Elsevier

Hearing Research

Volume 128, Issues 1–2, February 1999, Pages 40-44
Hearing Research

Attenuation of aminoglycoside-induced cochlear damage with the metabolic antioxidant α-lipoic acid

https://doi.org/10.1016/S0378-5955(98)00195-6Get rights and content

Abstract

Free radical generation is increasingly implicated in a variety of pathological processes, including drug toxicity. Recently, a number of studies have demonstrated the ability of gentamicin to facilitate the generation of radical species both in vivo and in vitro, which suggests that this process plays an important role in aminoglycoside-induced ototoxicity. Free radical scavengers are compounds capable of inactivating free radicals, thereby attenuating their tissue damaging capacity. In this study we have determined the ability of the powerful free radical scavenger α-lipoic acid (100 mg/kg/day) to attenuate the cochlear damage induced by a highly ototoxic regimen of the aminoglycoside amikacin (450 mg/kg/day, i.m.). Experiments were carried out on pigmented guinea pigs initially weighing 200–250 g. Changes in cochlear function were characterized as shifts in compound action potential (CAP) thresholds, estimated every 5 days, by use of chronic indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. Results showed that animals receiving α-lipoic acid in combination with amikacin demonstrated a significantly less severe elevation in CAP thresholds compared with animals receiving amikacin alone (P<0.001; t-test). These results provide further evidence of the recently reported intrinsic role of free radical generation in aminoglycoside ototoxicity, and highlight a potential clinical therapeutic use of α-lipoic acid in the management of patients undergoing aminoglycoside treatment.

Introduction

Most free radicals are highly reactive tissue damaging species that can disrupt normal cellular processes by virtue of their ability to strip electrons from organic molecules (Freeman and Crappo, 1982; Halliwell and Gutteridge, 1984). The ability of aminoglycosides to induce intracellular free radical generation is now virtually irrefutable following the direct detection of reactive oxygen species in cochlear tissue after gentamicin exposure (Priuska and Schacht, 1995; Clerici et al., 1996; Hirose et al., 1997). Furthermore, low concentrations of such free radicals have been shown to have direct toxic effects upon the outer hair cell membrane (Clerici et al., 1995).

This new understanding of the pathogenesis of aminoglycoside-induced toxicity has, for the first time since the introduction of these agents over half a century ago, allowed a rationalized approach to the study of agents with potential protective properties against aminoglycoside-induced cochlear damage.

α-Lipoic acid is a powerful, lipophilic, free radical scavenger that possesses several properties which suggest its suitability as a possible candidate for this toxic protection. These properties include a demonstrated low toxicity and good penetration across the blood-brain barrier (Packer and Tritschler, 1996; Panigrahi et al., 1996). Furthermore, α-lipoic acid has been shown to be an effective neuroprotectant against numerous other free radical-mediated disease processes (for a review see Packer et al., 1995).

Section snippets

Recording techniques for compound action potentials

Prior to drug administration, all animals were implanted with chronic, Teflon®-coated, silver-wire electrodes on the round window, vertex, and contralateral mastoid. The indwelling electrodes served to ensure stability of recordings made over extended intervals. The implanted electrodes terminated in a percutaneous connector mounted on the vertex of the skull with methacrylate dental cement. For electrode implantation, the animals were anesthetized with an intramuscular injection of ketamine

Results

Pretreatment CAP thresholds were comparable to within 10 dB in all animals at all testing frequencies. To account for small differences in baseline thresholds across animals, we computed post-treatment threshold shifts for each subject relative to pretreatment thresholds. The data presented are group means.

Animals receiving amikacin alone demonstrated a rapid, progressive elevation in mean CAP thresholds over the 20-day recording period. As expected, mean threshold shifts were

Discussion

This study suggests that the free radical scavenger, α-lipoic acid, significantly protects the cochlea against aminoglycoside-induced damage. α-Lipoic acid possesses a variety of attributes that render it a highly effective antioxidant. It has been shown to effectively scavenge hydroxyl radicals, hypochlorous acid, singlet oxygen, nitric oxide radical and hydrogen peroxide (Packer et al., 1995). The reduced form of α-lipoic acid, dihydrolipoic acid, is an even more powerful antioxidant with

Acknowledgements

The authors are grateful to Dr. Jochen Schacht for helpful comments during the conduct of this study. We are also thankful to Dr. Hans J. Tritschler of Asta Medica for kindly providing α-lipoic acid. This work was sponsored in part by NIH-NIDCD Grants DC 01692 and DC 02832.

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