{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T16:16:41Z","timestamp":1779207401402,"version":"3.51.4"},"reference-count":79,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2018,7,18]],"date-time":"2018-07-18T00:00:00Z","timestamp":1531872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["20152HKF3Z"],"award-info":[{"award-number":["20152HKF3Z"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is the most common form of dementia among older people. Although soluble amyloid species are recognized triggers of the disease, no therapeutic approach is able to stop it. 6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a major bioactive compound in Wasabia japonica, which is a typical Japanese pungent spice. Recently, in vivo and in vitro studies demonstrated that 6-MSITC has several biological properties. The aim of the present study was to investigate the neuroprotective activity of 6-MSITC in a murine AD model, induced by intracerebroventricular injection of \u03b2-amyloid oligomers (A\u03b21-42O). The treatment with 6-MSITC started 1 h after the surgery for the next 10 days. Behavioral analysis showed that 6-MSITC ameliorated A\u03b21-42O-induced memory impairments. The decrease of glutathione levels and increase of reactive oxygen species in hippocampal tissues following A\u03b21-42O injection were reduced by 6-MSITC. Moreover, activation of caspases, increase of inflammatory factors, and phosphorylation of ERK and GSK3 were inhibited by 6-MSITC. These results highlighted an interesting neuroprotective activity of 6-MSITC, which was able to restore a physiological oxidative status, interfere positively with Nrf2-pathway, decrease apoptosis and neuroinflammation and contribute to behavioral recovery. Taken together, these findings demonstrated that 6-MSITC could be a promising complement for AD therapy.<\/jats:p>","DOI":"10.3390\/ijms19072083","type":"journal-article","created":{"date-parts":[[2018,7,19]],"date-time":"2018-07-19T03:50:43Z","timestamp":1531972243000},"page":"2083","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Protective Effects of 6-(Methylsulfinyl)hexyl Isothiocyanate on A\u03b21-42-Induced Cognitive Deficit, Oxidative Stress, Inflammation, and Apoptosis in Mice"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6494-5968","authenticated-orcid":false,"given":"Fabiana","family":"Morroni","sequence":"first","affiliation":[{"name":"Department of Pharmacy and Biotechnology, Alma Mater Studiorum\u2014University of Bologna, via Irnerio 48, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6627-7078","authenticated-orcid":false,"given":"Giulia","family":"Sita","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, Alma Mater Studiorum\u2014University of Bologna, via Irnerio 48, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4992-7902","authenticated-orcid":false,"given":"Agnese","family":"Graziosi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, Alma Mater Studiorum\u2014University of Bologna, via Irnerio 48, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4743-1126","authenticated-orcid":false,"given":"Eleonora","family":"Turrini","sequence":"additional","affiliation":[{"name":"Department for Life Quality Studies, Alma Mater Studiorum\u2014University of Bologna, Corso d\u2019Augusto, 237, 47900 Rimini, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2461-8214","authenticated-orcid":false,"given":"Carmela","family":"Fimognari","sequence":"additional","affiliation":[{"name":"Department for Life Quality Studies, Alma Mater Studiorum\u2014University of Bologna, Corso d\u2019Augusto, 237, 47900 Rimini, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7983-8575","authenticated-orcid":false,"given":"Andrea","family":"Tarozzi","sequence":"additional","affiliation":[{"name":"Department for Life Quality Studies, Alma Mater Studiorum\u2014University of Bologna, Corso d\u2019Augusto, 237, 47900 Rimini, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8415-3711","authenticated-orcid":false,"given":"Patrizia","family":"Hrelia","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, Alma Mater Studiorum\u2014University of Bologna, via Irnerio 48, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.trci.2017.05.002","article-title":"Alzheimer\u2019s disease drug development pipeline: 2017","volume":"3","author":"Cummings","year":"2017","journal-title":"Alzheimers Dement. Transl. Res. Clin. Interv."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1126\/science.1566067","article-title":"Alzheimer\u2019s disease: The amyloid cascade hypothesis","volume":"256","author":"Hardy","year":"1992","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.bbr.2008.02.016","article-title":"Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior","volume":"192","author":"Selkoe","year":"2008","journal-title":"Behav. Brain Res."