{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T08:13:18Z","timestamp":1785831198030,"version":"3.56.0"},"reference-count":92,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T00:00:00Z","timestamp":1717718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health NIDCD","award":["1R01DC018850"],"award-info":[{"award-number":["1R01DC018850"]}]},{"name":"American Hearing Research Foundation 2020","award":["1R01DC018850"],"award-info":[{"award-number":["1R01DC018850"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Noise-induced hearing loss (NIHL) is a major cause of hearing impairment and is linked to dementia and mental health conditions, yet no FDA-approved drugs exist to prevent it. Downregulating the mitogen-activated protein kinase (MAPK) cellular pathway has emerged as a promising approach to attenuate NIHL, but the molecular targets and the mechanism of protection are not fully understood. Here, we tested specifically the role of the kinases ERK1\/2 in noise otoprotection using a newly developed, highly specific ERK1\/2 inhibitor, tizaterkib, in preclinical animal models. Tizaterkib is currently being tested in phase 1 clinical trials for cancer treatment and has high oral bioavailability and low predicted systemic toxicity in mice and humans. In this study, we performed dose\u2013response measurements of tizaterkib\u2019s efficacy against permanent NIHL in adult FVB\/NJ mice, and its minimum effective dose (0.5 mg\/kg\/bw), therapeutic index (&gt;50), and window of opportunity (&lt;48 h) were determined. The drug, administered orally twice daily for 3 days, 24 h after 2 h of 100 dB or 106 dB SPL noise exposure, at a dose equivalent to what is prescribed currently for humans in clinical trials, conferred an average protection of 20\u201325 dB SPL in both female and male mice. The drug shielded mice from the noise-induced synaptic damage which occurs following loud noise exposure. Equally interesting, tizaterkib was shown to decrease the number of CD45- and CD68-positive immune cells in the mouse cochlea following noise exposure. This study suggests that repurposing tizaterkib and the ERK1\/2 kinases\u2019 inhibition could be a promising strategy for the treatment of NIHL.<\/jats:p>","DOI":"10.3390\/ijms25126305","type":"journal-article","created":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T08:05:17Z","timestamp":1717747517000},"page":"6305","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["ERK1\/2 Inhibition via the Oral Administration of Tizaterkib Alleviates Noise-Induced Hearing Loss While Tempering down the Immune Response"],"prefix":"10.3390","volume":"25","author":[{"given":"Richard D.","family":"Lutze","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE 68178, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Ingersoll","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE 68178, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alena","family":"Thotam","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE 68178, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjali","family":"Joseph","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE 68178, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE 68178, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7897-1630","authenticated-orcid":false,"given":"Tal","family":"Teitz","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE 68178, USA"},{"name":"The Scintillon Research Institute, San Diego, CA 92121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/ng.3217","article-title":"Common variants in ACYP2 influence susceptibility to cisplatin-induced hearing loss","volume":"47","author":"Xu","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1080\/14992027.2017.1291264","article-title":"Promoting global action on hearing loss: World hearing day","volume":"56","author":"Chadha","year":"2017","journal-title":"Int. J. Audiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"525","DOI":"10.12968\/hmed.2019.80.9.525","article-title":"What is noise-induced hearing loss?","volume":"80","author":"Ding","year":"2019","journal-title":"Br. J. Hosp. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"eabd0561","DOI":"10.1126\/sciadv.abd0561","article-title":"BRAF inhibition protects against hearing loss in mice","volume":"6","author":"Ingersoll","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"166","DOI":"10.4103\/ijcm.ijcm_1267_21","article-title":"Occupational Noise Induced Hearing Loss in India: A Systematic Review and Meta-Analysis","volume":"47","author":"Basu","year":"2022","journal-title":"Indian J. Community Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Yang, P., Xie, H., Li, Y., and Jin, K. (2023). The Effect of Noise Exposure on High-Frequency Hearing Loss among Chinese Workers: A Meta-Analysis. Healthcare, 11.","DOI":"10.3390\/healthcare11081079"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1080\/00016489.2022.2162959","article-title":"Hearing loss in school-aged children","volume":"143","author":"Torrente","year":"2023","journal-title":"Acta Oto-Laryngol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"108459","DOI":"10.1016\/j.heares.2022.108459","article-title":"Review of blast noise and the auditory system","volume":"425","author":"Paik","year":"2022","journal-title":"Hear. Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Moore, B.C.J. (2021). The Effect of Exposure to Noise during Military Service on the Subsequent Progression of Hearing Loss. Int. J. Environ. Res. Public Health, 18.","DOI":"10.3390\/ijerph18052436"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S0140-6736(20)30367-6","article-title":"Dementia prevention, intervention, and care: 2020 report of the Lancet Commission","volume":"396","author":"Livingston","year":"2020","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.puhe.2022.01.025","article-title":"Hearing loss, depression, and medical service utilization among older adults: Evidence from China","volume":"205","author":"Guan","year":"2022","journal-title":"Public Health"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e00970","DOI":"10.1002\/prp2.970","article-title":"Hearing loss: The final frontier of pharmacology","volume":"10","author":"Foster","year":"2022","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.heares.2016.11.013","article-title":"Cellular mechanisms of noise-induced hearing loss","volume":"349","author":"Kurabi","year":"2017","journal-title":"Hear. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1016\/S0140-6736(13)61613-X","article-title":"Auditory and non-auditory effects of noise on health","volume":"383","author":"Basner","year":"2014","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.freeradbiomed.2019.02.022","article-title":"Targeting dysregulation of redox homeostasis in noise-induced hearing loss: Oxidative stress and ROS signaling","volume":"135","author":"Fetoni","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1080\/17460441.2020.1806232","article-title":"Drug development for noise-induced hearing loss","volume":"15","author":"Calvino","year":"2020","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1084\/jem.20172246","article-title":"CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss","volume":"215","author":"Teitz","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1097\/MAO.0000000000004002","article-title":"Metformin Protects Against Noise-Induced Hearing Loss in Male Mice","volume":"44","author":"Kennedy","year":"2023","journal-title":"Otol. Neurotol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/s41580-020-0255-7","article-title":"ERK signalling: A master regulator of cell behaviour, life and fate","volume":"21","author":"Lavoie","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3279","DOI":"10.1038\/sj.onc.1210421","article-title":"MAP kinase signalling pathways in cancer","volume":"26","author":"Dhillon","year":"2007","journal-title":"Oncogene"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4918","DOI":"10.1523\/JNEUROSCI.4914-07.2008","article-title":"Damage-Induced Activation of ERK1\/2 in Cochlear Supporting Cells Is a Hair Cell Death-Promoting Signal That Depends on Extracellular ATP and Calcium","volume":"28","author":"Lahne","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Maeda, Y., Fukushima, K., Omichi, R., Kariya, S., and Nishizaki, K. (2013). Time Courses of Changes in Phospho- and Total- MAP Kinases in the Cochlea after Intense Noise Exposure. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058775"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"400","DOI":"10.4103\/1463-1741.144418","article-title":"Noise exposure immediately activates cochlear mitogen-activated protein kinase signaling","volume":"16","author":"Alagramam","year":"2014","journal-title":"Noise Health"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Braicu, C., Buse, M., Busuioc, C., Drula, R., Gulei, D., Raduly, L., Rusu, A., Irimie, A., Atanasov, A.G., and Slaby, O. (2019). A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer. Cancers, 11.","DOI":"10.3390\/cancers11101618"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1111\/j.1523-1755.2005.67102.x","article-title":"MEK inhibitor, U0126, attenuates cisplatin-induced renal injury by decreasing inflammation and apoptosis","volume":"67","author":"Jo","year":"2005","journal-title":"Kidney Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1007\/s10162-018-00691-2","article-title":"The Stress Response in the Non-sensory Cells of the Cochlea Under Pathological Conditions\u2014Possible Role in Mediating Noise Vulnerability","volume":"19","author":"Herranen","year":"2018","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Yue, J., and L\u00f3pez, J.M. (2020). Understanding MAPK Signaling Pathways in Apoptosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072346"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/j.1742-4658.2009.07366.x","article-title":"ERK and cell death: Mechanisms of ERK-induced cell death\u2014Apoptosis, autophagy and senescence","volume":"277","author":"Cagnol","year":"2010","journal-title":"FEBS J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1158\/1535-7163.MCT-20-0002","article-title":"AZD0364 Is a Potent and Selective ERK1\/2 Inhibitor That Enhances Antitumor Activity in KRAS-Mutant Tumor Models when Combined with the MEK Inhibitor, Selumetinib","volume":"20","author":"Flemington","year":"2021","journal-title":"Mol. Cancer Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11004","DOI":"10.1021\/acs.jmedchem.9b01295","article-title":"Discovery of a Potent and Selective Oral Inhibitor of ERK1\/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC)","volume":"62","author":"Ward","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.3892\/ijmm.2014.1967","article-title":"Prednisone inhibits the IL-1\u03b2-induced expression of COX-2 in HEI-OC1 murine auditory cells through the inhibition of ERK-1\/2, JNK-1 and AP-1 activity","volume":"34","author":"Hong","year":"2014","journal-title":"Int. J. Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3962","DOI":"10.1523\/JNEUROSCI.3111-15.2016","article-title":"Adenosine A1 Receptor Protects Against Cisplatin Ototoxicity by Suppressing the NOX3\/STAT1 Inflammatory Pathway in the Cochlea","volume":"36","author":"Kaur","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4020","DOI":"10.1121\/1.5132545","article-title":"Inflammation associated with noise-induced hearing loss","volume":"146","author":"Frye","year":"2019","journal-title":"J. Acoust. Soc. Am."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"191","DOI":"10.14336\/AD.2019.0723","article-title":"Macrophages in Noise-Exposed Cochlea: Changes, Regulation and the Potential Role","volume":"11","author":"He","year":"2020","journal-title":"Aging Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"109758","DOI":"10.1016\/j.celrep.2021.109758","article-title":"A cell-type-specific atlas of the inner ear transcriptional response to acoustic trauma","volume":"36","author":"Milon","year":"2021","journal-title":"Cell Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"844480","DOI":"10.3389\/fncel.2022.844480","article-title":"The Time Course of Monocytes Infiltration After Acoustic Overstimulation","volume":"16","author":"Shin","year":"2022","journal-title":"Front. Cell. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"106","DOI":"10.3389\/fncel.2017.00106","article-title":"The Contribution of Immune Infiltrates to Ototoxicity and Cochlear Hair Cell Loss","volume":"11","author":"Wood","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ramkumar, V., Mukherjea, D., Dhukhwa, A., and Rybak, L.P. (2021). Oxidative Stress and Inflammation Caused by Cisplatin Ototoxicity. Antioxidants, 10.","DOI":"10.3390\/antiox10121919"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"107576","DOI":"10.1016\/j.intimp.2021.107576","article-title":"Oridonin ameliorates noise-induced hearing loss by blocking NLRP3-NEK7 mediated inflammasome activation","volume":"95","author":"Li","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Chen, M.-B., Li, M.-H., Wu, L.-Y., Wang, R., Long, X., Zhang, L., Sun, W., Guo, W.-W., Pan, Y., and Zhang, Y.-S. (2023). Oridonin employs interleukin 1 receptor type 2 to treat noise-induced hearing loss by blocking inner ear inflammation. Biochem. Pharmacol., 210.","DOI":"10.1016\/j.bcp.2023.115457"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"444","DOI":"10.3389\/fncel.2019.00444","article-title":"Targeting Inflammatory Processes Mediated by TRPVI and TNF-\u03b1 for Treating Noise-Induced Hearing Loss","volume":"13","author":"Dhukhwa","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1125948","DOI":"10.3389\/fimmu.2023.1125948","article-title":"Targeting CXCL1 chemokine signaling for treating cisplatin ototoxicity","volume":"14","author":"Alanisi","year":"2023","journal-title":"Front. