Mechanisms of hearing loss from trauma and inflammation: otoprotective therapies from the laboratory to the clinic

Abstract

This article reviews a series of in vitro and in vivo studies that examined the otoprotective efficacy of locally delivered dexamethasone and explored the mechanisms by which dexamethasone protects auditory hair cells. These studies used auditory threshold testing in response to pure tone stimuli, organ of Corti explant cultures, FITC-phalloidin-stained explants, and surface preparations to determine hair cell density, osmotic pump delivery of dexamethasone into the scala tympani, an animal model of electrode insertion trauma (EIT)-induced hearing loss, and real-time RT-PCR studies of gene expression levels. Local delivery of two different formulations of dexamethasone conserved hearing and protected hair cells in an animal model of cochlear implantation. Dexamethasone treatment protected hair cells in organ of Corti explants exposed to an ototoxic level of an inflammatory cytokine, and gene expression studies showed that this protection was accomplished by increased expression levels of anti-apoptosis genes (e.g. Bcl-2) and decreased levels of pro-apoptosis genes (e.g. Bax). We conclude that dexamethasone is an effective otoprotective drug for both the conservation of hearing and preservation of hair cells against trauma-induced losses. Locally delivered dexamethasone is a promising therapeutic approach for the conservation of hearing during the process of cochlear implantation.

Evidence Supporting the Hypothesis That Inflammation-Induced Vasospasm Is Involved in the Pathogenesis of Acquired Sensorineural Hearing Loss

“…Cytokine-exposed explants treated with DXM prevented TNFa-induced loss of auditory hair cells and resulted in the downregulation of Bax gene expression with upregulation of both Bcl-2 and Bcl-xl gene expression compared with baseline levels of gene expression in control explants and with the expression levels of the housekeeping gene, β -actin. Biopolymer- (i.e., poly(styrene-b-isobutylene-b-styrene); SIBS) eluted DXMb retains its ability to prevent the death of explant auditory hair cells that were exposed to TNFa and to initiate the same patterns of upregulation and downregulation of antiapoptosis- and proapoptosis-related genes (i.e., Bcl-2, Bcl-xl, and Bax) that were observed in TNFa-challenged and TNFa-challenged, DXM-treated organ of Corti explants [54].…”

New Insights on the Effect of TNF Alpha Blockade by Gene Silencing in Noise-Induced Hearing Loss

“…Studies reported that in situations with acoustic overstimulation, not only inflammatory responses but also oxidative stress can be involved in the induction of auditory hair cell apoptosis [15,17]. In this sense, it is widely accepted that TNFα is a pro-inflammatory cytokine that, among other properties, can induce auditory hair cell apoptosis through the extrinsic cell death pathway [14].…”

Implant-associated local drug delivery systems based on biodegradable polymers: customized designs for different medical applications

“…One factor that reduces the durability of the implant is again fibrosis, i.e., the growth of connective tissue around the electrodes after insertion of the CI into the inner ear. Because of their hair cell-protecting properties in combination with an antiproliferative effect on fibroblasts, glucocorticoids such as dexamethasone (DMS) are often administered via injection in conjunction with the implantation procedure [20,55]. To better control the drug concentration in the therapeutic window, we developed a CI-associated LDD system based on DMS.…”