Attenuation of Aminoglycoside Ototoxicity by Glutathione

Nishida, Isao; Takumida, Masaya

doi:10.1159/000276801

Cited by 15 publications

(10 citation statements)

References 23 publications

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“…cochlear disruption by cisplatinum [23], GM [24], kanamycin [12,25], noise [26] and ischemia/reperfusion injury [27]. Conversely, administration of buthionine sulfoximine, an inhibitor of glutathione synthesis, potentiates the ototoxic effects of kanamycin and ethacrynic acid [28].…”

Section: Discussionmentioning

confidence: 99%

“…ROS generation is believed to contribute to pathological changes in a wide variety of etiologies, including all classic categories of ototoxic agents. The presence of ROS and their importance in hair cell death due to aminoglycosides is suggested by a number of studies that have demonstrated a prophylactic effect of antioxidants [7,12,13]. Concerning the interaction between ROS and NO in aminoglycoside ototoxicity, however, little is known to date.…”

Section: Introductionmentioning

confidence: 99%

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Free Radicals in the Guinea Pig Inner Ear following Gentamicin Exposure

Takumida

Popa²,

Anniko³

1999

ORL

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The purpose of this study was to investigate the occurrence of free radicals, nitric oxide (NO), superoxide (O^–₂) and peroxynitrite, in the inner ear of the guinea pig following intratympanic injection with 5 mg of gentamicin (GM). Forty-eight hours after GM injection, varying degrees of degeneration of the inner ear were observed. Immunohistochemical study revealed immunoreactivity to NO synthase II (which generates NO) and to xanthine oxidase (which generates O^–₂) in both the vestibular organ and the organ of Corti. Immunohistochemical investigation, using a specific antinitrotyrosine antibody, also showed intense staining, suggesting formation of peroxynitrite in the inner ear through the reaction of NO with O^–₂. Scanning electron-microscopic study showed that the ototoxic effects could be blocked with N-nitro-L-arginine methylester, a competitive inhibitor of NO synthase, with superoxide dismutase, an O^–₂ scavenger, and with ebselen, a scavenger of peroxynitrite. On the basis of these findings, it can be concluded that NO together with O^–₂, which form more reactive peroxynitrite, play an important role in GM ototoxicity in the guinea pig.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Free Radicals in the Guinea Pig Inner Ear following Gentamicin Exposure

Takumida

Popa²,

Anniko³

1999

ORL

Self Cite

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“…Two strategies utilized to demonstrate the association between ROS formation and cochlear disruption are: (i) the use of ROS scavengers to protect against cochlear damage by agents that elicit ROS generation in other organ systems, and (ii) disturbance of the glutathione detoxification system, to potentiate ROSinduced ototoxicity. ROS scavengers have been shown to provide protection against cochlear disruption due to cisplatinum [26,27], gentamicin [28], kanamycin [15,29], noise [30] and ischemia/reperfusion injury [31,32]. Conversely, administration of buthionine sulfoximine, an inhibitor of glutathione synthesis, potentiates the ototoxic effects of kanamycin and ethacrynic acid [33].…”

Section: Discussionmentioning

confidence: 99%

“…ROS generation is believed to contribute to pathological changes in a wide variety of etiologies, including all classic categories of ototoxicants. The presence of ROS and their importance in hair cell death due to aminoglycosides is suggested by a number of studies that have demonstrated a protective effect of antioxidants [11,15,16]. NO in the inner ear mediates neurotransmission and may play an important role in regulating vascular tone, and in maintaining endolymph and ion homeostasis [8,10,17].…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide-Induced Expression of Reactive Oxygen Species and Peroxynitrite in the Guinea Pig Vestibular Organ

Takumida

Popa²,

Anniko³

1998

ORL

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The purpose of this study was to investigate the occurrence of reactive oxygen species and peroxynitrite in the vestibular organ of the guinea pig following inoculation with bacterial lipopolysaccharide (LPS). The animals were injected transtympanically with 1 mg of LPS 24 h after the intraperitoneal injection of 0.1 mg LPS. Forty-eight hours after the inoculation, varying degrees of degeneration of the vestibular end organs were observed. Immunohistochemical study revealed immunoreactivity to xanthine oxidase (which generates O^–₂) in the vestibular organ after inoculation with LPS. Immunohistochemical investigation with a specific antinitrotyrosine antibody also showed intense staining of sensory epithelium, fluid transporting cells and the endolymphatic sac, suggesting formation of peroxynitrite in the vestibular organ through the reaction of NO with O^–₂. On the basis of these data, it can be concluded that NO together with O^–₂, which form more reactive peroxynitrite, may be the most important pathogenic agents in LPS-induced labyrinthitis in the guinea pig.

