A Novel Animal Model of Hearing Loss Caused by Acute Endoplasmic Reticulum Stress in the Cochlea

• Published in: Journal of Pharmacological Sciences Vol. 118; no. 3; pp. 363 - 372
• Main Authors: Fujinami, Yoshiaki, Mutai, Hideki, Mizutari, Kunio, Nakagawa, Susumu, Matsunaga, Tatsuo
• Format: Journal Article
• Language: English
• Published: Japan Elsevier B.V 2012; The Japanese Pharmacological Society; Elsevier
• Subjects: Activating Transcription Factor 4 - genetics; animal model; Animals; Cochlea - pathology; Cochlea - physiopathology; Disease Models, Animal; endoplasmic reticulum stress; Endoplasmic Reticulum Stress - physiology; Gene Expression Regulation; hearing loss; Hearing Loss - genetics; Hearing Loss - pathology; Hearing Loss - physiopathology; Male; Membrane Glycoproteins - genetics; Rats; Rats, Sprague-Dawley; Transcription Factor CHOP - genetics; tunicamycin; Tunicamycin - administration & dosage; hearing loss; animal model; endoplasmic reticulum stress; tunicamycin
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.11227FP

Many stimuli such as ischemia, hypoxia, heat shock, amino acid starvation, and gene mutation, exhibit a cellular response called endoplasmic reticulum (ER) stress. ER stress induces expression of a series of genes, leading to cell survival or apoptosis. Previously, we found that in an animal model of hearing loss caused by acute mitochondrial dysfunction, several ER stress markers including C/EBP homologous protein were induced in the cochlear lateral wall. To elucidate the mechanism of hearing loss caused by ER stress, we established a novel animal model of hearing loss by perilymphatic perfusion of tunicamycin, an ER stress activator that inhibits N-acetylglucosamine transferases. Subacute and progressive hearing loss was observed at all sound frequencies studied, and stimulation of ER stress marker genes was noted in the cochlea. The outer hair cells were the most sensitive to ER stress in the cochlea. Electron microscopic analysis demonstrated degeneration of the subcellular organelles of the inner hair cells and nerve endings of the spiral ganglion cells. This newly established animal model of hearing loss from ER stress will provide additional insight into the mechanism of sensorineural hearing loss.