{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T21:14:26Z","timestamp":1762377266785,"version":"build-2065373602"},"reference-count":25,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,11,27]],"date-time":"2022-11-27T00:00:00Z","timestamp":1669507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003718","name":"Korea Institute of Oriental Medicine (KIOM)","doi-asserted-by":"publisher","award":["KSN2022230"],"award-info":[{"award-number":["KSN2022230"]}],"id":[{"id":"10.13039\/501100003718","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Arecae Pericarpium has been found to exert anti-migraine, antidepressant, and antioxidative effects. However, the mechanisms involved are unclear. This study explored the possibility that Arecae Pericarpium ethanol extract (APE) exerts neuroprotective effects against oxidative stress-induced neuronal cell death. Since glutamate excitotoxicity has been implicated in the pathogenesis and development of several neurodegenerative disorders, we explored the mechanisms of action of APE on oxidative stress-induced by glutamate. Our results revealed that pretreatment with APE prevents glutamate-induced HT22 cell death. APE also reduced both the levels of intracellular reactive oxygen species and the apoptosis of cells, while maintaining glutamate-induced mitochondrial membrane potentials. Western blotting showed that pretreatment with APE facilitates the upregulation of phosphoinositide 3-kinase (PI3K)\/protein kinase B (Akt) phosphorylation; the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2); and the production of antioxidant enzymes, including catalase, glutamate-cysteine ligase catalytic subunits, NAD(P)H quinone oxidoreductase 1, and heme oxygenase (HO)-1. The administration of LY294002, a PI3K\/Akt inhibitor, attenuated the neuroprotective effects of APE on oxidative stress-induced neuronal cell damage. This allowed us to infer that the protective effects of APE on oxidative damage to cells can be attributed to the PI3K\/Akt-mediated Nrf-2\/HO-1 signaling pathway.<\/jats:p>","DOI":"10.3390\/cimb44120402","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T08:43:03Z","timestamp":1669624983000},"page":"5902-5914","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Neuroprotective Effects of Arecae Pericarpium against Glutamate-Induced HT22 Cell Cytotoxicity"],"prefix":"10.3390","volume":"44","author":[{"given":"Yun Hee","family":"Jeong","sequence":"first","affiliation":[{"name":"Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, 70, Cheomdanro, Dong-gu, Daegu 41062, Republic of Korea"},{"name":"College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80, Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9889-7770","authenticated-orcid":false,"given":"You-Chang","family":"Oh","sequence":"additional","affiliation":[{"name":"Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, 70, Cheomdanro, Dong-gu, Daegu 41062, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9495-3782","authenticated-orcid":false,"given":"Tae In","family":"Kim","sequence":"additional","affiliation":[{"name":"Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, 70, Cheomdanro, Dong-gu, Daegu 41062, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5756-9367","authenticated-orcid":false,"given":"Jong-Sup","family":"Bae","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80, Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin Yeul","family":"Ma","sequence":"additional","affiliation":[{"name":"Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, 70, Cheomdanro, Dong-gu, Daegu 41062, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/jnc.12304","article-title":"Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer\u2019s disease","volume":"126","author":"Ferreira","year":"2013","journal-title":"J. Neurochem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/aps.2009.24","article-title":"Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases","volume":"30","author":"Dong","year":"2009","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3389\/fncel.2015.00091","article-title":"Researching glutamate-induced cytotoxicity in different cell lines: A comparative\/collective analysis\/study","volume":"9","author":"Kritis","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.neuint.2004.03.007","article-title":"Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer\u2019s disease","volume":"45","author":"Hynd","year":"2004","journal-title":"Neurochem. Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s12264-010-0813-7","article-title":"Excitotoxicity effects of glutamate on human neuroblastoma SH-SY5Y cells via oxidative damage","volume":"26","author":"Sun","year":"2010","journal-title":"Neurosci. Bull."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1126\/science.7901908","article-title":"Oxidative stress, glutamate, and neurodegenerative disorders","volume":"262","author":"Coyle","year":"1993","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1007\/s11064-010-0212-5","article-title":"The Role of Oxidative Stress in Amyotrophic Lateral Sclerosis and Parkinson\u2019s Disease","volume":"35","author":"Baillet","year":"2010","journal-title":"Neurochem. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"69","DOI":"10.2174\/157339912798829232","article-title":"The role of peroxidation of mitochondrial membrane phospholipids in pancreatic \u03b2-cell failure","volume":"8","author":"Ma","year":"2012","journal-title":"Curr. Diabetes Rev."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Baek, S.Y., and Kim, M.R. (2020). Neuroprotective effect of carotenoid-rich enteromorpha prolifera extract via TrkB\/Akt pathway against oxidative stress in hippocampal neuronal cells. Mar. Drugs, 18.","DOI":"10.3390\/md18070372"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1016\/j.redox.2016.12.034","article-title":"Neuroprotective action of N-acetyl serotonin in oxidative stress-induced apoptosis through the activation of both TrkB\/CREB\/BDNF pathway and Akt\/Nrf2\/Antioxidant enzyme in neuronal cells","volume":"11","author":"Yoo","year":"2017","journal-title":"Redox Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.neurobiolaging.2005.01.016","article-title":"Glial heme oxygenase-1 expression in Alzheimer disease and mild cognitive impairment","volume":"27","author":"Schipper","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/S0197-4580(00)00114-7","article-title":"NAD (P) H: Quinone oxidoreductase activity is increased in hippocampal pyramidal neurons of patients with Alzheimer\u2019s disease","volume":"21","author":"Wang","year":"2000","journal-title":"Neurobiol. Aging"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.jep.2015.02.010","article-title":"Areca catechu L. (Arecaceae): A review of its traditional uses, botany, phytochemistry, pharmacology and toxicology","volume":"164","author":"Peng","year":"2015","journal-title":"J. Ethnopharmacol."},{"key":"ref_14","first-page":"48","article-title":"Wound healing profile of Areca catechu extracts on different wound models in wistar rats","volume":"39","author":"Azeez","year":"2007","journal-title":"Kuwait Med. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.jep.2015.05.052","article-title":"Anti-migraine effect of Areca catechu L. nut extract in bradykinin-induced plasma protein extravasation and vocalization in rats","volume":"171","author":"Bhandare","year":"2015","journal-title":"J. Ethnopharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0944-7113(97)80026-8","article-title":"Anti-depressant activities of Areca catechu fruit extract","volume":"4","author":"Dar","year":"1997","journal-title":"Phytomedicine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jep.2006.03.021","article-title":"Leads from Indian medicinal plants with hypoglycemic potentials","volume":"106","author":"Mukherjee","year":"2006","journal-title":"J. Ethnopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"28","DOI":"10.5530\/ax.2011.1.6","article-title":"Antioxidant activity and the effect of different parts of areca catechu extracts on Glutathione-S-Transferase activity in vitro","volume":"1","author":"Hamsar","year":"2011","journal-title":"Free Radic. Antioxid."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Hao, Y.M., Liu, J., Wang, Z.Y., Yu, L.L., and Wang, J. (2019). Piceatannol Protects Human Retinal Pigment Epithelial Cells against Hydrogen Peroxide Induced Oxidative Stress and Apoptosis through Modulating PI3K\/Akt Signaling Pathway. Nutrients, 11.","DOI":"10.3390\/nu11071515"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0149-7634(05)80046-6","article-title":"Excitatory amino acids and memory: Evidence from research on Alzheimer\u2019s disease and behavioral pharmacology","volume":"16","author":"Advokat","year":"1992","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.ejphar.2012.10.032","article-title":"Excitotoxicity: Bridge to various triggers in neurodegenerative disorders","volume":"698","author":"Mehta","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_22","first-page":"4","article-title":"Glutamate excitotoxicity and neurodegeneration","volume":"8","author":"Ezza","year":"2014","journal-title":"J. Mol. Genet. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0014-5793(01)02437-1","article-title":"Glutamate neurotoxicity, oxidative stress and mitochondria","volume":"497","author":"Atlante","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7770","DOI":"10.1074\/jbc.273.13.7770","article-title":"The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition","volume":"273","author":"Pastorino","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1002\/ptr.4931","article-title":"Caffeoylserotonin Protects Human Keratinocyte HaCaT Cells against H2O2-Induced Oxidative Stress and Apoptosis through Upregulation of HO-1 Expression via Activation of the PI3K\/Akt\/Nrf2 Pathway","volume":"27","author":"Nguyen","year":"2013","journal-title":"Phytother. Res."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/44\/12\/402\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:27:46Z","timestamp":1760146066000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/44\/12\/402"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,27]]},"references-count":25,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["cimb44120402"],"URL":"https:\/\/doi.org\/10.3390\/cimb44120402","relation":{},"ISSN":["1467-3045"],"issn-type":[{"type":"electronic","value":"1467-3045"}],"subject":[],"published":{"date-parts":[[2022,11,27]]}}}