Attenuation of Neomycin Ototoxicity by Iron Chelation

Abstract

Increasing evidence suggests that aminoglycoside ototoxicity is mediated by the formation of an aminoglycoside-iron complex and that the creation of this complex is a preliminary step in generation of free radical species and subsequent hair cell death. In this study we have assessed the ability of the iron chelator deferoxamine to attenuate the hearing loss induced by an ototoxic dose of the aminoglycoside neomycin (100 mg/kg per day for 14 days). Experiments were carried out on pigmented guinea pigs weighing 250 to 300 g. Changes in auditory sensitivity were characterized by monitoring shifts in compound action potential (CAP) thresholds, recorded through indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. Results show that animals receiving neomycin alone suffered a mean threshold shift exceeding 35 dB at all test frequencies (2.0, 4.0, and 8.0 kHz) 30 days after initiation of treatment. In comparison, all animals receiving cotherapy of neomycin and deferoxamine (150 mg/kg twice daily for 14 days) maintained their CAP threshold, suggesting significant protection from neomycin ototoxicity. A statistical comparison of treatment groups showed that in the animals receiving cotherapy with neomycin and deferoxamine, deferoxamine produced a significant protective effect against neomycin-induced ototoxicity (P < 0.001). These results provide further evidence of the intrinsic role of iron in aminoglycoside ototoxicity and suggest that deferoxamine may have a therapeutic role in attenuating the cytotoxic action of aminoglycoside antibiotics.

Aminoglycoside Antibiotics

“…A similar chelation treatment also protected against both the cochlear and vestibular toxicity induced by kanamycin and streptomycin [Song et al, 1998]. Subsequently, successful antioxidant therapy was extended to neomycin and amikacin [Conlon and Smith, 1998a;Conlon et al, 1999].…”

Recent Advances in Understanding Aminoglycoside Ototoxicity and Its Prevention

“…Both the cochlear and vestibular toxicity of aminoglycosides can be attenuated by cotherapy with a wide spectrum of antioxidants or iron chelators. Specifically, the toxic side effects of gentamicin, kanamycin and streptomycin [Song et al, 1997[Song et al, , 1998] as well as of neomycin and kanamycin [Conlon and Smith, 1998;Conlon et al, 1999] have been reduced by iron chelators such as 2,3-dihydroxybenzoate or antioxidants including d-methionine and lipoic acid. Threshold shifts as high as 60-70 dB were decreased to 10-15 dB with concomitant preservation of hair cells.…”

Gentamicin-Induced Cytotoxicity Involves Protein Kinase C Activation, Glutathione Extrusion and Malondialdehyde Production in an Immortalized Cell Line from the Organ of Corti

“…In particular, hair cell death occurs by apoptosis [Takumida et al, 1999;Forge, 1985;Nakagawa et al, 1998], probably induced by a mechanism involving free radical formation and lipid peroxidation [Forge and Schacht, 2000]. Accordingly, in vivo and in vitro experiments confirmed that several radical scavengers [Garetz et al, 1994a, b] and iron chelators attenuate aminoglycoside-induced ototoxicity and nephrotoxicity [Conlon et al, 1998[Conlon et al, , 1999Sha and Schacht, 2000;Song and Schacht, 1996;Song et al, 1997].…”