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