Identifying targets to prevent aminoglycoside ototoxicity

Abstract

Aminoglycosides are potent antibiotics that are commonly prescribed worldwide. Their use carries significant risks of ototoxicity by directly causing inner ear hair cell degeneration. Despite their ototoxic side effects, there are currently no approved antidotes. Here we review recent advances in our understanding of aminoglycoside ototoxicity, mechanisms of drug transport, and promising sites for intervention to prevent ototoxicity.

Keywords: Aminoglycoside; Cochlea; Hair cell; Ototoxicity.

Fig. 1.. General mechanisms of aminoglycoside bacteria entry.

Aminoglycoside (AG) enters into a periplasmic space (light blue) through outer membrane (dark blue), and enters into cytosol through inner membrane (green). AG binding to ribosome (red) induces mistranslation, resulting in bacteria cell death.

Fig. 2.. Anatomy of the mammalian cochlea.

(Left) Cross section of the cochlea. (Center) apical turn of the cochlea (magnified view). Cochlea are composed of three chambers, and filled with endolymph and perilymph. Dense capillaries and transporters in the stria vascularis selectively regulate endolymph composition. SV, scala vestibuli; SM, scala media; ST, scala tympani. (Right) organ of Corti (OoC) (magnified view). OoC contains inner and outer hair cells (IHCs and OHCs) as well as supporting cells. TM, tectorial membrane; SGN, spiral ganglion neuron; NF, nerve fiber.

Fig. 3.. Proposed mechanisms of aminoglycoside entry into the endolymph.

Aminoglycoside (AG) is detected in the capillaries [1] and individual cell subtypes [2] in the stria vascularis. In vivo work showed that AG enters into endolymph [3]. AG uptake into the perilymph has also been suggested [4]. Reissner’s and basilar membranes (RM and BM) are also considered as possible entry routes of AG from the perilymph to the endolymph [5]. Thick arrows indicate the AG entry routes with stronger evidences than narrow arrows. SV, scala vestibuli; SM, scala media; ST, scala tympani; StV, stria vascularis; SL, spiral ligament; SpL, spiral limbus; OSL, osseous spital lamina; SGN, spiral ganglion neuron; NF, nerve fiber.

Fig. 4.. Proposed mechanisms of aminoglycoside entry into hair cells.

Aminoglycoside (AG) enters into hair cells (IHCs and OHCs) through mechanotransducer (MET) (1), transient receptor potential (TRP) (2), adenosine triphosphate (ATP) receptor (3) channels, and endocytosis (4). Lower number depicts stronger evidence (1 > 2 > 3 > 4). Each star indicates the location of the channels or endocytosis in hair cells (pink, IHC stereocilia; yellow, OHC stereocilia; brown, IHC cell body; blue, OHC cell body).

Fig. 5.. Intracellular mechanism of aminoglycoside toxicity in hair cells.

A simplified schematic of the effect of aminoglycosides (AG) in hair cells. AG interacts with organelles like mitochondria, ribosomes and endoplasmic reticulum, triggering reactive oxygen species production. Excess of reactive oxygen species within the cells can trigger hair cell death. Interaction of AGs with the lipid bilayer components like PIP2 can render the hair cells nonfunctional.