Rosmarinic acid up-regulates the noise-activated Nrf2/HO-1 pathway and protects against noise-induced injury in rat cochlea |
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| Affiliation: | 1. Department of Head and Neck Surgery, Medical School, Università Cattolica, Largo F. Vito 1, 00168 Rome, Italy;2. Institute of Human Physiology, Medical School, Università Cattolica, Largo F. Vito 1, 00168, Rome, Italy;3. Institute of Pharmacology, Medical School, Università Cattolica, Largo F. Vito 1, 00168, Rome, Italy;1. Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea;2. School of Life Sciences, KNU Creative BioResearch Group (BK21 plus project), Kyungpook National University, Daegu, Republic of Korea;3. Division of Life Sciences, Korea Polar Research Institute (KOPRI), Incheon, Republic of Korea;4. Department of Internal Medicine, Research Institute of Aging and Metabolism, School of Medicine, Kyungpook National University, Daegu, Republic of Korea;5. Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, Kyungpook National University, Daegu, Republic of Korea;1. Department of Otolaryngology-Head and Neck Surgery, Qianfo Shan Hospital Affiliated to Shandong University, Jinan 250014, Shandong, China;2. Department of Otolaryngology-Head and Neck Surgery, Qilu Hospital of Shandong University/Key Laboratory of Otolaryngology, Chinese Ministry of Health, 107 west Wenhua Road, Jinan 250012, Shandong, China;3. Department of Ophthalmology, Jinan Sixth People''s Hospital, Jinan 250200, China;4. Department of Otolaryngology-Head and Neck Surgery, Jinan Sixth People''s Hospital, Jinan 250200, China;1. Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland, New Zealand;2. Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, 92019, Auckland, New Zealand;3. RS Dow Neurobiology Laboratories, Legacy Research, Portland, OR, 97232, USA;4. Department of Physiology and Translational Neuroscience Facility, School of Medical Sciences, UNSW Australia, Sydney, NSW, 2052, Australia;1. Ahi Evran University, Training and Research Hospital Department of Otorhinolaryngology, Kırşehir, Turkey;2. Gaziosmanpaşa University, Department of Histology and Embryology, Tokat, Turkey;3. Gaziosmanpaşa University, Department of Emergency Medicine, Tokat, Turkey;1. Hough Ear Institute, University of Oklahoma, USA;2. Yale University School of Medicine, New Haven, CT, USA;3. Spatial Orientation Center, Department of Otolaryngology, Naval Medical Center, San Diego, CA, USA;4. VA Medical Center, R & D-NCRAR, Portland, OR, USA;5. Department of Otolaryngology, University of Colorado Health Sciences Center, Denver, CO, USA;6. Auditory Physiology and Psychoacoustics Laboratory, San Diego State University, San Diego, CA, USA;7. TLC Research Solutions, LLC, New Braunfels, TX, USA |
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| Abstract: | Noise-induced hearing loss depends on progressive increase of reactive oxygen species and lipoperoxidative damage in conjunction with the imbalance of antioxidant defenses. The redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in the regulation of cellular defenses against oxidative stress, including heme oxygenase-1 (HO-1) activation. In this work we describe a link between cochlear oxidative stress damage, induced by noise exposure, and the activation of the Nrf2/HO-1 pathway. In our model, noise induces superoxide production and overexpression of the lipid peroxidation marker 4-hydroxy-nonenals (4-HNE). To face the oxidative stress, the endogenous defense system is activated as well, as shown by the slight activation of superoxide dismutases (SODs). In addition, we observed the activation of the Nrf2/HO-1 pathway after noise exposure. Nrf2 appears to promote the maintenance of cellular homeostasis under stress conditions. However, in this model the endogenous antioxidant system fails to counteract noise-induced cell damage and its activation is not effective enough in preventing cochlear damage. The herb-derived phenol rosmarinic acid (RA) attenuates noise-induced hearing loss, reducing threshold shift, and promotes hair cell survival. In fact, RA enhances the endogenous antioxidant defenses, as shown by decreased superoxide production, reduced expression of 4-HNE, and up-regulation of SODs. Interestingly, RA potentiates the Nrf2/HO-1 signaling pathway, as shown by immunohistochemical and Western blot analyses. Thus, protective effects of RA are associated with the induction/activation of the Nrf2-ARE signaling pathway in addition to RA direct scavenging capability. |
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| Keywords: | Inner ear Acoustic trauma Oxidative stress Antioxidants |
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