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1002\/lary.26394","article-title":"Intratympanic dexamethasone in sudden sensorineural hearing loss: A systematic review and meta-analysis","volume":"127","author":"Sewitch","year":"2017","journal-title":"Laryngoscope"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1016\/j.cub.2019.06.057","article-title":"Circadian regulation of cochlear sensitivity to noise by circulating glucocorticoids","volume":"29","author":"Cederroth","year":"2019","journal-title":"Curr. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1002\/cne.20619","article-title":"Mononuclear phagocytes migrate into the murine cochlea after acoustic trauma","volume":"489","author":"Hirose","year":"2005","journal-title":"J. Comp. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"108378","DOI":"10.1016\/j.heares.2021.108378","article-title":"LCCL peptide cleavage after noise exposure exacerbates hearing loss and is associated with the monocyte infiltration in the cochlea","volume":"412","author":"Bae","year":"2021","journal-title":"Hear. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s12974-022-02414-0","article-title":"Sox2 overexpression alleviates noise-induced hearing loss by inhibiting inflammation-related hair cell apoptosis","volume":"19","author":"Chen","year":"2022","journal-title":"J. Neuroinflamm."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1042\/BST20220271","article-title":"ERK1\/2 in immune signalling","volume":"50","author":"Lucas","year":"2022","journal-title":"Biochem. Soc. Trans."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/nri3495","article-title":"Mitogen-activated protein kinases in innate immunity","volume":"13","author":"Arthur","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.bbrc.2014.04.118","article-title":"Alpha-lipoic acid protects against cisplatin-induced ototoxicity via the regulation of MAPKs and proinflammatory cytokines","volume":"449","author":"Kim","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1002\/hed.20892","article-title":"Role of proinflammatory cytokines in cisplatin-induced vestibular hair cell damage","volume":"30","author":"Kim","year":"2008","journal-title":"Head Neck"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.smim.2014.02.009","article-title":"TNF and MAP kinase signaling pathways","volume":"26","author":"Sabio","year":"2014","journal-title":"Semin. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3035","DOI":"10.1128\/MCB.22.9.3035-3045.2002","article-title":"Kinase Suppressor of Ras (KSR) Is a Scaffold Which Facilitates Mitogen-Activated Protein Kinase Activation In Vivo","volume":"22","author":"Nguyen","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"7592","DOI":"10.1128\/MCB.25.17.7592-7604.2005","article-title":"The Molecular Scaffold Kinase Suppressor of Ras 1 (KSR1) Regulates Adipogenesis","volume":"25","author":"Kortum","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e2174232024","DOI":"10.1523\/JNEUROSCI.2174-23.2024","article-title":"KSR1 knockout mouse model demonstrates MAPK pathway\u2019s key role in cisplatin- and noise-induced hearing loss","volume":"44","author":"Ingersoll","year":"2024","journal-title":"J. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.neuroscience.2019.11.051","article-title":"Noise-induced Cochlear Synaptopathy with and Without Sensory Cell Loss","volume":"427","author":"Fernandez","year":"2020","journal-title":"Neuroscience"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"25056","DOI":"10.1038\/srep25056","article-title":"Noise exposure modulates cochlear inner hair cell ribbon volumes, correlating with changes in auditory measures in the FVB\/nJ mouse","volume":"6","author":"Paquette","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"108518","DOI":"10.1016\/j.heares.2022.108518","article-title":"Inner ear immunity","volume":"419","author":"Keithley","year":"2022","journal-title":"Hear. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1177\/01945998211028796","article-title":"Immune-Mediated Sensorineural Hearing Loss in the Pediatric Population","volume":"166","author":"Gorthey","year":"2022","journal-title":"Otolaryngol.\u2013Head Neck Surg."