Spironolactone blocks glucocorticoid-mediated hearing preservation in autoimmune mice

Hypothesis: Although autoimmune sensorineural hearing loss can be effectively treated with corticosteroids, little is known about how these drugs affect cochlear function. MRL/MpJ-Fas^lpr autoimmune mice treated with a mineralocorticoid (aldosterone) have previously been shown to have hearing improvement equal to those treated with a glucocorticoid (prednisolone). This suggested that the restoration of hearing with steroids was the result of an effect on sodium transport rather than an antiinflammatory or immunosuppressive role. We hypothesized that corticosteroids reverse autoimmune hearing loss through the mineralocorticoid receptor and that blocking the mineralocorticoid receptor will prevent glucocorticoid effects. Methods: Spironolactone, a mineralocorticoid receptor antagonist, was administered to MRL/MpJ-Fas^lpr autoimmune mice alone or in combination with corticosteroids. The four treatment groups were: spironolactone, spironolactone + aldosterone, spironolactone + prednisolone, and untreated water controls. Auditory brainstem response (ABR) thresholds were recorded before and during treatment (2, 3, and 4 mo) to measure the effect of steroids on hearing decline. Results: Hearing in spironolactone and spironolactone + prednisolone mice showed progressive decline in hearing similar to water controls. The hearing was preserved in spironolactone + aldosterone mice, presumably as a result of the fact that aldosterone has a higher affinity for the mineralocorticoid receptor than spironolactone. Thus, aldosterone was able to maintain cochlear function with autoimmune disease progression, similar to previous reports of aldosterone treatment effects. Conclusions: Spironolactone effectively blocked prednisolone from improving hearing in MRL/MpJ-Fas^lpr autoimmune mice. This offers evidence that the inner ear mineralocorticoid receptor is the therapeutic target for corticosteroids used to treat autoimmune and sudden sensorineural hearing loss. Pharmacologic treatments that selectively target the mineralocorticoid receptor may provide greater clinical benefit with fewer systemic side effects than prednisone in patients with autoimmune sensorineural hearing loss.