},{"key":"ref_4","first-page":"3","article-title":"Oxidative stress mediates the pathogenic effect of different Alzheimer\u2019s disease risk factors","volume":"2","author":"Guglielmotto","year":"2010","journal-title":"Front. Aging Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.2174\/1871527313666140806124322","article-title":"Neuroprotection by association of palmitoylethanolamide with luteolin in experimental Alzheimer\u2019s disease models: The control of neuroinflammation","volume":"13","author":"Paterniti","year":"2014","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.bbr.2016.08.002","article-title":"Early effects of A\u03b21-42 oligomers injection in mice: Involvement of PI3K\/Akt\/GSK3 and MAPK\/ERK1\/2 pathways","volume":"314","author":"Morroni","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1602\/neurorx.1.1.117","article-title":"Neuroprotective strategies in Alzheimer\u2019s disease","volume":"1","author":"Longo","year":"2004","journal-title":"NeuroRx"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Subedi, L., Venkatesan, R., and Kim, S.Y. (2017). Neuroprotective and anti-inflammatory activities of allyl isothiocyanate through attenuation of JNK\/NF-\u03baB\/TNF-\u03b1 signaling. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071423"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sita, G., Hrelia, P., Tarozzi, A., and Morroni, F. (2016). Isothiocyanates are promising compounds against oxidative stress, neuroinflammation and cell death that may benefit neurodegeneration in Parkinson\u2019s disease. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17091454"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.phrs.2014.05.003","article-title":"Sulforaphane alleviates scopolamine-induced memory impairment in mice","volume":"85","author":"Lee","year":"2014","journal-title":"Pharmacol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1039\/b204039p","article-title":"A critical review of the bioavailability of glucosinolates and related compounds","volume":"21","author":"Holst","year":"2004","journal-title":"Nat. Prod. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.fitote.2014.03.018","article-title":"Antiinflammatory activity of glucomoringin isothiocyanate in a mouse model of experimental autoimmune encephalomyelitis","volume":"95","author":"Galuppo","year":"2014","journal-title":"Fitoterapia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.neuro.2013.03.004","article-title":"Neuroprotective effect of sulforaphane in 6-hydroxydopamine-lesioned mouse model of Parkinson\u2019s disease","volume":"36","author":"Morroni","year":"2013","journal-title":"Neurotoxicology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.brainres.2010.04.036","article-title":"Sulforaphane protects brains against hypoxic-ischemic injury through induction of Nrf2-dependent phase 2 enzyme","volume":"1343","author":"Ping","year":"2010","journal-title":"Brain Res."},{"key":"ref_15","first-page":"614046","article-title":"Molecular mechanisms underlying anti-inflammatory actions of 6-(methylsulfinyl)hexyl isothiocyanate derived from Wasabi (Wasabia japonica)","volume":"2012","author":"Uto","year":"2012","journal-title":"Adv. Pharmacol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S0047-6374(00)00114-7","article-title":"Antiplatelet and anticancer isothiocyanates in Japanese domestic horseradish, Wasabi","volume":"116","author":"Morimitsu","year":"2000","journal-title":"Mech. Ageing Dev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.3389\/fmicb.2016.01403","article-title":"Antibacterial activities of Wasabi against Escherichia coli O157:H7 and Staphylococcus aureus","volume":"7","author":"Lu","year":"2016","journal-title":"Front. Microbiol."},{"key":"ref_18","first-page":"233","article-title":"Effects of 6-(methylsulfinyl)hexyl isothiocyanate on cyclooxygenase-2 expression induced by lipopolysaccharide, interferon-\u03b3 and 12-O-tetradecanoylphorbol-13-acetate","volume":"17","author":"Uto","year":"2007","journal-title":"Oncol. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1007\/s11418-013-0784-x","article-title":"6-Methylsulfinylhexyl isothiocyanate modulates endothelial cell function and suppresses leukocyte adhesion","volume":"68","author":"Okamoto","year":"2014","journal-title":"J. Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1007\/s00394-015-0866-5","article-title":"The induction of apoptosis and autophagy by Wasabia japonica extract in colon cancer","volume":"55","author":"Hsuan","year":"2016","journal-title":"Eur. J. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.cdp.2004.07.010","article-title":"Selective sensitivity to wasabi-derived 6-(methylsulfinyl)hexyl isothiocyanate of human breast cancer and melanoma cell lines studied in vitro","volume":"29","author":"Nomura","year":"2005","journal-title":"Cancer Detect. Prev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1093\/carcin\/bgr255","article-title":"The molecular basis that unifies the metabolism, cellular uptake and chemopreventive activities of dietary isothiocyanates","volume":"33","author":"Zhang","year":"2012","journal-title":"Carcinogenesis"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/bbrc.1997.7812","article-title":"Recent trends in glutathione biochemistry-glutathione-protein interactions: A molecular link between oxidative stress and cell proliferation?","volume":"242","author":"Cotgreave","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.brainres.2014.09.033","article-title":"Neuroprotection by 6-(methylsulfinyl)hexyl isothiocyanate in a 6-hydroxydopamine mouse model of Parkinson\u2019s disease","volume":"1589","author":"Morroni","year":"2014","journal-title":"Brain Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1007\/s10495-010-0463-2","article-title":"The role of caspases in Alzheimer\u2019s disease; potential novel therapeutic opportunities","volume":"15","author":"Rohn","year":"2010","journal-title":"Apoptosis"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1016\/j.cellsig.2012.03.007","article-title":"A molecular view on signal transduction by the apoptosome","volume":"24","author":"Reubold","year":"2012","journal-title":"Cell Signal."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.brainresrev.2005.03.004","article-title":"Are mitochondria critical in the pathogenesis of Alzheimer\u2019s disease?","volume":"49","author":"Reddy","year":"2005","journal-title":"Brain Res. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3233\/JAD-2007-12208","article-title":"Du Amyloid-\u03b2-induced mitochondrial dysfunction","volume":"12","author":"Chen","year":"2007","journal-title":"J. Alzheimers. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Morroni, F., Sita, G., Graziosi, A., Turrini, E., Fimognari, C., Tarozzi, A., and Hrelia, P. (2018). Neuroprotective effect of caffeic acid phenethyl ester in a mouse model of Alzheimer\u2019s disease involves Nrf2\/HO-1 pathway. Aging Dis.","DOI":"10.14336\/AD.2017.0903"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/S0301-0082(99)00060-X","article-title":"Metabolism and functions of glutathione in brain","volume":"62","author":"Dringen","year":"2000","journal-title":"Prog. Neurobiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.brainresbull.2016.10.010","article-title":"Neuroprotective effects of N-adamantyl-4-methylthiazol-2-amine against amyloid \u03b2-induced oxidative stress in mouse hippocampus","volume":"128","author":"Kim","year":"2017","journal-title":"Brain Res. Bull."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e2499","DOI":"10.1038\/cddis.2016.389","article-title":"Therapeutic advantage of pro-electrophilic drugs to activate the Nrf2\/ARE pathway in Alzheimer\u2019s disease models","volume":"7","author":"Lipton","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1111\/jnc.13592","article-title":"Hippocampal metabotropic glutamate receptor long-term depression in health and disease: Focus on mitogen-activated protein kinase pathways","volume":"139","author":"Sanderson","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.3233\/JAD-161111","article-title":"Modulation of A\u03b2PP and GSK3\u03b2 by endoplasmic reticulum stress and involvement in Alzheimer\u2019s disease","volume":"57","author":"Liu","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"85","DOI":"10.3389\/fnagi.2018.00085","article-title":"Methyl salicylate lactoside protects neurons ameliorating cognitive disorder through inhibiting amyloid beta-induced neuroinflammatory response in Alzheimer\u2019s disease","volume":"10","author":"Li","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"470S","DOI":"10.1093\/ajcn\/83.2.470S","article-title":"Inflammation and neurodegenerative diseases","volume":"83","author":"Griffin","year":"2006","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/acel.12522","article-title":"Distinct inflammatory phenotypes of microglia and monocyte-derived macrophages in Alzheimer\u2019s disease models: Effects of aging and amyloid pathology","volume":"16","author":"Martin","year":"2017","journal-title":"Aging Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.2174\/13816128113199990497","article-title":"In vivo application of beta amyloid oligomers: A simple tool to evaluate mechanisms of action and new therapeutic approaches","volume":"20","author":"Balducci","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/S1359-6446(03)03000-9","article-title":"Interrupting apoptosis in neurodegenerative disease: Potential for effective therapy?","volume":"9","author":"Waldmeier","year":"2004","journal-title":"Drug Discov. Today"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.ajpath.2011.03.021","article-title":"Time-course and regional analyses of the physiopathological changes induced after cerebral injection of an amyloid \u03b2 fragment in rats","volume":"179","author":"Zussy","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/s12031-015-0645-z","article-title":"Neuroglobin attenuates beta amyloid-induced apoptosis through inhibiting caspases activity by activating PI3K\/Akt signaling pathway","volume":"58","author":"Li","year":"2016","journal-title":"J. Mol. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/S0891-5849(96)00629-6","article-title":"Oxidative stress hypothesis in Alzheimer\u2019s disease","volume":"23","author":"Markesbery","year":"1997","journal-title":"Free Radic. Biol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3233\/JAD-160673","article-title":"Acceleration of amyloidosis by inflammation in the amyloid-beta Marmoset monkey model of Alzheimer\u2019s disease","volume":"55","author":"Philippens","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.jns.2009.01.027","article-title":"Peoniflorin attentuates A\u03b21-42-mediated neurotoxicity by regulating calcium homeostasis and ameliorating oxidative stress in hippocampus of rats","volume":"280","author":"Zhong","year":"2009","journal-title":"J. Neurol. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1089\/ars.2016.6802","article-title":"The proteasome and oxidative stress in Alzheimer\u2019s disease","volume":"25","author":"Pomatto","year":"2016","journal-title":"Antioxid. Redox Signal."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4823","DOI":"10.1093\/hmg\/ddx361","article-title":"Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer\u2019s disease","volume":"26","author":"Branca","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3109\/13506129.2012.751367","article-title":"Amelioration of Alzheimer\u2019s disease by neuroprotective effect of sulforaphane in animal model","volume":"20","author":"Kim","year":"2013","journal-title":"Amyloid"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuint.2017.10.002","article-title":"Resveratrol activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against amyloid-beta-induced inflammation and oxidative stress","volume":"115","author":"Chiang","year":"2018","journal-title":"Neurochem. Int."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.freeradbiomed.2018.03.028","article-title":"Rosmarinic acid attenuates \u03b2-amyloid-induced oxidative stress via Akt\/GSK-3\u03b2\/Fyn-mediated Nrf2 activation in PC12 cells","volume":"120","author":"Rong","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_50","first-page":"73","article-title":"DNA microarray highlights Nrf2-mediated neuron protection targeted by Wasabi-derived isothiocyanates in IMR-32 cells","volume":"10","author":"Trio","year":"2016","journal-title":"Gene Regul. Syst. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"11975","DOI":"10.1021\/jf2032439","article-title":"Dynamics of Nrf2 and Keap1 in ARE-mediated NQO1 expression by wasabi 6-(methylsulfinyl)hexyl isothiocyanate","volume":"59","author":"Hou","year":"2011","journal-title":"J. Agric. Food Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/0306-4522(95)00146-A","article-title":"Increased expression and subcellular translocation of the mitogen activated protein kinase kinase and mitogen-activated protein kinase in Alzheimer\u2019s disease","volume":"68","author":"Arendt","year":"1995","journal-title":"Neuroscience"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1097\/00001756-199507100-00020","article-title":"Induction of p21ras in Alzheimer pathology","volume":"6","author":"Holzer","year":"1995","journal-title":"Neuroreport"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s12640-010-9231-x","article-title":"Extracellular HMGB1 released by NMDA treatment confers neuronal apoptosis via RAGE-p38 MAPK\/ERK signaling pathway","volume":"20","author":"Kim","year":"2011","journal-title":"Neurotox. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1007\/s12640-012-9352-5","article-title":"\u03b1-Synuclein protects neurons from apoptosis downstream of free-radical production through modulation of the MAPK signalling pathway","volume":"23","author":"Musgrove","year":"2013","journal-title":"Neurotox. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2006.03.126","article-title":"p44\/42 MAP kinase and c-Jun N-terminal kinase contribute to the up-regulation of caspase-3 in manganese-induced apoptosis in PC12 cells","volume":"1099","author":"Ito","year":"2006","journal-title":"Brain Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"11578","DOI":"10.1073\/pnas.1010678108","article-title":"Transient Receptor Potential Melastatin 2 (TRPM2) ion channel is required for innate immunity against Listeria monocytogenes","volume":"108","author":"Knowles","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1101\/lm.028449.112","article-title":"The roles of protein kinases in learning and memory","volume":"20","author":"Giese","year":"2013","journal-title":"Learn. Mem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"222","DOI":"10.3390\/ijms11010222","article-title":"ERK in learning and memory: A review of recent research","volume":"11","author":"Peng","year":"2010","journal-title":"Int. J. Mol. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.ejmech.2015.10.018","article-title":"Pivotal role of glycogen synthase kinase-3: A therapeutic target for Alzheimer\u2019s disease","volume":"107","author":"Maqbool","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/emboj\/20.1.27","article-title":"Decreased nuclear \u03b2-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3\u03b2 conditional transgenic mice","volume":"20","author":"Lucas","year":"2001","journal-title":"EMBO J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"7392","DOI":"10.1523\/JNEUROSCI.0889-12.2012","article-title":"Selectively silencing GSK-3 isoforms reduces plaques and tangles in mouse models of Alzheimer\u2019s disease","volume":"32","author":"Hurtado","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1097\/00005072-199701000-00007","article-title":"Distribution, levels, and activity of glycogen synthase kinase-3 in the Alzheimer disease brain","volume":"56","author":"Pei","year":"1997","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1111\/j.0953-816X.2004.03365.x","article-title":"Increased MAP kinase activity in Alzheimer\u2019s and Down syndrome but not in schizophrenia human brain","volume":"19","author":"Swatton","year":"2004","journal-title":"Eur. J. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.pneurobio.2006.07.006","article-title":"The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways","volume":"79","author":"Beurel","year":"2006","journal-title":"Prog. Neurobiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/j.neo.2014.07.012","article-title":"Glycogen synthase kinase 3 regulates cell death and survival signaling in tumor cells under redox stress","volume":"16","author":"Cardinali","year":"2014","journal-title":"Neoplasia"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1111\/j.1750-3639.1994.tb00838.x","article-title":"GFAP and astrogliosis","volume":"4","author":"Eng","year":"1994","journal-title":"Brain Pathol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1146\/annurev.neuro.22.1.219","article-title":"Microglia as mediators of inflammatory and degenerative diseases","volume":"22","author":"Baltuch","year":"1999","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neures.2013.10.004","article-title":"Neuroinflammation: The role and consequences","volume":"79","author":"Lyman","year":"2014","journal-title":"Neurosci. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1016\/j.bcp.2005.07.011","article-title":"6-(Methylsulfinyl)hexyl isothiocyanate suppresses inducible nitric oxide synthase expression through the inhibition of Janus kinase 2-mediated JNK pathway in lipopolysaccharide-activated murine macrophages","volume":"70","author":"Uto","year":"2005","journal-title":"Biochem. Pharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1097\/WNR.0b013e32830fe4b8","article-title":"Cyanidin 3-O-glucopyranoside protects and rescues SH-SY5Y cells against amyloid-beta peptide-induced toxicity","volume":"19","author":"Tarozzi","year":"2008","journal-title":"Neuroreport"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.brainres.2006.10.093","article-title":"Combining the rapid MTT formazan exocytosis assay and the MC65 protection assay led to the discovery of carbazole analogs as small molecule inhibitors of A\u03b2 oligomer-induced cytotoxicity","volume":"1130","author":"Hong","year":"2007","journal-title":"Brain Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1111\/j.1471-4159.2007.04972.x","article-title":"Congo red and thioflavin-T analogs detect A\u03b2 oligomers","volume":"104","author":"Maezawa","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S0031-9384(02)00979-4","article-title":"Stress-induced impairment of inhibitory avoidance learning in female neuromedin B receptor-deficient mice","volume":"78","author":"Yamada","year":"2003","journal-title":"Physiol. Behav."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"27","DOI":"10.12659\/MSMBR.890438","article-title":"Effects of 7-NI and ODQ on memory in the passive avoidance, novel object recognition, and social transmission of food preference tests in mice","volume":"20","author":"Akar","year":"2014","journal-title":"Med. Sci. Monit. Basic Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/0166-4328(88)90157-X","article-title":"A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data","volume":"31","author":"Ennaceur","year":"1988","journal-title":"Behav. Brain Res."},{"key":"ref_77","first-page":"3","article-title":"Hematoxylin and eosin staining of tissueand cell sections","volume":"3","author":"Fischer","year":"2008","journal-title":"Cold Spring Harb. Protoc."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/S0006-291X(02)02593-7","article-title":"Ceramide induces neuronal apoptosis through the caspase-9\/caspase-3 pathway","volume":"299","author":"Movsesyan","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using Real-Time Quantitative PCR and the 2\u2212\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/7\/2083\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:12:43Z","timestamp":1760195563000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/7\/2083"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,7,18]]},"references-count":79,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2018,7]]}},"alternative-id":["ijms19072083"],"URL":"https:\/\/doi.org\/10.3390\/ijms19072083","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,7,18]]}}}