Mechanisms of aminoglycoside ototoxicity and targets of hair cell protection

Abstract

Aminoglycosides are commonly prescribed antibiotics with deleterious side effects to the inner ear. Due to their popular application as a result of their potent antimicrobial activities, many efforts have been undertaken to prevent aminoglycoside ototoxicity. Over the years, understanding of the antimicrobial as well as ototoxic mechanisms of aminoglycosides has increased. These mechanisms are reviewed in regard to established and potential future targets of hair cell protection.

Figure 1

Proposed mechanisms of aminoglycoside transport in the inner ear. Possible entry sites for aminoglycosides into the scala media include via (1) the Reissner's membrane, (2) stria vascularis, and (3) basilar membrane. Published work supports the notion of entry via the Reissner's membrane and the stria vascularis through and between the marginal cells. At the hair cell level, aminoglycosides can potentially enter via mechanotransducer channels located on stereocilia of hair cells (A), endocytosis on the apical or basolateral membranes (A, B, or C), TRP channels (A, B or C), or ATP receptors (A).

Figure 2

A simplified schematic of the cell death cascade in hair cells damaged by aminoglycosides. Reactive oxygen species (ROS), stress kinases, and the caspase family of proteases are activated and mediate hair cell degeneration caused by aminoglycoside exposure, whereas overexpression of Bcl-2 protects against caspase activation and hair cell loss. Aminoglycosides damage the mitochondria and can result in generation of ROS and activation of stress kinases. Both ROS and stress kinases can cause cell death directly as well as amplify insults targeting the mitochondria. The balance between pro-apoptotic and anti-apoptotic Bcl-2 family members determines the integrity of the mitochondria. Cytochrome c leaking out of damaged mitochondria leads to caspase-9 activation, which in turn activates caspase-3 to execute cell death.