Abstract
Mutations in GJB2, gene coding for connexin 26 (Cx26), and GJB6, gene coding for connexin 30 (Cx30), are the most common genetic defects causing non-syndromic hereditary hearing loss. We previously reported that overexpression of Cx26 completely rescues the hearing in a mouse model of human GJB6 null mutations. The results suggest that therapeutic agents up-regulating the expression of Cx26 may potentially be a novel treatment for non-syndromic hereditary deafness caused by Cx30 null mutations. Retinoids are a family of vitamin A derivatives that exert broad and profound effects on cochlear protein expression including connexins. They are readily available and already utilized as therapeutic agents for recurrent otitis media and hearing loss due to noise exposure. In this study, we characterized the expression of Cx26 and Cx30 in the postnatal inner ear by different retinoids including retinyl palmitate (RP), the main source of vitamin A in over-the-counter (OTC) supplements, retinyl acetate (RAc) which is an isomer of RP, and all-trans-retinoic acid (ATRA), the most active retinoid derivative. The results revealed ATRA significantly increased cochlear Cx26 expression and improved hearing in Cx30 knockout (KO) mice by 10 dB suggesting its potential benefits as a therapeutic agent. In contrast, RP selectively reduced cochlear Cx30 expression and did not improve hearing thresholds at the dosages we tested.
Highlights
Found in a variety of animal and plant sources, retinoids or the family of vitamin A derivatives are essential nutrients for normal development [1]
Balance Med. 2018, 1, 2 (GJs) in the cochlea are co-assembled from connexin 26 (Cx26) and connexin 30 (Cx30), and overexpression of Cx26 will rescue hearing in the mouse model of human GJB6 null mutations [14]. These results suggest that therapeutic agents, such as vitamin A known to up-regulate the expression of Cx26, may be used as a novel drug treatment for non-syndromic hereditary deafness caused by Cx30 functionally null mutations in critical developmental periods
Placement of gel foam soaked with retinyl palmitate (RP, 30 μM) on the round window (RW)
Summary
Found in a variety of animal (e.g., liver, eggs & milk) and plant (as provitamin beta-carotene) sources, retinoids or the family of vitamin A derivatives are essential nutrients for normal development [1]. Vitamin A plays a critical role in the development of the inner ear [2]. Excessive exposure to vitamin A causes a multitude of congenital pathologies such as microtia, anotia, and inner ear malformations clinically known as Michel aplasia and Mondini dysplasia [4,5]. Vitamin A has been implicated as a treatment for hearing loss in recurrent otitis media and noise exposures [6,7,8]. Delineating benefits and potentially damaging developmental effects of vitamin A, for the treatment of hearing loss, are challenging tasks and continue to be a topic of investigation. The central mechanism for treating hearing loss appears to be vitamin
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