Blocking the glucocorticoid receptor with RU-486 does not prevent glucocorticoid control of autoimmune mouse hearing loss.
OBJECTIVE
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.


CONCLUSIONS
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.
Trune
Dennis R
DR
Oregon Hearing Research Center, Department of Otolaryngology/Head and Neck Surgery, Oregon Health & Science University, Portland, OR 97239-3098, USA. truned @ ohsu.edu
Kempton
J Beth
JB
D000704:Analysis of Variance; D000818:Animals; D001301:Audiometry, Pure-Tone; D001309:Auditory Threshold / Q000187:drug effects / Q000502:physiology; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000378:metabolism; D003051:Cochlea / Q000187:drug effects / Q000502:physiology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects / Q000502:physiology; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D034381:Hearing Loss / Q000188:drug therapy* / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D015735:Mifepristone / Q000494:pharmacology*; D011239:Prednisolone / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D013997:Time Factors
D005938:Glucocorticoids; D006727:Hormone Antagonists; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D015735:Mifepristone; D011239:Prednisolone