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Glucocorticoid Receptor and Nuclear Factor-B Interactions in Restraint Stress-Mediated Protection against Acoustic Trauma

Department of Physiology and Pharmacology (Y.T., I.M., P.J., B.C.), Karolinska Institutet, 171 77 Stockholm, Sweden; and National Institute on Alcohol Abuse and Alcoholism (A.C.H.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Barbara Canlon, Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden. E-mail: barbara.canlon{at}ki.se.

The role of glucocorticoid receptors (GRs) in the protective effect of restraint stress (RS) before acoustic trauma was studied in spiral ganglion neurons of CBA mice. RS increased corticosterone and protected against elevated auditory brain stem thresholds caused by acoustic trauma. This protection was inhibited by the pretreatment with a corticosterone synthesis inhibitor, metyrapone (MET), and a GR antagonist (RU486). RS followed by acoustic trauma caused an immediate increase in corticosterone that triggered nuclear translocation of GR, without a change in the expression of GR protein. RU486 + MET before RS and acoustic trauma caused an immediate increase in GR mRNA followed by increased GR protein expression (24 h after trauma). GR signaling was further characterized by analyzing nuclear factor-B (NFB) nuclear translocation and protein expression. NFB nuclear translocation was reduced after acoustic trauma or pretreatment with RU486 + MET before RS and acoustic trauma. On the contrary, RS protected against the trauma-induced NFB reduction of its nuclear translocation in inhibitory-B (IB)-dependent manner. RU486 + MET caused a simultaneous decreased IB expression and NFB nuclear translocation, demonstrating an interference with the IB-mediated activation of NFB. In summary, RS protects the cochlea from acoustic trauma by increasing corticosterone and activating GRs. These results emphasis how GR activity modulates hearing sensitivity and its importance for the rationale use of glucocorticoids in inner ear diseases.