Cochlear Glucocorticoid Receptor and Serum Corticosterone Expression in a Rodent Model of Noise-induced Hearing Loss: Comparison of Timing of Dexamethasone Administration

Abstract

Glucocorticoid (GC) is a steroid hormone secreted from the adrenal cortex in response to stress, which acts by binding to cytoplasmic glucocorticoid receptors (GRs). Dexamethasone (DEX) is a synthetic GC exhibiting immunosuppressive effects in both human and rodent models of hearing loss. While clinical evidence has shown the effectiveness of DEX for treatment of various inner ear diseases, its mechanisms of action and the optimal timing of treatment are not well understood. In the present study, intergroup comparisons were conducted based on the time point of treatment with DEX: (1) pretreatment; (2) posttreatment; and (3) pre&post-noise. The pre&post DEX treatment group showed a significant improvement in threshold shift at 1 day post-noise exposure as compared to the TTS (transient threshold shift)-only group at 8 and 16 kHz. Both TTS and PTS (permanent threshold shift) significantly reduced cochlear GR mRNA expression and increased serum corticosterone and cochlear inflammatory cytokines. The pre&post DEX treatment group showed a significant decrease in serum corticosterone level as compared to other DEX treatment groups and TTS-treated group at 3 days after acoustic trauma. Our results suggest that the timing of DEX administration differentially modulates systemic steroid levels, GR expression and cochlear cytokine expression.

Mitochondrial Damage and Necroptosis in Aging Cochlea

“…Samples from mice aged 2 and 20 months were collected. Cochlear tissues were obtained to localize inner and outer hair cells and neuronal fibers as previously described [20,21]. Briefly, tissues were fixed in 4% paraformaldehyde in phosphate-buffered saline (PBS) for 1 h at room temperature to remove the cochlear bony walls and lateral wall tissues and separated individual cochlear turns.…”

Evaluating the Efficacy of L-N-acetylcysteine and Dexamethasone in Combination to Provide Otoprotection for Electrode Insertion Trauma

“…Notably, in rodents, glucocorticoid receptors are found throughout the cochlea, particularly in the stria vascularis, inner hair cells, outer hair cells, and spiral ligament of the cochlea and cochlear nerve. In humans, the highest concentration of receptors is found on the spiral ligament [32][33][34]. Moreover, it has been demonstrated that the intratympanic application of dexamethasone supports cochlear homeostasis under stress conditions such as noise-trauma in multiple animal models [35][36][37].…”

Differential Effects of Low- and High-Dose Dexamethasone on Electrically Induced Damage of the Cultured Organ of Corti

“…In the study presented herein, a genomic mechanism of action could be expected due to the applied dexamethasone concentrations ranging from 5 pg to 5 fg. In humans, the highest concentration of glucocorticoid receptors required for the action of dexamethasone are mainly located in the spiral ligament (Rarey and Curtis 1996 ; Lee et al 2019 ) and increase from basal to apical in type I, II and V fibrocytes (Kil and Kalinec 2013 ). In addition, glucocorticoid receptors are also located in inner and outer hair cells as well as in the auditory nerve (Lee et al 2019 ).…”

“…In humans, the highest concentration of glucocorticoid receptors required for the action of dexamethasone are mainly located in the spiral ligament (Rarey and Curtis 1996 ; Lee et al 2019 ) and increase from basal to apical in type I, II and V fibrocytes (Kil and Kalinec 2013 ). In addition, glucocorticoid receptors are also located in inner and outer hair cells as well as in the auditory nerve (Lee et al 2019 ). Understanding the exact mode of action would give us important information about the time frame before or after electrical stimulation in which treatment should have been initiated.…”