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“…Experimental evidence. Guinea pigs treated with glutathione in combination with amikacin show reduced damage to the organ of Corti, compared to amikacin-only controls (40). In the Garetz report (41), Guinea pigs were injected with 100 mg/ kg/day gentamicin.…”

Section: Drug/compound: Glutathionementioning

confidence: 99%

Prevention and modulation of aminoglycoside ototoxicity (Review)

Perletti¹,

Vral²,

Patrosso³

et al. 2008

Mol Med Report

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Abstract. More than 60 years after their isolation and characterization, aminoglycoside (AG) antibiotics remain powerful agents in the treatment of severe gram-negative, enterococcal or mycobacterial infections. However, the clinical use of AGs is hampered by nephrotoxicity and ototoxicity, which often develop as a consequence of prolonged courses of therapy, or of administration of increased doses of these drugs. The discovery of non-ototoxic antibacterial agents, showing a wider spectrum of activity, has gradually decreased the use of AGs as first line antibiotics for many systemic infections. However, AGs are now undergoing an unexpected revival, being increasingly indicated for the treatment of severe emerging infections caused by organisms showing resistance to most first-line agents (e.g., multidrug-resistant tuberculosis, complicated nosocomially-acquired acute urinary tract infections). Increasing adoption of aminoglycosides poses again to scientists and physicians the problem of toxicity directed to the kidneys and to the inner ear. In particular, aminoglycoside-induced deafness can be profound and irreversible, especially in genetically predisposed patients. For this reason, an impressive amount of molecular strategies have been developed in the last decade to counteract the ototoxic effect of aminoglycosides. The present article overviews: i) the molecular mechanisms by which aminoglycosides exert their bactericidal activity, ii) the mechanisms whereby AGs exert their ototoxic activity in genetically-predisposed patients, iii) the drugs and compounds that have so far proven to prevent or modulate AG ototoxicity at the preclinical and/or clinical level, and iv) the dosage regimens that have so far been suggested to decrease the incidence of episodes of AG-induced ototoxicity. Aminoglycoside antibiotics: a revival?Aminoglycoside (AG) antibiotics have been extensively used for the prophylaxis and the treatment of a wide variety of systemic infections, for the outstanding features displayed by these antibacterial agents, i.e., the concentration-dependent bactericidal activity, the post-antibiotic effect, the favorable pharmacokinetic profile, and the strong synergism with other antibiotics such as vancomycin and ß-lactams (1). More than 60 years after their isolation and characterization, these drugs remain powerful tools for treatment of severe gram-negative, enterococcal or mycobacterial infections. AGs are usually administered in combination with ß-lactam antibiotics for a variety of systemic infections (e.g., bacterial endocarditis or various pseudomonal infections), but are also used as monotherapy for infections of the urinary tract. Streptomycin, the first AG isolated and adopted for human therapy (Fig. 1), MOLECULAR MEDICINE REPORTS 1: 3-13, 2008 3 Prevention and modulation of aminoglycoside ototoxicity (Review) GIANPAOLO

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Attenuation of Aminoglycoside Ototoxicity by Glutathione

Cited by 15 publications

References 23 publications

Free Radicals in the Guinea Pig Inner Ear following Gentamicin Exposure

Free Radicals in the Guinea Pig Inner Ear following Gentamicin Exposure

Lipopolysaccharide-Induced Expression of Reactive Oxygen Species and Peroxynitrite in the Guinea Pig Vestibular Organ

Prevention and modulation of aminoglycoside ototoxicity (Review)

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