{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T01:19:43Z","timestamp":1780449583446,"version":"3.54.1"},"reference-count":39,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T00:00:00Z","timestamp":1668556800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea (NRF)","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Korea government (MSIT)","award":["2021RIF1A1060212"],"award-info":[{"award-number":["2021RIF1A1060212"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>To date, the effect of resveratrol on tinnitus has not been reported. The attenuative effects of resveratrol (RSV) on a salicylate-induced tinnitus model were evaluated by in vitro and in vivo experiments. The gene expression of the activity-regulated cytoskeleton-associated protein (ARC), tumor necrosis factor-alpha (TNF\u03b1), and NMDA receptor subunit 2B (NR2B) in SH-SY5Y cells was examined using qPCR. Phosphorylated cAMP response element-binding protein (p-CREB), apoptosis markers, and reactive oxygen species (ROS) were evaluated by in vitro experiments. The in vivo experiment evaluated the gap-prepulse inhibition of the acoustic startle reflex (GPIAS) and auditory brainstem response (ABR) level. The NR2B expression in the auditory cortex (AC) was determined by immunohistochemistry. RSV significantly reduced the salicylate-induced expression of NR2B, ARC, and TNF\u03b1 in neuronal cells; the GPIAS and ABR thresholds altered by salicylate in rats were recovered close to their normal range. RSV also reduced the salicylate-induced NR2B overexpression of the AC. These results confirmed that resveratrol exerted an attenuative effect on salicylate-induced tinnitus and may have a therapeutic potential.<\/jats:p>","DOI":"10.3390\/ijms232214183","type":"journal-article","created":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T03:05:21Z","timestamp":1668654321000},"page":"14183","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Protective Effect of Resveratrol in an Experimental Model of Salicylate-Induced Tinnitus"],"prefix":"10.3390","volume":"23","author":[{"given":"Anji","family":"Song","sequence":"first","affiliation":[{"name":"Department of Biology, College of Natural Science, Chosun University, Gwangju 61452, Republic of Korea"},{"name":"BK21 FOUR Education Research Group for Age-Associated Disorder Control Technology, Department of Integrative Biological Science, Chosun University, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2149-5095","authenticated-orcid":false,"given":"Gwang-Won","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Natural Science, Chosun University, Gwangju 61452, Republic of Korea"},{"name":"BK21 FOUR Education Research Group for Age-Associated Disorder Control Technology, Department of Integrative Biological Science, Chosun University, Gwangju 61452, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2451-0374","authenticated-orcid":false,"given":"Changjong","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Veterinary Anatomy, College of Veterinary Medicine and BK21 FOUR Program, Chonnam Natioanal University, Gwanjgu 61186, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1613-4209","authenticated-orcid":false,"given":"Ilyong","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, College of Medicine, Dankook University, Cheonan 31116, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4084-2301","authenticated-orcid":false,"given":"Chul Ho","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/978-981-13-6123-4_7","article-title":"Advances in Understanding, Diagnosis, and Treatment of Tinnitus","volume":"1130","author":"Tang","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"24428","DOI":"10.1038\/srep24428","article-title":"Effects of long-term salicylate administration on synaptic ultrastructure and metabolic activity in the rat CNS","volume":"6","author":"Yi","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/j.cell.2016.10.021","article-title":"Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior","volume":"167","author":"Schafer","year":"2016","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/bcpt.12640","article-title":"Concentration-Response Relationship of Hearing Impairment Caused by Quinine and Salicylate: Pharmacological Similarities but Different Molecular Mechanisms","volume":"120","author":"Alvan","year":"2017","journal-title":"Basic. Clin. Pharmacol. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2544","DOI":"10.1056\/NEJMra2010852","article-title":"Salicylate Toxicity","volume":"382","author":"Palmer","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_6","first-page":"3941","article-title":"Changes in GABA and glutamate receptors on auditory cortical excitatory neurons in a rat model of salicylate-induced tinnitus","volume":"10","author":"Wu","year":"2018","journal-title":"Am. J. Transl. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1159\/000374000","article-title":"Cochlear NMDA receptors as a therapeutic target of noise-induced tinnitus","volume":"35","author":"Bing","year":"2015","journal-title":"Cell Physiol. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.heares.2012.09.010","article-title":"Tinnitus-related neural activity: Theories of generation, propagation, and centralization","volume":"295","author":"Farley","year":"2013","journal-title":"Hear. Res."},{"key":"ref_9","first-page":"51","article-title":"Long-term treatment with salicylate enables NMDA receptors and impairs AMPA receptors in C57BL\/6J mice inner hair cell ribbon synapse","volume":"19","author":"Cui","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3989201","DOI":"10.1155\/2018\/3989201","article-title":"N-Methyl-D-Aspartate Receptors Involvement in the Gentamicin-Induced Hearing Loss and Pathological Changes of Ribbon Synapse in the Mouse Cochlear Inner Hair Cells","volume":"2018","author":"Hong","year":"2018","journal-title":"Neural. Plast."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/S0006-8993(98)01123-8","article-title":"Aminoglycoside neurotoxicity involves NMDA receptor activation","volume":"815","author":"Segal","year":"1999","journal-title":"Brain Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1111\/bph.13492","article-title":"Antioxidant effects of resveratrol in the cardiovascular system","volume":"174","author":"Xia","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"28","DOI":"10.3389\/fnmol.2016.00028","article-title":"Intrahippocampal Administration of Ibotenic Acid Induced Cholinergic Dysfunction via NR2A\/NR2B Expression: Implications of Resveratrol against Alzheimer Disease Pathophysiology","volume":"9","author":"Karthick","year":"2016","journal-title":"Front. Mol. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"108249","DOI":"10.1016\/j.exer.2020.108249","article-title":"Resveratrol protects retinal ganglion cell axons through regulation of the SIRT1-JNK pathway","volume":"200","author":"Wu","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.ijporl.2014.11.008","article-title":"Protective effect of resveratrol against cisplatin-induced ototoxicity in HEI-OC1 auditory cells","volume":"79","author":"Lee","year":"2015","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1037\/0735-7044.102.6.811","article-title":"Phantom auditory sensation in rats: An animal model for tinnitus","volume":"102","author":"Jastreboff","year":"1988","journal-title":"Behav. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1007\/s12640-019-0006-8","article-title":"Salicylate-Induced Ototoxicity of Spiral Ganglion Neurons: Ca2+\/CaMKII-Mediated Interaction Between NMDA Receptor and GABA(A) Receptor","volume":"35","author":"Qin","year":"2019","journal-title":"Neurotox. Res."},{"key":"ref_18","first-page":"79","article-title":"Review of salicylate-induced hearing loss, neurotoxicity, tinnitus and neuropathophysiology","volume":"34","author":"Sheppard","year":"2014","journal-title":"Acta Otorhinolaryngol. Ital."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.neulet.2013.03.010","article-title":"NMDA receptor-dependent glutamate excitotoxicity in human embryonic stem cell-derived neurons","volume":"543","author":"Gupta","year":"2013","journal-title":"Neurosci. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1017\/S095442241700021X","article-title":"Resveratrol and inflammatory bowel disease: The evidence so far","volume":"31","author":"Nunes","year":"2018","journal-title":"Nutr. Res. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Shaito, A., Posadino, A.M., Younes, N., Hasan, H., Halabi, S., Alhababi, D., Al-Mohannadi, A., Abdel-Rahman, W.M., Eid, A.H., and Nasrallah, G.K. (2020). Potential Adverse Effects of Resveratrol: A Literature Review. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21062084"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e12515","DOI":"10.1111\/jpi.12515","article-title":"Melatonin induces mechanisms of brain resilience against neurodegeneration","volume":"65","author":"Corpas","year":"2018","journal-title":"J. Pineal. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.neuint.2008.11.001","article-title":"Inhibitory effect of glutamate release from rat cerebrocortical nerve terminals by resveratrol","volume":"54","author":"Chang","year":"2009","journal-title":"Neurochem. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e00251","DOI":"10.1016\/j.heliyon.2017.e00251","article-title":"Dietary supplementation of coenzyme Q10 plus multivitamins to hamper the ROS mediated cisplatin ototoxicity in humans: A pilot study","volume":"3","author":"Scasso","year":"2017","journal-title":"Heliyon"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4866","DOI":"10.2174\/092986711797535254","article-title":"Ototoxicity: Mechanisms of cochlear impairment and its prevention","volume":"18","author":"Tabuchi","year":"2011","journal-title":"Curr. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s12640-013-9384-5","article-title":"Salicylate selectively kills cochlear spiral ganglion neurons by paradoxically up-regulating superoxide","volume":"24","author":"Deng","year":"2013","journal-title":"Neurotox. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6390","DOI":"10.1038\/s41598-017-06231-x","article-title":"CREB Regulates Distinct Adaptive Transcriptional Programs in Astrocytes and Neurons","volume":"7","author":"Pardo","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s11010-018-3314-z","article-title":"Up-regulation of Ca(2+)\/CaMKII\/CREB signaling in salicylate-induced tinnitus in rats","volume":"448","author":"Zhao","year":"2018","journal-title":"Mol. Cell Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e173","DOI":"10.1097\/MAO.0000000000001717","article-title":"Long-term Administration of Salicylate-induced Changes in BDNF Expression and CREB Phosphorylation in the Auditory Cortex of Rats","volume":"39","author":"Yi","year":"2018","journal-title":"Otol. Neurotol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s00726-013-1518-9","article-title":"Involvement of heme oxygenase-1 expression in neuroprotection by piceatannol, a natural analog and a metabolite of resveratrol, against glutamate-mediated oxidative injury in HT22 neuronal cells","volume":"45","author":"Son","year":"2013","journal-title":"Amino Acids"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1124\/jpet.120.000096","article-title":"Different Antioxidative and Antiapoptotic Effects of Piceatannol and Resveratrol","volume":"376","author":"Hosoda","year":"2021","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"495","DOI":"10.5607\/en.2019.28.4.495","article-title":"Memantine Attenuates Salicylate-induced Tinnitus Possibly by Reducing NR2B Expression in Auditory Cortex of Rat","volume":"28","author":"Jang","year":"2019","journal-title":"Exp. Neurobiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"88","DOI":"10.3389\/fneur.2015.00088","article-title":"Gap-Prepulse Inhibition of the Acoustic Startle Reflex (GPIAS) for Tinnitus Assessment: Current Status and Future Directions","volume":"6","author":"Galazyuk","year":"2015","journal-title":"Front. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.heares.2012.11.016","article-title":"Salicylate-induced cochlear impairments, cortical hyperactivity and re-tuning, and tinnitus","volume":"295","author":"Chen","year":"2013","journal-title":"Hear. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.neuropharm.2007.10.017","article-title":"The aspirin metabolite salicylate enhances neuronal excitation in rat hippocampal CA1 area through reducing GABAergic inhibition","volume":"54","author":"Gong","year":"2008","journal-title":"Neuropharmacology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S0378-5955(02)00708-6","article-title":"Effects of salicylate on serotoninergic activities in rat inferior colliculus and auditory cortex","volume":"175","author":"Liu","year":"2003","journal-title":"Hear. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"51","DOI":"10.4196\/kjpp.2021.25.1.51","article-title":"Oxidative stress-induced aberrant G9a activation disturbs RE-1-containing neuron-specific genes expression, leading to degeneration in human SH-SY5Y neuroblastoma cells","volume":"25","author":"Kim","year":"2021","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_38","first-page":"198","article-title":"The effect of the NMDA channel blocker memantine on salicylate-induced tinnitus in rats","volume":"34","author":"Ralli","year":"2014","journal-title":"Acta Otorhinolaryngol. Ital."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.heares.2012.06.001","article-title":"The gap-startle paradigm for tinnitus screening in animal models: Limitations and optimization","volume":"295","author":"Lobarinas","year":"2013","journal-title":"Hear. Res."}],"updated-by":[{"DOI":"10.3390\/ijms24119460","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T00:00:00Z","timestamp":1668556800000}}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14183\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T22:11:30Z","timestamp":1754259090000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14183"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,16]]},"references-count":39,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232214183"],"URL":"https:\/\/doi.org\/10.3390\/ijms232214183","relation":{"correction":[{"id-type":"doi","id":"10.3390\/ijms24119460","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,16]]}}}