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Neuronal erythropoietin overexpression is protective against kanamycin-induced hearing loss in mice


Bächinger, David; Horvath, Lukas; Eckhard, Andreas; Goosmann, Madeline M; Honegger, Tim; Gassmann, Max; Vogel, Johannes; Naldi, Arianne Monge (2018). Neuronal erythropoietin overexpression is protective against kanamycin-induced hearing loss in mice. Toxicology Letters, 291:121-128.

Abstract

Aminoglycosides have detrimental effects on the hair cells of the inner ear, yet these agents indisputably are one of the cornerstones in antibiotic therapy. Hence, there is a demand for strategies to prevent aminoglycoside-induced ototoxicity, which are not available today. In vitro data suggests that the pleiotropic growth factor erythropoietin (EPO) is neuroprotective against aminoglycoside-induced hair cell loss.Here, we use a mouse model with EPO-overexpression in neuronal tissue to evaluate whether EPO could also in vivo protect from aminoglycosideinduced hearing loss. Auditory brainstem response (ABR) thresholds were measured in 12-weeks-old mice before and after treatment with kanamycin for 15 days, which resulted in both C57BL/6 and EPO-transgenic animals in a high-frequency hearing loss. However, ABR threshold shifts in EPOtransgenic mice were significantly lower than in C57BL/6 mice (mean difference in ABR threshold shift 13.6 dB at 32 kHz, 95% CI 3.8 to 23.4 dB, p = 0.003). Correspondingly, quantification of hair cells and spiral ganglion neurons by immunofluorescence revealed that EPO-transgenic mice had a significantly lower hair cell and spiral ganglion neuron loss than C57BL/6 mice. In conclusion, neuronal overexpression of EPO is protective against aminoglycoside-induce hearing loss, which is in accordance with its known neuroprotective effects in other organs, such as the eye or the brain.

Abstract

Aminoglycosides have detrimental effects on the hair cells of the inner ear, yet these agents indisputably are one of the cornerstones in antibiotic therapy. Hence, there is a demand for strategies to prevent aminoglycoside-induced ototoxicity, which are not available today. In vitro data suggests that the pleiotropic growth factor erythropoietin (EPO) is neuroprotective against aminoglycoside-induced hair cell loss.Here, we use a mouse model with EPO-overexpression in neuronal tissue to evaluate whether EPO could also in vivo protect from aminoglycosideinduced hearing loss. Auditory brainstem response (ABR) thresholds were measured in 12-weeks-old mice before and after treatment with kanamycin for 15 days, which resulted in both C57BL/6 and EPO-transgenic animals in a high-frequency hearing loss. However, ABR threshold shifts in EPOtransgenic mice were significantly lower than in C57BL/6 mice (mean difference in ABR threshold shift 13.6 dB at 32 kHz, 95% CI 3.8 to 23.4 dB, p = 0.003). Correspondingly, quantification of hair cells and spiral ganglion neurons by immunofluorescence revealed that EPO-transgenic mice had a significantly lower hair cell and spiral ganglion neuron loss than C57BL/6 mice. In conclusion, neuronal overexpression of EPO is protective against aminoglycoside-induce hearing loss, which is in accordance with its known neuroprotective effects in other organs, such as the eye or the brain.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Otorhinolaryngology
05 Vetsuisse Faculty > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:11 April 2018
Deposited On:19 Apr 2018 12:33
Last Modified:04 Jun 2019 11:59
Publisher:Elsevier
ISSN:0378-4274
OA Status:Green
Publisher DOI:https://doi.org/10.1016/j.toxlet.2018.04.007
PubMed ID:29654830

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