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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Cisplatin is an effective platinum-based chemotherapeutic agent used to treat a variety of cancers. However, its clinical utility is limited by dose-dependent neurotoxicity, yet no approved neuroprotective strategy currently exists. Our integrated cellular, metabolic, and in vivo approaches unraveled the neuroprotective potential of Areca catechu ethyl acetate extract (AC-EA) against cisplatin-induced neurotoxicity. Importantly, AC-EA did not reduce cisplatin-induced cytotoxicity in A549 lung cancer cells. In HT22 hippocampal neurons, AC-EA restored cell viability, suppressed reactive oxygen species generation, preserved mitochondrial-associated fluorescence, and attenuated phosphorylated histone H2AX (\u03b3H2AX)-marked DNA damage. AC-EA was associated with increased pNRF2 expression, consistent with activation of NRF2-dependent antioxidant signaling, suppressed inducible nitric oxide synthase iNOS (inducible nitric oxide synthase )-mediated neuroinflammation, and prevented the depletion of total AKT (protein kinase B) protein. Untargeted metabolomics and Caenorhabditis elegans survival assays were performed for mechanistic and in vivo validation. Metabolomics data showed restoration of several critical amino acids, including L-tyrosine and \u03b2-alanine, disrupted by cisplatin. Moreover, C. elegans studies confirmed in vivo activation of antioxidants via the SKN-1\/GST-4 (glutathione S-transferase 4) pathway. While AC-EA shows neuroprotective potential, arecoline\u2019s toxicity demands caution. To our knowledge, this is the first study to demonstrate the neuroprotective activity of A. catechu against cisplatin-induced neurotoxicity, laying the foundation for developing plant-derived adjunct therapies for chemotherapy-associated neuropathy.<\/jats:p>","DOI":"10.3390\/ijms27157004","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T12:32:43Z","timestamp":1785846763000},"page":"7004","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-Targeted Neuroprotection by Areca catechu Against Cisplatin-Induced Neurotoxicity: Cellular, Caenorhabditis elegans, and Metabolomic Evidence"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0693-6366","authenticated-orcid":false,"given":"Kishore K.","family":"Kumaree","sequence":"first","affiliation":[{"name":"College of Public Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence on Natural Products for Neuroprotection and Anti-Ageing (Neur-Age NatChula), Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5968-8936","authenticated-orcid":false,"given":"Clerance Su Yee","family":"Cheong","sequence":"additional","affiliation":[{"name":"Center of Excellence on Natural Products for Neuroprotection and Anti-Ageing (Neur-Age NatChula), Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanika","family":"Verma","sequence":"additional","affiliation":[{"name":"Center of Excellence on Natural Products for Neuroprotection and Anti-Ageing (Neur-Age NatChula), Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6142-6702","authenticated-orcid":false,"given":"Kartina","family":"Nadyani","sequence":"additional","affiliation":[{"name":"Center of Excellence on Natural Products for Neuroprotection and Anti-Ageing (Neur-Age NatChula), Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Program in Biotechnology, Faculty of Science, Chulalongkorn University, Pathum Wan, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nureesun","family":"Mahamud","sequence":"additional","affiliation":[{"name":"The Halal Science Center, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence in Metabolomics for Life Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pornpimol","family":"Mahamad","sequence":"additional","affiliation":[{"name":"The Halal Science Center, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4177-2165","authenticated-orcid":false,"given":"Tewin","family":"Tencomnao","sequence":"additional","affiliation":[{"name":"Center of Excellence on Natural Products for Neuroprotection and Anti-Ageing (Neur-Age NatChula), Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Program in Biotechnology, Faculty of Science, Chulalongkorn University, Pathum Wan, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8884-3077","authenticated-orcid":false,"given":"Anchalee","family":"Prasansuklab","sequence":"additional","affiliation":[{"name":"College of Public Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence on Natural Products for Neuroprotection and Anti-Ageing (Neur-Age NatChula), Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2074-8262","authenticated-orcid":false,"given":"James M.","family":"Brimson","sequence":"additional","affiliation":[{"name":"Center of Excellence on Natural Products for Neuroprotection and Anti-Ageing (Neur-Age NatChula), Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Research, Innovation and International Affairs, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1158\/1535-7163.MCT-08-0840","article-title":"Platinum neurotoxicity pharmacogenetics","volume":"8","author":"McWhinney","year":"2009","journal-title":"Mol. 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