Mechanism underlying the protective effect of tempol and Nω-nitro-L-arginine methyl ester on acoustic injury: possible involvement of c-Jun N-terminal kinase pathway and connexin26 in the cochlear spiral ligament.
There is evidence that reactive oxygen species (ROS) are formed in the cochlea during acoustic injury. However, very little is known about the involvement of ROS signals in the spiral ligament (SL) during such injury. The purpose of this study was to determine the effect of the multifunctional antioxidant tempol and the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) on acoustic injury and the c-Jun N-terminal kinase (JNK) pathway in the SL. Exposure of adult mice to noise (8-kHz octave band, 110-dB SPL for 1 h) produced permanent hearing loss. Noise exposure increased not only the formation of a protein modified by 4-hydroxynonenal and formation of nitrotyrosine, but also the level of phospho-JNK in the SL. Pretreatment with tempol or L-NAME was effective in protecting the noise-exposed animals from hearing loss, as well as in abolishing the noise-induced activation of the JNK signaling pathway. Interestingly, noise exposure caused a dramatic decrease in connexin26 level in the SL. This decrease was prevented by tempol or L-NAME. Taken together, our data suggest that noise-induced hearing loss is due at least in part to ROS / nitric oxide-mediated activation of the JNK pathway and down-regulation of connexin26 in the SL of mice.
Nagashima
Reiko
R
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka, Japan.
Yamaguchi
Taro
T
Tanaka
Hajime
H
Ogita
Kiyokazu
K
D000161:Acoustic Stimulation / Q000009:adverse effects; D000818:Animals; D000072259:Connexin 26; D017630:Connexins / Q000037:antagonists & inhibitors / Q000502:physiology*; D003497:Cyclic N-Oxides / Q000008:administration & dosage* / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006317:Hearing Loss, Noise-Induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000008:administration & dosage; D013113:Spin Labels; D055493:Spiral Ligament of Cochlea / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*
D017630:Connexins; D003497:Cyclic N-Oxides; D018696:Neuroprotective Agents; D013113:Spin Labels; D000072259:Connexin 26; D048031:JNK Mitogen-Activated Protein Kinases; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester