{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T19:17:23Z","timestamp":1789240643138,"version":"build-2803163510"},"reference-count":39,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2018,3,15]],"date-time":"2018-03-15T00:00:00Z","timestamp":1521072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"GRRC program of Gyeonggi province, Korea","award":["GRRC-DONGGUK 2017-B01"],"award-info":[{"award-number":["GRRC-DONGGUK 2017-B01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Excitotoxicity and oxidative stress play vital roles in the development of neurodegenerative disorders including Alzheimer\u2019s disease (AD). In the present study, we investigated the effect of N-((3,4-dihydro-2H-benzo[h]chromen-2-yl)methyl)-4-methoxyaniline (BL-M) on excitotoxic neuronal cell damage in primary cultured rat cortical cells, and compared to that of memantine, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist clinically used to treat AD. We found that BL-M inhibited glutamate- or N-methyl-d-aspartate (NMDA)-induced excitotoxic cell damage. The IC50 value of BL-M against NMDA toxicity was comparable to that of memantine. BL-M potently inhibited intracellular reactive oxygen species generated by glutamate or NMDA. Additionally, it inhibited the formation of 1,1-diphenyl-2-picryl-hydrazyl radicals in vitro and lipid peroxidation in rat brain homogenates. In contrast, memantine showed minimal or negligible antioxidant activity. Western blotting and immunocytochemical analyses showed that BL-M, not memantine, increased the ERK1\/2 phosphorylation and subsequent phosphorylation of cAMP response element-binding protein (CREB). The inhibition of NMDA toxicity by BL-M was dramatically reversed by U0126, a well-known MEK inhibitor, suggesting that ERK1\/2-mediated CREB phosphorylation is required for the neuroprotective action. Collectively, in this study, we demonstrated the neuroprotective effect of a newly synthesized chromene derivative BL-M and its underlying action mechanism(s). In contrast to memantine, BL-M exhibited marked antioxidant activity. Furthermore, it enhanced the ERK-mediated phosphorylation of CREB, which plays a crucial neuroprotective role. Our findings suggest that BL-M may be beneficial for AD and other neurodegenerative disorders associated with excitotoxicity as well as oxidative stress.<\/jats:p>","DOI":"10.3390\/molecules23030669","type":"journal-article","created":{"date-parts":[[2018,3,15]],"date-time":"2018-03-15T16:07:17Z","timestamp":1521130037000},"page":"669","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Antioxidant and Neuroprotective Effects of N-((3,4-Dihydro-2H-benzo[h]chromen-2-yl)methyl)-4-methoxyaniline in Primary Cultured Rat Cortical Cells: Involvement of ERK-CREB Signaling"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9037-6172","authenticated-orcid":false,"given":"Kyeongjun","family":"Lee","sequence":"first","affiliation":[{"name":"College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chowee","family":"Park","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeonsoo","family":"Oh","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heesoon","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungsook","family":"Cho","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/0165-6147(90)90116-P","article-title":"Excitatory amino acids and synaptic transmission: The evidence for a physiological function","volume":"11","author":"Headley","year":"1990","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1007S","DOI":"10.1093\/jn\/130.4.1007S","article-title":"Glutamate as a neurotransmitter in the brain: Review of physiology and pathology","volume":"130","author":"Meldrum","year":"2000","journal-title":"J. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/nrd2462","article-title":"Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders","volume":"7","author":"Sanacora","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1146\/annurev.pa.30.040190.000403","article-title":"Excitotoxic amino acids and neuropsychiatric disorders","volume":"30","author":"Olney","year":"1990","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"219","DOI":"10.31887\/DCNS.2000.2.3\/jnewcomer","article-title":"NMDA receptor function, memory, and brain aging","volume":"2","author":"Newcomer","year":"2000","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"a006171","DOI":"10.1101\/cshperspect.a006171","article-title":"The neuropsychological profile of Alzheimer disease","volume":"2","author":"Weintraub","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1097\/00008877-200609000-00007","article-title":"Potential role of N-methyl-d-aspartate receptors as executors of neurodegeneration resulting from diverse insults: Focus on memantine","volume":"17","author":"Wenk","year":"2006","journal-title":"Behav. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1126\/science.7046051","article-title":"The cholinergic hypothesis of geriatric memory dysfunction","volume":"217","author":"Bartus","year":"1982","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.coph.2005.09.007","article-title":"Mechanism of action of memantine","volume":"6","author":"Johnson","year":"2006","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S0031-6997(24)01394-2","article-title":"The glutamate receptor ion channels","volume":"51","author":"Dingledine","year":"1999","journal-title":"Pharmacol. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1007\/s12640-013-9398-z","article-title":"Memantine and cholinesterase inhibitors: Complementary mechanisms in the treatment of Alzheimer\u2019s disease","volume":"24","author":"Parsons","year":"2013","journal-title":"Neurotox. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/(SICI)1099-1166(199901)14:1<3::AID-GPS897>3.0.CO;2-7","article-title":"The glutamatergic system and neurodegeneration in dementia: Preventive strategies in Alzheimer\u2019s disease","volume":"14","author":"Cacabelos","year":"1999","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1016\/j.bmcl.2014.04.053","article-title":"Design and synthesis of 3,4-dihydro-2H-benzo[h]chromene derivatives as potential NF-\u03baB inhibitors","volume":"24","author":"Choi","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1248\/bpb.b15-00473","article-title":"Antioxidant and Anti-inflammatory Activities of N-((3,4-Dihydro-2H-benzo[h]chromene-2-yl)methyl)-4-methoxyaniline in LPS-Induced BV2 Microglial Cells","volume":"38","author":"Moniruzzaman","year":"2015","journal-title":"Biol. Pharm. Bull."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S191","DOI":"10.33549\/physiolres.932678","article-title":"Structure, function, and pharmacology of NMDA receptor channels","volume":"63","author":"Vyklicky","year":"2014","journal-title":"Physiol. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/brb3.118","article-title":"Galantamine potentiates the neuroprotective effect of memantine against NMDA-induced excitotoxicity","volume":"3","author":"Lopes","year":"2013","journal-title":"Brain Behav."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1002\/ana.21508","article-title":"Free radical damage to cerebral cortex in Alzheimer\u2019s disease, microvascular brain injury, and smoking","volume":"65","author":"Sonnen","year":"2009","journal-title":"Ann. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"621S","DOI":"10.1093\/ajcn\/71.2.621s","article-title":"Oxidative stress and Alzheimer disease","volume":"71","author":"Christen","year":"2000","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1007\/s00204-015-1517-6","article-title":"Biomarkers of lipid peroxidation in Alzheimer disease (AD): An update","volume":"89","author":"Lovell","year":"2015","journal-title":"Arch. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1523\/JNEUROSCI.0133-09.2009","article-title":"NMDA receptor activation increases free radical production through nitric oxide and NOX2","volume":"29","author":"Girouard","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1248\/bpb.b16-00579","article-title":"Protection of Cultured Cortical Neurons by Luteolin against Oxidative Damage through Inhibition of Apoptosis and Induction of Heme Oxygenase-1","volume":"40","author":"Kim","year":"2017","journal-title":"Biol. Pharm. Bull."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"a001271","DOI":"10.1101\/cshperspect.a001271","article-title":"NF-\u03baB in the nervous system","volume":"1","author":"Kaltschmidt","year":"2009","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1046\/j.1471-4159.1999.01836.x","article-title":"CREB phosphorylation promotes nerve cell survival","volume":"73","author":"Walton","year":"1999","journal-title":"J. Neurochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1471-4159.2010.07080.x","article-title":"CREB: A multifaceted regulator of neuronal plasticity and protection","volume":"116","author":"Sakamoto","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.expneurol.2006.01.003","article-title":"Increases in the activated forms of ERK 1\/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury","volume":"199","author":"Crown","year":"2006","journal-title":"Exp. Neurol."},{"key":"ref_26","unstructured":"Purves, D. (1988). Body and Brain: A Trophic Theory of Neural Connections, Harvard University Press."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/S0896-6273(00)81010-7","article-title":"Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism","volume":"20","author":"Tao","year":"1998","journal-title":"Neuron"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1007\/s12031-013-0226-y","article-title":"Neuroprotective effects of 3,6\u2032-disinapoyl sucrose through increased BDNF levels and CREB phosphorylation via the CaMKII and ERK1\/2 pathway","volume":"53","author":"Hu","year":"2014","journal-title":"J. Mol. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1248\/bpb.28.455","article-title":"Neuroprotective and antioxidant effects of the ethyl acetate fraction prepared from Tussilago farfara L","volume":"28","author":"Cho","year":"2005","journal-title":"Biol. Pharm. Bull."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1016\/S0024-3205(01)00944-4","article-title":"NMDA recepter-mediated neuroprotection by essential oils from the rhizomes of Acorus gramineus","volume":"68","author":"Cho","year":"2001","journal-title":"Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0378-8741(00)00262-2","article-title":"Inhibition of excitotoxic neuronal death by methanol extract of Acori graminei rhizoma in cultured rat cortical neurons","volume":"73","author":"Cho","year":"2000","journal-title":"J. Ethnopharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1248\/bpb.b13-00880","article-title":"Korean red ginseng extract exhibits neuroprotective effects through inhibition of apoptotic cell death","volume":"37","author":"Kim","year":"2014","journal-title":"Biol. Pharm. Bull."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"275","DOI":"10.4062\/biomolther.2015.030","article-title":"Neuroprotective and antioxidant effects of novel benzofuran-2-carboxamide derivatives","volume":"23","author":"Cho","year":"2015","journal-title":"Biomol. Ther. (Seoul)"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jep.2016.01.023","article-title":"The ethyl acetate fraction from Physalis alkekengi inhibits LPS-induced pro-inflammatory mediators in BV2 cells and inflammatory pain in mice","volume":"181","author":"Moniruzzaman","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.cyto.2016.02.001","article-title":"Effect of CCL2 on BV2 microglial cell migration: Involvement of probable signaling pathways","volume":"81","author":"Bose","year":"2016","journal-title":"Cytokine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.jneuroim.2008.05.011","article-title":"The chemokine CCL2 activates p38 mitogen-activated protein kinase pathway in cultured rat hippocampal cells","volume":"199","author":"Cho","year":"2008","journal-title":"J. Neuroimmunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8541","DOI":"10.1073\/pnas.1323161111","article-title":"Intestinal cell kinase, a protein associated with endocrine-cerebro-osteodysplasia syndrome, is a key regulator of cilia length and Hedgehog signaling","volume":"111","author":"Moon","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/S0006-8993(02)04150-1","article-title":"Neuroprotective effects of antioxidative flavonoids, quercetin, (+)-dihydroquercetin and quercetin 3-methyl ether, isolated from Opuntia ficus-indica var. saboten","volume":"965","author":"Lee","year":"2003","journal-title":"Brain Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.ejphar.2003.11.064","article-title":"Wogonin inhibits excitotoxic and oxidative neuronal damage in primary cultured rat cortical cells","volume":"485","author":"Cho","year":"2004","journal-title":"Eur. J. Pharmacol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/3\/669\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:57:16Z","timestamp":1760194636000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/3\/669"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,15]]},"references-count":39,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2018,3]]}},"alternative-id":["molecules23030669"],"URL":"https:\/\/doi.org\/10.3390\/molecules23030669","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,15]]}}}