title: 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, 300 U/kg) or normal saline to rats 30 min before exposure to a sound pressure level (SPL) of 126 dB 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.
authors.affiliation: Department of Otolaryngology, National Defense Medical College, Saitama 359-8513, Japan.
authors.forename: Takaomi
authors.initials: T
authors.lastname: Kurioka
authors.affiliation: Department of Otolaryngology, National Defense Medical College, Saitama 359-8513, Japan. Electronic address: takeshim@ndmc.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsunobu
authors.affiliation: Department of Otolaryngology, National Defense Medical College, Saitama 359-8513, Japan.
authors.forename: Katsuki
authors.initials: K
authors.lastname: Niwa
authors.affiliation: Department of Otolaryngology, National Defense Medical College, Saitama 359-8513, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tamura
authors.affiliation: Department of Anesthesiology, National Defense Medical College, Saitama 359-8513, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Satoh
authors.affiliation: Department of Otolaryngology, National Defense Medical College, Saitama 359-8513, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Shiotani
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003051:Cochlea / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D053938:DNA Fragmentation / Q000187:drug effects; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D006317:Hearing Loss, Noise-Induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017084:Otoacoustic Emissions, Spontaneous / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011486:Protein C / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013136:Spiral Ganglion / Q000187:drug effects / Q000503:physiopathology; D016896:Treatment Outcome; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D011486:Protein C; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: Activated protein C; Anti-apoptosis; Noise-induced hearing loss; Phospho-Akt