{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:24:12Z","timestamp":1787027052647,"version":"build-2736575974"},"reference-count":93,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Plant phenolics are increasingly being investigated for their diverse biological activities, including neuroprotective effects relevant to conditions like Alzheimer\u2019s disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      The neurobiological potential of 37 plant phenolics was screened through a multifaceted approach encompassing\n                      <jats:italic>in vitro<\/jats:italic>\n                      enzyme inhibition and antioxidant assays,\n                      <jats:italic>in vivo<\/jats:italic>\n                      antiamnesic evaluation, and\n                      <jats:italic>in silico<\/jats:italic>\n                      molecular docking and toxicity predictions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The compounds were tested for their cholinesterase (ChE) inhibition potentials, metal-chelation activities, and copper-reducing antioxidant capacities (CUPRACs) using a microtiter assay as well as ferric-reducing antioxidant power assays. Additionally, the\n                      <jats:italic>in silico<\/jats:italic>\n                      ADME, pharmacokinetic, and toxicokinetic profiles of the compounds were predicted using computational platforms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Several compounds exhibited significant inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities. Of these, quercetin was found to be the most active inhibitor, with IC\n                      <jats:sub>50<\/jats:sub>\n                      values of 1.22 \u00b1 0.79\u00a0mM against AChE and 2.51 \u00b1 0.04\u00a0mM against BChE. Some of the other compounds, including caffeic acid (IC\n                      <jats:sub>50<\/jats:sub>\n                      : 3.51 \u00b1 0.62\u00a0mM), apigenin (IC\n                      <jats:sub>50<\/jats:sub>\n                      : 3.52 \u00b1 0.08\u00a0mM), and taxifolin (IC\n                      <jats:sub>50<\/jats:sub>\n                      : 7.18 \u00b1 2.05\u00a0mM), also showed AChE inhibition. Then, oleuropein, rosmarinic acid, gallic acid, epigallocatechin gallate, and 3-hydroxytyrosol were further investigated for their antiamnesic activities using a passive avoidance test in scopolamine-induced mice; our data showed that these compounds were effective considering the latency time of the mice and that 3-hydroxytyrosol showed the highest antiamnesic effect. The dual inhibitory compounds were subjected to molecular docking experiments with ChEs, and the\n                      <jats:italic>in silico<\/jats:italic>\n                      toxicities of three compounds were assessed using the PASS and SwissADME prediction programs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our data provide compelling evidence for the neuroprotective potentials of several plant phenolics. Notably, 3-hydroxytyrosol was identified for the first time as a ChE inhibitor with significant\n                      <jats:italic>in vivo<\/jats:italic>\n                      antiamnesic activity and warrants further investigation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1640034","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T05:34:35Z","timestamp":1759815275000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["3-Hydroxytyrosol as a phenolic cholinesterase inhibitor with antiamnesic activity: a multimethodological study of selected plant phenolics"],"prefix":"10.3389","volume":"16","author":[{"given":"Tugba","family":"Ucar Akyurek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. Sezer","family":"Senol Deniz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ipek","family":"Suntar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gokcen","family":"Eren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onur Kenan","family":"Ulutas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilkay Erdogan","family":"Orhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,7]]},"reference":[{"key":"B1","first-page":"1589","article-title":"To estimate effective antiamyloidogenic property of melatonin and fisetin and their actions to destabilize amyloid fibrils","volume":"30","author":"Aarabi","year":"2017","journal-title":"Pak. J. Pharm. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3659","DOI":"10.1007\/s11356-018-3907-9","article-title":"Curcumin and quercetin synergistically attenuate subacute diazinon\u2013induced inflammation and oxidative neurohepatic damage, and acetylcholinesterase inhibition in albino rats","volume":"26","author":"Abdel-Diam","year":"2019","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1007\/s11064-016-2162-z","article-title":"Quercetin improves neurobehavioral performance through restoration of brain antioxidant status and acetylcholinesterase activity in manganese-treated rats","volume":"42","author":"Adedara","year":"2017","journal-title":"Neurochem. Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1007\/s12272-013-0036-3","article-title":"A review on cholinesterase inhibitors for Alzheimer's disease","volume":"36","author":"Anand","year":"2013","journal-title":"Arch. Pharm. Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1007\/s12640-014-9492-x","article-title":"3,4-Dihydroxyphenylethanol attenuates spatio-cognitive deficits in an Alzheimer's disease mouse model: modulation of the molecular signals in neuronal survival-apoptotic programs","volume":"27","author":"Arunsundar","year":"2015","journal-title":"Neurotox. Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e18261","DOI":"10.1590\/s2175-97902019000218261","article-title":"Effects of gallic acid and physical exercise on passive avoidance memory in male rat","volume":"55","author":"Azadeh","year":"2019","journal-title":"Braz. J. Pharm. Sci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"2719","DOI":"10.1021\/jm901137j","article-title":"New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays","volume":"53","author":"Baell","year":"2010","journal-title":"J. Med. Chem."