appear during treatment. To evaluate this effect, we tested gentamicin (GENT) in the inner ear following CGP delivery with/without regulation...
March 28, 2013: Journal of Controlled Release: Official Journal of the Controlled Release Society
Tian Wang, Yu-Qin Yang, Takatoshi Karasawa, Qi Wang, Amanda Phillips, Bing-Cai Guan, Ke-Tao Ma, Meiyan Jiang, Ding-Hua Xie, Peter S Steyger, Zhi-Gen Jiang
Loop diuretics such as bumetanide and furosemide enhance aminoglycoside ototoxicity when co-administered to patients and animal models. The underlying mechanism(s) is poorly understood. We investigated the effect of these diuretics on cellular uptake of aminoglycosides, using Texas Red-tagged gentamicin (GTTR), and intracellular/whole-cell recordings of Madin-Darby canine kidney (MDCK) cells. We found that bumetanide and furosemide dose-dependently enhanced cytoplasmic GTTR fluorescence by ~60 %. This enhancement was suppressed by La(3+), a non-selective cation channel (NSCC) blocker, and by K(+) channel blockers Ba(2+) and clotrimazole, but not by tetraethylammonium (TEA), 4-aminopyridine (4-AP) or glipizide, nor by Cl(-) channel blockers diphenylamine-2-carboxylic acid (DPC), niflumic acid (NFA), and CFTRinh-172...
April 2013: Cell Biochemistry and Biophysics
Jianfen Luo, Lei Xu
OBJECTIVES: We examined the distribution of gentamicin sulfate in the inner ear after delivery via a chitosan glycerophosphate (CGP) hydrogel system and examined the change in morphology of the hair cells so as to determine how gentamicin affected the function of the inner ear. METHODS: A matrix of CGP hydrogel loaded with gentamicin conjugated with Texas Red (GTTR) was injected into the round window niche of the left ear of C57/BL6 mice. The mice were painlessly killed on day 1 or day 7 after injection...
March 2012: Annals of Otology, Rhinology, and Laryngology
Ruben S Stepanyan, Artur A Indzhykulian, A Catalina Vélez-Ortega, Erich T Boger, Peter S Steyger, Thomas B Friedman, Gregory I Frolenkov
Aminoglycoside ototoxicity involves the accumulation of antibiotic molecules in the inner ear hair cells and the subsequent degeneration of these cells. The exact route of entry of aminoglycosides into the hair cells in vivo is still unknown. Similar to other small organic cations, aminoglycosides could be brought into the cell by endocytosis or permeate through large non-selective cation channels, such as mechanotransduction channels or ATP-gated P2X channels. Here, we show that the aminoglycoside antibiotic gentamicin can enter mouse outer hair cells (OHCs) via TRPA1, non-selective cation channels activated by certain pungent compounds and by endogenous products of lipid peroxidation...
December 2011: Journal of the Association for Research in Otolaryngology: JARO
Abdelrahman Alharazneh, Lauren Luk, Markus Huth, Ashkan Monfared, Peter S Steyger, Alan G Cheng, Anthony J Ricci
Aminoglycosides (AG) are commonly prescribed antibiotics with potent bactericidal activities. One main side effect is permanent sensorineural hearing loss, induced by selective inner ear sensory hair cell death. Much work has focused on AG's initiating cell death processes, however, fewer studies exist defining mechanisms of AG uptake by hair cells. The current study investigated two proposed mechanisms of AG transport in mammalian hair cells: mechanotransducer (MET) channels and endocytosis. To study these two mechanisms, rat cochlear explants were cultured as whole organs in gentamicin-containing media...
2011: PloS One
T Karasawa, Q Wang, L L David, P S Steyger
Aminoglycoside-induced nephrotoxicity and ototoxicity is a major clinical problem. To understand how aminoglycosides, including gentamicin, induce cytotoxicity in the kidney proximal tubule and the inner ear, we identified gentamicin-binding proteins (GBPs) from mouse kidney cells by pulling down GBPs with gentamicin-agarose conjugates and mass spectrometric analysis. Among several GBPs specific to kidney proximal tubule cells, cytoskeleton-linking membrane protein of 63 kDa (CLIMP-63) was the only protein localized in the endoplasmic reticulum, and was co-localized with gentamicin-Texas Red (GTTR) conjugate after cells were treated with GTTR for 1 h...
2010: Cell Death & Disease
Ja-Won Koo, Qi Wang, Peter S Steyger
Inflammatory mediators released during bacterial infection include vasoactive peptides such as histamine and serotonin, and their serum levels are frequently elevated. These peptides also modulate the vascular permeability of endothelial cells lining the blood-brain and blood-labyrinth barriers (BLB). These peptides may also modulate the permeability of the BLB to ototoxic aminoglycoside antibiotics prescribed to resolve bacterial sepsis. To test this hypothesis, we compared the effect of histamine and serotonin on the cochlear distribution of fluorescently conjugated gentamicin (GTTR) in control animals at 0...
2011: Audiology & Neuro-otology
Yiliang Zhang, Ru Zhang, Chunfu Dai, Peter S Steyger, Yongfu Yu
OBJECTIVE/HYPOTHESIS: The distribution of gentamicin in the inner ear via the endolymphatic sac (ES) or round window (RW) routes was investigated. STUDY DESIGN: Experimental study. METHODS: A fluorescent gentamicin-Texas Red conjugate (GTTR) was adopted to visualize the gentamicin. Adult guinea pigs were treated with GTTR applied to the ES or RW, the animals were allowed to recover for 3 days, then confocal microscopy was used to observe and quantify GTTR distributions in cochlear and vestibular sensory epithelium...
October 2010: Laryngoscope
Qi Wang, Allan Kachelmeier, P S Steyger
Aminoglycosides enter inner ear hair cells via apical endocytosis, or mechanoelectrical transduction channels, implying that, in vivo, aminoglycosides enter hair cells from endolymph prior to exerting their cytotoxic effect. If so, circulating aminoglycosides likely cross the strial blood-labyrinth barrier and enter marginal cells prior to clearance into endolymph. We characterized the competitive antagonism of unconjugated aminoglycosides on the uptake of fluorescent gentamicin (GTTR) in the stria vascularis and kidney cells at an early time point...
September 1, 2010: Hearing Research
Feng Zhai, Jian-Ping Liu, Chun-Fu Dai, Qi Wang, Peter S Steyger
OBJECTIVES: To compare the cochlear distribution of low-dose fluorescent gentamicin after intra-tympanic administration in guinea pig (GPs) with clinical data of low dose intra-tympanic gentamicin in patients with intractable vertigo. MATERIALS AND METHODS: Purified gentamicin-Texas Red (GTTR) was injected intratympanically into GPs and the cochlear distribution and time course of GTTR fluorescence in outer hair cells (OHCs) was determined using confocal microscopy...
June 2010: Otology & Neurotology
Qi Wang, Peter S Steyger
Aminoglycosides enter inner ear hair cells across their apical membranes via endocytosis, or through the mechanoelectrical transduction channels in vitro, suggesting that these drugs enter cochlear hair cells from endolymph to exert their cytotoxic effect. We used zebrafish to determine if fluorescently tagged gentamicin (GTTR) also enters hair cells via apically located calcium-sensitive cation channels and the cytotoxicity of GTTR to hair cells. We then examined the serum kinetics of GTTR following systemic injection in mice and which murine cochlear sites preferentially loaded with systemically administered GTTR over time by confocal microscopy...
June 2009: Journal of the Association for Research in Otolaryngology: JARO
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