TY - JOUR
T1 - NRF2 is a key target for prevention of noise-induced hearing loss by reducing oxidative damage of cochlea
AU - Honkura, Yohei
AU - Matsuo, Hirotaka
AU - Murakami, Shohei
AU - Sakiyama, Masayuki
AU - Mizutari, Kunio
AU - Shiotani, Akihiro
AU - Yamamoto, Masayuki
AU - Morita, Ichiro
AU - Shinomiya, Nariyoshi
AU - Kawase, Tetsuaki
AU - Katori, Yukio
AU - Motohashi, Hozumi
N1 - Funding Information:
We thank Dr. Jun Yasuda for providing important advice and instruction regarding the whole study; Drs. Kazuhiro Nomura, Ryoukichi Ikeda and Jun Suzuki for support regarding the mouse experiments; Drs. Tomoyoshi Soga and Masahiro Sugimoto for providing their special skills for metabolite analysis; and Ms. Nao Ota and Yuka Matsuyama for their technical support regarding the metabolite analysis. We thank the Biomedical Research Core of the Tohoku University Graduate School of Medicine for their technical support. We also thank Drs. Takashi Hinata, Takashi Suzuki, Toshimitsu Ito, Takeshi Matsunobu, Takaomi Kurioka, Katsuki Niwa, Akiyoshi Nakayama and Toshihide Higashino for their contributions to human sample collection and genetic analysis. This work was supported by JSPS KAKENHI grant numbers 24390075 (H. Motohashi) and 15K18999 (S.M.), MEXT KAKENHI grant numbers 23116002 (H. Motohashi) and 25293145 (H. Matsuo), the Ministry of Defense of Japan (H. Matsuo, K.M., A.S., I.M.), the Takeda Scientific Foundation (H. Motohashi), the Core Research for Evolutional Science and Technology from the JST (H. Motohashi and M.Y.) and the GSK Japan Research Grant (S.M.).
PY - 2016/1/18
Y1 - 2016/1/18
N2 - Noise-induced hearing loss (NIHL) is one of the most common sensorineural hearing deficits. Recent studies have demonstrated that the pathogenesis of NIHL is closely related to ischemia-reperfusion injury of cochlea, which is caused by blood flow decrease and free radical production due to excessive noise. This suggests that protecting the cochlea from oxidative stress is an effective therapeutic approach for NIHL. NRF2 is a transcriptional activator playing an essential role in the defense mechanism against oxidative stress. To clarify the contribution of NRF2 to cochlear protection, we examined Nrf2 -/- mice for susceptibility to NIHL. Threshold shifts of the auditory brainstem response at 7 days post-exposure were significantly larger in Nrf2 -/- mice than wild-type mice. Treatment with CDDO-Im, a potent NRF2-activating drug, before but not after the noise exposure preserved the integrity of hair cells and improved post-exposure hearing levels in wild-type mice, but not in Nrf2 -/- mice. Therefore, NRF2 activation is effective for NIHL prevention. Consistently, a human NRF2 SNP was significantly associated with impaired sensorineural hearing levels in a cohort subjected to occupational noise exposure. Thus, high NRF2 activity is advantageous for cochlear protection from noise-induced injury, and NRF2 is a promising target for NIHL prevention.
AB - Noise-induced hearing loss (NIHL) is one of the most common sensorineural hearing deficits. Recent studies have demonstrated that the pathogenesis of NIHL is closely related to ischemia-reperfusion injury of cochlea, which is caused by blood flow decrease and free radical production due to excessive noise. This suggests that protecting the cochlea from oxidative stress is an effective therapeutic approach for NIHL. NRF2 is a transcriptional activator playing an essential role in the defense mechanism against oxidative stress. To clarify the contribution of NRF2 to cochlear protection, we examined Nrf2 -/- mice for susceptibility to NIHL. Threshold shifts of the auditory brainstem response at 7 days post-exposure were significantly larger in Nrf2 -/- mice than wild-type mice. Treatment with CDDO-Im, a potent NRF2-activating drug, before but not after the noise exposure preserved the integrity of hair cells and improved post-exposure hearing levels in wild-type mice, but not in Nrf2 -/- mice. Therefore, NRF2 activation is effective for NIHL prevention. Consistently, a human NRF2 SNP was significantly associated with impaired sensorineural hearing levels in a cohort subjected to occupational noise exposure. Thus, high NRF2 activity is advantageous for cochlear protection from noise-induced injury, and NRF2 is a promising target for NIHL prevention.
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U2 - 10.1038/srep19329
DO - 10.1038/srep19329
M3 - Article
C2 - 26776972
AN - SCOPUS:84955077948
SN - 2045-2322
VL - 6
JO - Scientific Reports
JF - Scientific Reports
M1 - 19329
ER -