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Chemical chaperone 4-phenylbutyrate prevents hearing loss and cochlear hair cell death in Cdh23 erl/erl mutant mice

Li, Boa,b,*; Zheng, Tihuaa,b,*; Yan, Caifanga,b,*; Wang, Wenjuna,b; Zhang, Jinjina; Zhang, Lupinga,b; Hu, Juanb; Zhang, Lia,b; Wan, Yuzhub; Zhang, Minyanb; Zheng, Qingyina,b,c

doi: 10.1097/WNR.0000000000001173

We previously developed Cdh23 erl/erl mutant mice (erl mice) as a model of hearing loss for otoprotective drug evaluation and showed that the erl mutation leads to hearing loss related to endoplasmic reticulum (ER) stress-induced cochlear hair cell apoptosis. Small molecular chemical chaperones, 4-phenylbutyrate (4PBA), targeting ER stress exert a neuroprotective effect. To evaluate whether 4PBA exerts an otoprotective effect, we intraperitoneally injected erl mice with 4PBA daily from postnatal age day 7 up to 12 weeks. Our results showed that treatment with 4PBA significantly alleviated hearing loss and suppressed hair cell death in erl mice. In addition, ER stress-related proteins were downregulated by 4PBA treatment. Our study showed that 4PBA exerts an otoprotective effect, which provides the potential to repurpose the drug for otoprotection.

aTransformative Otology and Neuroscience Center, Binzhou Medical University, Yantai, People’s Republic of China

Departments of bOtolaryngology-HNS

cGenetics, Case Western Reserve University, Cleveland, Ohio, USA

*Bo Li, Tihua Zheng, and Caifang Yan contributed equally to the writing of this article.

Correspondence to Qingyin Zheng, MD, Department of Otolaryngology-HNS, Case Western Reserve University, 11100 Euclid Avenue, LKS 5045, Cleveland, OH 44106, USA Tel: +1 216 844 3441; fax: +1 216 844 7268; e-mail:

Received August 14, 2018

Accepted November 2, 2018

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