Blocking the Glucocorticoid Receptor with RU-486 Does Not Prevent Glucocorticoid Control of Autoimmune Mouse Hearing Loss

Abstract

Background/Aims: Glucocorticoids effectively manage autoimmune hearing loss, although the cochlear mechanisms involved are unknown. Previous studies of steroid-responsive hearing loss in autoimmune (lupus) mice showed glucocorticoids and mineralocorticoids were equally effective, suggesting the ion homeostasis functions of glucocorticoids may be as relevant as immunosuppression for control of autoimmune-induced inner ear disease. Therefore, to better characterize the role of the glucocorticoid receptor in autoimmune hearing loss therapy, its function was blocked with the antagonist RU-486 (mifepristone) during glucocorticoid (prednisolone) treatments. Methods: Following baseline auditory brainstem response (ABR) thresholds, MRL/MpJ-Fas^lpr autoimmune mice were implanted with pellets providing combinations of 1.25 mg/kg of RU-486, 4 mg/kg of prednisolone, or their respective placebos. After 1 month, animals were retested with ABR and blood was collected for immune complex analyses. Results: Mice receiving no prednisolone (placebo + placebo and placebo + RU-486) showed continued declines in hearing. On the other hand, mice receiving prednisolone (prednisolone + placebo and prednisolone + RU-486) had significantly better hearing (p < 0.05) than the non-prednisolone groups. Immune complexes were significantly elevated in the placebo + RU-486 group, suggesting RU-486 effectively blocked glucocorticoid receptor-mediated immune suppression. These results showed that blockage of the glucocorticoid receptor with RU-486 did not prevent prednisolone’s effects in the ear, suggesting its ion homeostasis actions via the mineralocorticoid receptor were more relevant in hearing control. Conclusion: The mineralocorticoid receptor-mediated actions of glucocorticoids are potentially relevant in steroid-responsive hearing disorders, implying disrupted cochlear ion transport functions may underlie the vascular problems proposed in some forms of immune-mediated hearing loss.

Low dose combination steroids control autoimmune mouse hearing loss

“…Although the basis for this is undetermined, it is presumably the additive effects of the mineralocorticoid aldosterone to the mineralocorticoid impact of prednisolone. Previous studies have shown aldosterone alone will protect hearing in these mice and the glucocorticoids are effective because of their binding to the mineralocorticoid receptor (Trune and Kempton, 2009). Thus, the additional aldosterone, combined with a level of prednisolone that by itself was not enough (1.0 mg), may have sufficiently increased mineralocorticoid receptor functions sufficiently to preserve normal cochlear ion transport functions.…”

Advances in auditory and vestibular medicine

“…It also has been reported that loss of aldosterone with aging may lead to presbycusis, possibly by interfering with this process26. The impact of glucocorticoids on this mineralocorticoid function also has been shown experimentally27–29 suggesting the K + transport system may respond to therapeutic anti-inflammatory steroids, such as prednisone and dexamethasone.…”

Ion homeostasis in the ear: mechanisms, maladies, and management

“…If inflammation disrupts stria vascularis ion homeostatic mechanisms, then therapies may treat the inflammation, the ion transport problem, or both. For example, autoimmune disease mice have significant hearing loss that develops due to elevated serum immune complexes that compromise stria vascularis ion transport [25]. The mineralocorticoid aldosterone upregulates the epithelial sodium channel (ENaC) and Na + ,K + -ATPase, and is as effective as glucocorticoids in managing or preventing this hearing loss in mice.…”

“…These include the K + channels (KCNJ10, KCNE1, KCNQ1), ENaC, Na + ,K + -ATPase, NKCC, gap junctions, aquaporins, TRPV4, purinergic receptors, and tight junction claudins. Mineralocorticoids and glucocorticoids are the hormone drivers for some of these [4–5, 25, 34–35, 56], as well as arginine vasopressin, atrial natriuretic peptide, insulin, and endothelin [57]. However, the drivers of many of these channels are thus far undetermined.…”