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1002\/glia.24095","article-title":"Macrophages in the cochlea; an immunological link between risk factors and progressive hearing loss","volume":"70","author":"Hough","year":"2022","journal-title":"Glia"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A simple practice guide for dose conversion between animals and human","volume":"7","author":"Nair","year":"2016","journal-title":"J. Basic. Clin. Pharm."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1111\/cts.12902","article-title":"Optimizing the Therapeutic Window of Targeted Drugs in Oncology: Potency-Guided First-in-Human Studies","volume":"14","author":"Goldstein","year":"2021","journal-title":"Clin. Transl. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1007\/s11764-022-01312-x","article-title":"Special considerations in the design and implementation of pediatric otoprotection trials","volume":"17","author":"Freyer","year":"2023","journal-title":"J. Cancer Surviv."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1124\/dmd.122.001066","article-title":"Novel Approaches to Characterize Individual Drug Metabolism and Advance Precision Medicine","volume":"51","author":"Jackson","year":"2023","journal-title":"Drug Metab. Dispos."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.heares.2017.01.003","article-title":"Cochlear synaptopathy in acquired sensorineural hearing loss: Manifestations and mechanisms","volume":"349","author":"Liberman","year":"2017","journal-title":"Hear. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"7509","DOI":"10.1523\/JNEUROSCI.5138-14.2015","article-title":"Aging after Noise Exposure: Acceleration of Cochlear Synaptopathy in \u201cRecovered\u201d Ears","volume":"35","author":"Fernandez","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"13686","DOI":"10.1523\/JNEUROSCI.1783-13.2013","article-title":"Age-Related Cochlear Synaptopathy: An Early-Onset Contributor to Auditory Functional Decline","volume":"33","author":"Sergeyenko","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.heares.2015.04.014","article-title":"Cochlear neuropathy in human presbycusis: Confocal analysis of hidden hearing loss in post-mortem tissue","volume":"327","author":"Viana","year":"2015","journal-title":"Hear. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.heares.2015.02.009","article-title":"Synaptopathy in the noise-exposed and aging cochlea: Primary neural degeneration in acquired sensorineural hearing loss","volume":"330","author":"Kujawa","year":"2015","journal-title":"Hear. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"14077","DOI":"10.1523\/JNEUROSCI.2845-09.2009","article-title":"Adding Insult to Injury: Cochlear Nerve Degeneration after \u201cTemporary\u201d Noise-Induced Hearing Loss","volume":"29","author":"Kujawa","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1523\/JNEUROSCI.1273-22.2023","article-title":"Macrophages Promote Repair of Inner Hair Cell Ribbon Synapses following Noise-Induced Cochlear Synaptopathy","volume":"43","author":"Manickam","year":"2023","journal-title":"J. Neurosci."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Patel, S., Shah, L., Dang, N., Tan, X., Almudevar, A., and White, P.M. (2020). SIRT3 promotes auditory function in young adult FVB\/nJ mice but is dispensable for hearing recovery after noise exposure. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0235491"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s10162-015-0510-3","article-title":"Dynamics of cochlear synaptopathy after acoustic overexposure","volume":"16","author":"Liberman","year":"2015","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"108996","DOI":"10.1016\/j.heares.2024.108996","article-title":"Noise-induced synaptic loss and its post-exposure recovery in CBA\/CaJ vs. C57BL\/6J mice","volume":"445","author":"Wu","year":"2024","journal-title":"Hear. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"4784385","DOI":"10.1155\/2021\/4784385","article-title":"Noise-Induced Hearing Loss: Updates on Molecular Targets and Potential Interventions","volume":"2021","author":"Mao","year":"2021","journal-title":"Neural Plast."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e72681","DOI":"10.7554\/eLife.72681","article-title":"Repair of noise-induced damage to stereocilia F-actin cores is facilitated by XIRP2 and its novel mechanosensor domain","volume":"12","author":"Wagner","year":"2023","journal-title":"eLife"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Yang, S.-M., Chen, W., Guo, W.-W., Jia, S., Sun, J.-H., Liu, H.-Z., Young, W.-Y., and He, D.Z.Z. (2012). Regeneration of Stereocilia of Hair Cells by Forced Atoh1 Expression in the Adult Mammalian Cochlea. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046355"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s12943-018-0804-2","article-title":"Kinase-targeted cancer therapies: Progress, challenges and future directions","volume":"17","author":"Bhullar","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.heares.2006.09.004","article-title":"Immune cell recruitment following acoustic trauma","volume":"222","author":"Tornabene","year":"2006","journal-title":"Hear. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"781702","DOI":"10.3389\/fneur.2021.781702","article-title":"Distribution of Immune Cells Including Macrophages in the Human Cochlea","volume":"12","author":"Liu","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1097\/MAO.0b013e31818256a9","article-title":"Tumor Necrosis Factor \u03b1 Can Induce Recruitment of Inflammatory Cells to the Cochlea","volume":"29","author":"Keithley","year":"2008","journal-title":"Otol. Neurotol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/cne.21729","article-title":"Bone marrow-derived cells that home to acoustic deafened cochlea preserved their hematopoietic identity","volume":"509","author":"Tan","year":"2008","journal-title":"J. Comp. Neurol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuroscience.2015.05.081","article-title":"Activation of the antigen presentation function of mononuclear phagocyte populations associated with the basilar membrane of the cochlea after acoustic overstimulation","volume":"303","author":"Yang","year":"2015","journal-title":"Neuroscience"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2522","DOI":"10.7150\/thno.49121","article-title":"Neutrophils infiltrate into the spiral ligament but not the stria vascularis in the cochlea during lipopolysaccharide-induced inflammation","volume":"11","author":"Bae","year":"2021","journal-title":"Theranostics"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"15167","DOI":"10.1038\/s41598-020-72181-6","article-title":"The immune response after noise damage in the cochlea is characterized by a heterogeneous mix of adaptive and innate immune cells","volume":"10","author":"Rai","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Samson, S.C., Khan, A.M., and Mendoza, M.C. (2022). ERK signaling for cell migration and invasion. Front. Mol. Biosci., 9.","DOI":"10.3389\/fmolb.2022.998475"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1093\/jb\/mvx048","article-title":"ERK signalling as a regulator of cell motility","volume":"162","author":"Tanimura","year":"2017","journal-title":"J. Biochem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"6640","DOI":"10.1523\/JNEUROSCI.0515-17.2018","article-title":"Pharmacological Inhibition of ERK Signaling Rescues Pathophysiology and Behavioral Phenotype Associated with 16p11.2 Chromosomal Deletion in Mice","volume":"38","author":"Pucilowska","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Xu, Z., Sun, J., Tong, Q., Lin, Q., Qian, L., Park, Y., and Zheng, Y. (2016). The Role of ERK1\/2 in the Development of Diabetic Cardiomyopathy. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17122001"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1681\/ASN.0000000000000261","article-title":"Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced AKI","volume":"35","author":"Pushpan","year":"2024","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"pyv030","DOI":"10.1093\/ijnp\/pyv030","article-title":"NAc Shell Arc\/Arg3.1 Protein Mediates Reconsolidation of Morphine CPP by Increased GluR1 Cell Surface Expression: Activation of ERK-Coupled CREB is Required","volume":"18","author":"Lv","year":"2015","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"9054","DOI":"10.1523\/JNEUROSCI.2410-07.2007","article-title":"Actin polymerization and ERK phosphorylation are required for Arc\/Arg3.1 mRNA targeting to activated synaptic sites on dendrites","volume":"27","author":"Huang","year":"2007","journal-title":"J. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/12\/6305\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:55:13Z","timestamp":1760108113000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/12\/6305"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,7]]},"references-count":92,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["ijms25126305"],"URL":"https:\/\/doi.org\/10.3390\/ijms25126305","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.10.18.563007","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,7]]}}}