title: NRF2 Is a Key Target for Prevention of Noise-Induced Hearing Loss by Reducing Oxidative Damage of Cochlea.
abstract: 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.
authors.affiliation: Department of Otolaryngology-Head &Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.|Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Honkura
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsuo
authors.affiliation: Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Murakami
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sakiyama
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Mizutari
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Shiotani
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Self-Defense Forces Central Hospital, 1-2-24, Ikejiri, Setagaya, Tokyo 154-8532, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Morita
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Nariyoshi
authors.initials: N
authors.lastname: Shinomiya
authors.affiliation: Department of Otolaryngology-Head &Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.
authors.forename: Tetsuaki
authors.initials: T
authors.lastname: Kawase
authors.affiliation: Department of Otolaryngology-Head &Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Katori
authors.affiliation: Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
authors.forename: Hozumi
authors.initials: H
authors.lastname: Motohashi
mesh_terms: D000818:Animals; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D005978:Glutathione / Q000378:metabolism; D006317:Hearing Loss, Noise-Induced / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D015227:Lipid Peroxidation; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D020011:Protective Agents / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D007093:Imidazoles; D051267:NF-E2-Related Factor 2; D020011:Protective Agents; D017382:Reactive Oxygen Species; D009828:Oleanolic Acid; D005978:Glutathione