Mechanisms of Ototoxicity and Otoprotection

Abstract

Ototoxicity refers to damage to the inner ear that leads to functional hearing loss or vestibular disorders by selected pharmacotherapeutics as well as a variety of environmental exposures (eg, lead, cadmium, solvents). This article reviews the fundamental mechanisms underlying ototoxicity by clinically relevant, hospital-prescribed medications (ie, aminoglycoside antibiotics or cisplatin, as illustrative examples). Also reviewed are current strategies to prevent prescribed medication-induced ototoxicity, with several clinical or candidate interventional strategies being discussed.

Keywords: Aminoglycosides; Blood-labyrinth barrier; Cochleotoxicity; Ototherapeutics; Ototoxicity monitoring; Platinum-based therapeutics; Vestibulotoxicity.

Figure 1:. Primary trafficking routes of aminoglycosides and cisplatin from the vasculature to cochlear hair cells.

Circulating ototoxins typically enter the cochlea via capillaries in the stria vascularis and are cleared into endolymph via as-yet-unidentified ion channels or transporters, although several candidates exist, e.g., TRPV1 and TRPV4 non-selective cation channels for aminoglycosides, and potentially via OCT2 and CTR1 transporters for cisplatin. Once in endolymph, ototoxins can enter hair cells via one or more of several mechanisms. From Kros CJ, Steyger PS. Aminoglycoside- and Cisplatin-Induced Ototoxicity: Mechanisms and Otoprotective Strategies. Cold Spring Harb Perspect Med. 2019;9(11), with permission from Cold Spring Harbor Press.

Figure 2:. Aminoglycoside entry into hair cells.

Aminoglycosides preferentially enter mammalian hair cells via the TMC1 channel that consists of two TMC subunits (purple), each with a permeation groove (A). Entry of aminoglycosides can be blocked by curare, quinine and high levels of polyvalent cations (B). Other aminoglycoside-permeant channels on the apical membrane of hair cells include TRPV1 and TPRV4 (C), and TRPA1 on the basolateral membrane of outer hair cells (D). (E) Non-specific endocytosis enables aminoglycoside-laden endosomes to traffic to hair cell lysosomes. (F) Blocking endocytosis does not prevent hair cell death when aminoglycosides can enter hair cells via the TMC1 channel. From Steyger PS. Mechanisms of Aminoglycoside- and Cisplatin-induced Ototoxicity. American Journal of Audiology. 2021;in press, with permission from the American Journal of Audiology.

Figure 3:. Cisplatin entry into hair cells.

Cisplatin has multiple potential entry routes. (A) Neutral cisplatin can diffuse across the plasma membrane, and is readily aquated in the cytoplasm to the more toxic form of cisplatin that can form functionally disruptive adducts with proteins and DNA. (B) Uptake of aquated cisplatin is dependent on functional TMC channel complexes. (C) Cellular uptake of the aquated form of cisplatin can also occur via CTR1 and OCT2 transport proteins when expressed by the cell. From Steyger PS. Mechanisms of Aminoglycoside- and Cisplatin-induced Ototoxicity. American Journal of Audiology. 2021;in press, with permission from the American Journal of Audiology.