Cisplatin and aminoglycoside antibiotics: hearing loss and its prevention

Abstract

This review introduces the pathology of aminoglycoside antibiotic and the cisplatin chemotherapy classes of drugs, discusses oxidative stress in the inner ear as a primary trigger for cell damage, and delineates the ensuing cell death pathways. Among potentially ototoxic (damaging the inner ear) therapeutics, the platinum-based anticancer drugs and the aminoglycoside antibiotics are of critical clinical importance. Both drugs cause sensorineural hearing loss in patients, a side effect that can be reproduced in experimental animals. Hearing loss is reflected primarily in damage to outer hair cells, beginning in the basal turn of the cochlea. In addition, aminoglycosides might affect the vestibular system while cisplatin seems to have a much lower likelihood to do so. Finally, based on an understanding the mechanisms of ototoxicity pharmaceutical ways of protection of the cochlea are presented.

Figure 1. Typical morphological damage by aminoglycoside antibiotics

Explants of the postnatal mouse organ of Corti were cultured for 72 h with or without 3.5 μM gentamicin, then fixed and stained for actin with rhodamine phalloidin (Chen et al., 2009). A: Incubation without drug. The red stain outlines the orderly arrangement of the three rows of outer hair cells (OHC1, OHC2, OHC3) and one row of inner hair cells (IHC). B, C, D: Incubation with gentamicin. The middle section of the organ of Corti (B) shows a few missing outer hair cells, mostly in row 1. Further towards the base (C), more damage is evident. The basal segment (D) has essentially lost all outer hair cells while inner hair cells remain. Experiment and photo courtesy of Dr. Naoki Oishi.

Figure 2

Administration of NOX3 siRNA reduces immunolabeling of NOX3 and p-STAT1. Rats were injected trans-tympanically with scrambled or NOX3 siRNA 48 h prior to a cisplatin injection of 11 mg/kg i.p. Three days later cochleae were removed and processed for immunohistochemistry. NOX3 siRNA reduced both the basal and cisplatin-stimulated p-STAT1 (green) and NOX3 (red) immunoreactivity in various regions of the cochlea. NOX3 and p-STAT1 immunolabeling co-localized, demonstrated by the merged images (yellow). OHC, outer hair cells; SVA, stria vascularis; SG, spiral ganglion; SL, spiral ligament. Scale bars (lower right) represent 50 μm. The images shown are a representative of three independent experiments showing similar results. (This figure was published as supplementary figure 4 in Kaur et al, 2011).

Figure 3. Cisplatin-induced hearing loss is related to activation of STAT1

(a) Bar graphs depict ABR threshold measured in rats 72 h after treatment with cisplatin (11 mg/kg i.p.) which was begun 48 h after transtympanic injection of scrambled RNA or STAT1 siRNA (0.9 ug). (b) Scanning electron microscopy of the basal turn of the cochlea of these rats. The representative figure demonstrates significant damage to outer hair cells (white arrows) by cisplatin which is prevented by pretreatment with STAT1 siRNA. (c) Quantitation of the scanning electron microscopy data. Bar graphs depict mean +/− S.E.M. The asterisks indicate statistically significant difference between the STAT1 siRNA + cisplatin group (**) and scramble + cisplatin treatment group and the scramble-treated versus the scramble + cisplatin group (p <0.05, n = 6). (This figure was published as Figure 4 in Kaur et al, (2011).