Abstract
Glucocorticoids have been used to treat hearing loss and vestibular dysfunction for many years. However, some reports have indicated that a subset of patients with these disorders exhibit glucocorticoid insensitivity or resistance. A reduction in histone deacetylase 2 (HDAC2) activity and expression has been reported to play a critical role in glucocorticoid resistance. Here, we investigated the protective effects of aminophylline on HDAC2 expression and glucocorticoid sensitivity in lipopolysaccharide (LPS)-induced sudden sensorineural hearing loss in guinea pigs. We assessed hearing recovery in LPS-applied guinea pigs, which were either left untreated or were systemically treated with either dexamethasone, aminophylline, or a combination of the two. We utilized fluorescence microscopy and enzyme-linked immunosorbent assay to analyze the distribution patterns of HDAC2 and detect its levels in the cochlea. We used hematoxylin-eosin staining to examine cochlear histopathological changes. In the absence of treatment, significant hearing loss was detected in LPS-exposed animals. A synergistic effect was observed between aminophylline and dexamethasone in maintaining HDAC2 expression levels, preventing hearing loss in LPS-exposed animals and reducing cochlear damage. This study indicates that aminophylline can restore glucocorticoid sensitivity, which provides a new approach to treating patients with hearing disorders who are refractory to glucocorticoids.
Highlights
It has been 60 years since glucocorticoid therapy was first used to treat hearing and balance disorders, such as sudden idiopathic sensorineural hearing loss (SSNHL), autoimmune inner ear diseases, and Meniére’s disease[1,2,3]
The LPS-induced SNHL manifested in a basal-to-apical gradient, with the most pronounced loss observed at high frequencies (19.5 ± 14.33, 34.25 ± 15.28, 58.75 ± 20.66 dB, and 60.75 ± 6.02 for 4, 8, 16, and 32 kHz, respectively)
The auditory brainstem response (ABR) threshold shifts in both the LPS + DEX group and the LPS + AMI group were smaller than those measured in the untreated, LPS group, with statistically significant differences detected at 16 kHz (42.5 ± 22.64 dB, p = 0.036 and 31.75 ± 14.53 dB, p < 0.01, respectively) and 32 kHz (46 ± 16.80 dB, p = 0.018 and 34 ± 13.60 dB, p < 0.01, respectively)
Summary
It has been 60 years since glucocorticoid therapy was first used to treat hearing and balance disorders, such as sudden idiopathic sensorineural hearing loss (SSNHL), autoimmune inner ear diseases, and Meniére’s disease[1,2,3]. Despite the numerous benefits of glucocorticoid treatment for hearing and vestibular dysfunction, some clinical reports and reviews indicate that a subset of patients with these disorders do not respond to glucocorticoid treatment. In other words, these patients exhibit glucocorticoid insensitivity or resistance[10, 11]. Inflammation has been shown to impair HDAC2 activity, which may, for instance, contribute to the glucocorticoid insensitivity associated with chronic obstructive pulmonary disease (COPD)[9, 12]. The aims of this study were to demonstrate the relationship between HDAC2 levels and glucocorticoid responsiveness and to explore the potential effects of AMI in restoring glucocorticoid sensitivity in the cochleae of guinea pigs in an established animal model of SSNHL induced by intracochlear injection of lipopolysaccharide (LPS), at endotoxin levels which have been shown to cause rapid and pronounced auditory brainstem response (ABR) threshold shifts[16, 17]
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