title: Calpain inhibitor alleviates permanent hearing loss induced by intense noise by preventing disruption of gap junction-mediated intercellular communication in the cochlear spiral ligament.
abstract: Our previous studies demonstrated that intense noise-induced hearing loss might be at least in part due to an oxidative stress-induced decrease in the level of gap junction-composing protein connexins in the spiral ligament (SL) of the cochlear lateral wall structures in mice. Further, an in vivo exposure of mice to intense noise activates calpain in the cochlear SL. Based on these studies, we sought to determine whether a calpain inhibitor would prevent an intense noise exposure from causing hearing loss, disruption of gap junction-mediated intercellular communication (GJIC) in the SL. An exposure of mice to intense noise (8-Hz octave band noise, 110-dB sound pressure level, 1h) produced permanent hearing loss and cochlear hair cell death. The results of an ex vivo assay using gap-fluorescence recovery after photobleaching of dissected lateral wall structures revealed that the intense noise disrupted GJIC in the cochlear SL at day-7 post exposure. A prior intracochlear injection of the calpain inhibitor PD150606 significantly abolished this noise-induced hearing loss on days 5 and 7 post exposure. Similarly, PD150606 prevented noise-induced hair cell death and the GJIC disruption on day-7 post exposure. The intense noise temporarily enhanced the gene expression of calpain subtypes Capn1 and Capn2 immediately after exposure. Taken together, our data suggest that calpain inhibitor alleviated the noise-induced hearing loss, at least in part, by preventing disruption of GJIC in the cochlear SL. It possible that calpain inhibitors would be useful as a candidate of therapeutic drugs for sudden sensorineural hearing loss.
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka 573-0101, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka 573-0101, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoneyama
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka 573-0101, Japan. Electronic address: ogita@pharm.setsunan.ac.jp.
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Ogita
mesh_terms: D000179:Acrylates / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors*; D002450:Cell Communication / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D017629:Gap Junctions / Q000187:drug effects* / Q000473:pathology; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000473:pathology; D006317:Hearing Loss, Noise-Induced / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D051379:Mice; D010539:Permeability; D011480:Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D055493:Spiral Ligament of Cochlea / Q000187:drug effects* / Q000473:pathology
chemical_list: D000179:Acrylates; C100442:PD 150606; D011480:Protease Inhibitors; D002154:Calpain
keywords: Calpain; Calpain inhibitor; Cochlear spiral ligament; Gap junction-mediated intercellular communication; Hair cell death; Noise-induced hearing loss