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

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 aminoglycoside-induced 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 EPO-transgenic mice were significantly lower than in C57BL/6 mice (mean difference in ABR threshold shift 13.6 dB at 32 kHz, 95% CI 3.8-23.4 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.

Long non‑coding RNA EBLN3P promotes the recovery of the function of impaired spiral ganglion neurons by competitively binding to miR‑204‑5p and regulating TMPRSS3 expression

“…The mice were randomly divided into 2 groups as follows: An experimental group and a control group. The mice in the experimental group were intramuscularly injected with 500 mg/kg/day kanamycin sulfate (040810OG; Ameresco, Inc.) for 14 days, while those in the control group were injected with an equal volume of normal saline for 14 days, as previously described (21). For each group at the beginning, 8 mice in total were used for the whole experimental procedure.…”

Experimental animal models of drug-induced sensorineural hearing loss: a narrative review

“…For instance, a single dose of kanamycin (400-500 mg/kg) by subcutaneous injection accompanied by a dose of furosemide (100 mg/kg) by intraperitoneal injection can lead to permanent hearing loss in gerbils, with significant loss of both OHCs and IHCs as well as the injury of SGNs (42). In conclusion, animal species and dosage regimens are important factors in establishing AABs-induced animal models of SNHL, and selecting the appropriate animal species and adjusting dosage can obtain the expected model of specific lesions (Table 1) (39,(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54).…”

Adverse outcome pathway for aminoglycoside ototoxicity in drug-resistant tuberculosis treatment

“…Are the initiating and key events expected to be conserved across taxa? : Experimental studies in multiple types of animals across species, including zebrafishes (Kim et al 2018;Wang and Steyger 2009), bullfrogs (Dai et al 2006), chicks (Dai et al 2006;Hashino and Shero 1995), mice (Bächinger et al 2018;Corns et al 2017;Dai et al 2006;Hirose et al 2014;Koo et al 2015;Yu et al 2018), rats (Garcia-Alcantara et al 2017;Ladrech et al 2017;Lenoir and Puel 1987), turtles (Farris et al 2004), cats (Wersall and Hawkins 1962), and guinea pigs (Aran and Darrouzet 1975;Bareggi et al 1990;Campbell et al 2016;Dai et al 2006;Garetz et al 1994;Hayashida et al 1985;Imamura and Adams 2003;Tunstall et al 1995)-all show evidence in support of this pathway. Human autopsies have also shown this relationship (Keene et al 1982;Nordstrom et al 1990).…”