Activated protein C rescues the cochlea from noise-induced hearing loss

Abstract

Activated protein C (APC) is a serine/threonine protease and a physiological anticoagulant that exerts anti-inflammatory and anti-apoptotic effects. Although recent studies have revealed that APC has the potential to protect endothelial cells from apoptosis, the mechanisms of its cytoprotective effect are not fully understood. We examined the potential of APC to protect against noise-induced hearing loss (NIHL) and investigated phosphorylation of serine-threonine kinase (Akt) and inhibition of apoptosis as possible cytoprotective mechanisms. We administered intraperitoneal injections of APC (150, 300U/kg) or normal saline to rats 30min before exposure to a sound pressure level (SPL) of 126dB and 4-kHz octave band noise for 5h. The auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) were measured before and after exposure. ABR and DPOAE measurements revealed greater improvement in the APC group than in the control group 28 days after exposure. Our examination of outer hair cells (OHCs) at 28 days after noise exposure revealed a significantly higher OHC survival rate in the APC group than in the control group. Immunohistochemical analyses for cleaved-caspase 3, phospho-p38 (p-p38), TUNEL, and phospho-Akt (p-Akt) revealed strong immunoreactivities against cleaved-caspase 3, p-p38, and TUNEL in the inner ear tissues of the control group; however, these signals were decreased in the APC group. Moreover, APC significantly induced activation of p-Akt in the cochlea. These findings suggest that APC has a novel protective effect on the cochlea against NIHL that is mediated by p-Akt and the anti-apoptotic signaling pathway.