The role of glucocorticoid receptors and mitogen-regulated protein kinases in the cochlea

Abstract

Hearing loss induced by acoustic trauma is a common handicap for the human population. Acoustic trauma triggers a cascade of changes in the cochlea such as a direct mechanical damage of sensory hair cells, biochemical disturbances including reactive oxygen and nitrogen species generation, release of pro-inflammatory cytokines and exitotoxicity. Acoustic trauma can result in transient or permanent hearing loss depending on the physical and temporal characteristics of the acoustic stimulation as well as individual susceptibility. Interestingly, acoustic trauma triggers not only damaging, but also protective mechanisms in the cochlea such as the up-regulation of antioxidants, glucocorticoids and neurotrophins.

The overall goal of the present study was to characterize the molecular mechanisms underlying the protective effects of glucocorticoid receptors (GR) and their interactions with the family of mitogen-activated protein kinases (MAPKs).

The results demonstrate that GR plays an unequivocal role in modulating auditory sensitivity. In a GR-dependent manner, the p38 pathway is activated after restraint stress, and ERKs are down-regulated after restraint stress followed by acoustic trauma. ERKs and p38, as well as c-jun-N-terminal kinases (JNKs) regulate cell recovery and cell death. Cell recovery after acoustic trauma correlates with a down-regulation of p38 and an up-regulation of ERKs and JNKs 24 h post trauma. In contrast, hair cell loss is accompanied by immediate post-traumatic up-regulation of all three MAPKs.

A critical factor for protecting against cochlear trauma includes GR and ERK interactions and the down-stream activation of the otoprotective neurotrophin, brain-derived neurotrophic factor (BDNF). BDNF is up-regulated in the cochlea after acoustic trauma, and the duration of its elevation correlate with the pattern of ERKs activation and the severity of cochlea damage. BDNF acts through receptor tyrosine kinase TrkB followed by the downstream activation of ERKs and p38 cascades. Severe acoustic trauma leads to a down-regulation of the truncated form of TrkB thus probably providing a more robust activation of the full-length TrkB, the main mediator of BDNF-induced protective effects.

The knowledge of the glucocorticoids and MAPKs cellular mechanisms are of a great importance for clinical audiology since it opens new avenues for the prevention and treatment of hearing loss. These data will help to understand the nature of individual sensitivity to acoustic trauma since hypothalamic-pituitary adrenal (HPA) axis status is now demonstrated to be a critical factor for determining the overall sensitivity to acoustic trauma.