Academic journal article The Volta Review

Review of Cellular Changes in the Cochlea Due to Aminoglycoside Antibiotics

Academic journal article The Volta Review

Review of Cellular Changes in the Cochlea Due to Aminoglycoside Antibiotics

Article excerpt

Over the past two decades, considerable progress has been made in understanding the mechanisms underlying aminoglycoside ototoxicity. Aminoglycoside damage progresses from cochlear base to apex and from outer to inner hair cells. Aminoglycoside antibiotics enter hair cells at the apical pole and are taken up into lysosomes and mitochondria. Aminoglycosides generate damaging reactive oxygen species that can initiate a program of cell death. In cases of acute ototoxicity involving high doses of aminoglycosides, hair cells appear to die by apoptosis and their cuticular plates can be ejected from the epithelium. However, after long-term systemic administration, hair cell death occurs by either necrosis or apoptosis. Aminoglycoside ototoxicity is exacerbated by loop diuretics that accelerate drug entry into cochlear fluids resulting in rapid cell death. Knowledge of the signaling pathways involved in aminoglycoside ototoxicity has led to new strategies for preventing ototoxicity, involving antioxidants, protease inhibitors and neurotrophic factors. Such fundamental knowledge may one day lead to clinical procedures that block the ototoxic side effects of this important class of antibiotics.

Introduction

Aminoglycoside antibiotics, developed in the 1940s, are mainly used to treat gram-negative infections; however, their use is constrained by their toxic effects on the kidney and inner ear. Despite these side effects, aminoglycosides continue to be used extensively in many parts of the world because of their low cost, effectiveness in treating certain types of infections (Forge & Schacht, 2000) and ability to suppress premature stop codons in muscular dystrophy and cystic fibrosis, thereby allowing translation to continue to the normal termination of the transcript (Barton-Davis, Cordier, Shoturma, Leland, & Sweeney, 1999; Bidou et al., 2004; Howard et al., 2004; Kerem, 2004, 2005; Mulherin et al., 1991; Wilschanski et al., 2000).

Antibacterial Mechanisms of Aminoglycosides

To gain insights into their ototoxic effects, it is useful to review the antibacterial action of aminoglycoside antibiotics. The bactericidal effects of aminoglycosides arise from their ability to inhibit protein synthesis. Aminoglycosides preferentially bind to prokaryotic and mitochondrial ribosomes at the A (adenosine) decoding region of 16S ribosomal RNA (rRNA); this results in codon misreading and suppression of translation (Moazed & Noller, 1987; Recht, Douthwaite, Dahlquist, & Puglisi, 1999; Wilhelm, Pettitt, & Jessop, 1978). In contrast, eukaryotic cells exhibit low toxicity to aminoglycosides because the drugs bind weakly to cytoplasmic rRNA due to an A-to-G (guanosine) substitution in 16S rRNA. However, mitochondria, which are involved in protein synthesis and are abundantly expressed in hair cells, are sensitive to aminoglycosides because they have adenosine at the 1408 position on the 16S rRNA (Gutell, 1994; see Guan, 2005, this issue). These observations, which are consistent with the endosymbiosis theory that proposes that mitochondria arose from ancient prokaryotic organisms (Vellai, Takacs, & Vida, 1998), provide important insights into the mechanism of aminoglycoside-induced hair cell loss. However, they do not fully account for many features of aminoglycoside ototoxicity such as the base-to-apex gradient of hair cell loss and differential vulnerability between hair cells and other cell types in the ear such as spiral ganglion neurons.

Damage Gradients

Despite their widespread distribution throughout the body, aminoglycoside antibiotics tend to selectively damage the sensory hair cells in the cochlea and vestibular system. When aminoglycoside antibiotics are administered systemically, sensory cell loss in the cochlea occurs in a Stereotypie pattern; damage begins at the base of the cochlea and progresses toward the apex. At any given cochlear location, outer hair cell loss (OHC) precedes inner hair cell (IHC) loss. …

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