},{"key":"B8","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/j.bbr.2011.06.007","article-title":"Chronic epigallocatechin-3-gallate ameliorates learning and memory deficits in diabetic rats via modulation of nitric oxide and oxidative stress","volume":"224","author":"Baluchnejadmojarad","year":"2011","journal-title":"Behav. Brain Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"533","DOI":"10.13075\/ijomeh.1896.00283","article-title":"Evaluation of passive avoidance learning and spatial memory in rats exposed to low levels of lead during specific periods of early brain development","volume":"28","author":"Barkur","year":"2015","journal-title":"Int. J. Occup. Environ. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"8167","DOI":"10.1021\/jm501195e","article-title":"Discovery, biological evaluation, and crystal structure of a novel nano-molar selective butyrylcholinesterase inhibitor","volume":"57","author":"Brus","year":"2014","journal-title":"J. Med. Chem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1007\/s00213-014-3728-6","article-title":"Effects of imperatorin on scopolamine-induced cognitive impairment and oxidative stress in mice","volume":"232","author":"Budzynska","year":"2015","journal-title":"Psychopharmacology"},{"key":"B12","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/j.ijbiomac.2020.06.170","article-title":"Inhibition of human islet amyloid polypeptide aggregation and cellular toxicity by oleuropein and derivatives from olive oil","volume":"162","author":"Chaari","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"S141","DOI":"10.1002\/mnfr.200900504","article-title":"Effects of plant-derived polyphenols on TNF-alpha and nitric oxide production induced by advanced glycation endproducts","volume":"54","author":"Chandler","year":"2010","journal-title":"Mol. Nutr. Food Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e14032","DOI":"10.1111\/jfbc.14032","article-title":"Phenolic acids and flavonoids-rich Glechoma hederacea L. (Lamiaceae) water extract against H2O2-induced apoptosis in PC12 cells","volume":"46","author":"Chao","year":"2022","journal-title":"J. Food Biochem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"10282","DOI":"10.1021\/jm300871x","article-title":"Structures of human acetylcholinesterase in complex with pharmacologically important ligands","volume":"55","author":"Cheung","year":"2012","journal-title":"J. Med. Chem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1002\/cmdc.201600182","article-title":"A BOILED-Egg to predict gastrointestinal absorption and brain penetration of small molecules","volume":"11","author":"Daina","year":"2016","journal-title":"ChemMedChem"},{"key":"B17","doi-asserted-by":"publisher","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.2174\/1567205013666160404120542","article-title":"Butyrylcholinesterase as a diagnostic and therapeutic target for Alzheimer's disease","volume":"13","author":"Darvesh","year":"2016","journal-title":"Curr. Alzheimer Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1627","DOI":"10.1007\/s11011-021-00765-w","article-title":"Role of metals in Alzheimer's disease","volume":"36","author":"Das","year":"2021","journal-title":"Metab. Brain Dis."},{"key":"B20","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.pbb.2006.08.007","article-title":"Beneficial effects of galantamine on performance in the object recognition task in Swiss mice: deficits induced by scopolamine and by prolonging the retention interval","volume":"85","author":"De Bruin","year":"2006","journal-title":"Pharmacol. Biochem. Behav."},{"key":"B21","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1186\/s13195-018-0457-9","article-title":"Comparative safety and effectiveness of cholinesterase inhibitors and memantine for Alzheimer's disease: a network meta-analysis of 41 randomized controlled trials","volume":"10","author":"Dou","year":"2018","journal-title":"Alzheimers Res. Ther."},{"key":"B22","doi-asserted-by":"publisher","first-page":"a028035","DOI":"10.1101\/cshperspect.a028035","article-title":"Pathology of neurodegenerative diseases","volume":"9","author":"Dugger","year":"2017","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/0006-2952(61)90145-9","article-title":"A new and rapid colorimetric determination of acetylcholinesterase activity","volume":"7","author":"Ellman","year":"1961","journal-title":"Biochem. Pharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2141","DOI":"10.4103\/1673-5374.310669","article-title":"Apolipoprotein A1, the neglected relative of apolipoprotein E and its potential role in Alzheimer's disease","volume":"16","author":"Endres","year":"2021","journal-title":"Neural Regen. Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"3714","DOI":"10.1021\/jm000942e","article-title":"Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties","volume":"43","author":"Ertl","year":"2000","journal-title":"J. Med. Chem."},{"key":"B26","doi-asserted-by":"publisher","first-page":"104875","DOI":"10.1016\/j.neuint.2020.104875","article-title":"Chitosan-coated rosmarinic acid nanoemulsion nasal administration protects against LPS-induced memory deficit, neuroinflammation, and oxidative stress in Wistar rats","volume":"141","author":"Fachel","year":"2020","journal-title":"Neurochem. Int."},{"key":"B27","doi-asserted-by":"publisher","first-page":"718188","DOI":"10.3389\/fnins.2021.718188","article-title":"Green tea polyphenol epigallocatechin-gallate in amyloid aggregation and neurodegenerative diseases","volume":"15","author":"Fernandes","year":"2021","journal-title":"Front. Neurosci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"35","DOI":"10.2174\/1389557520666200730155928","article-title":"An insight in pathophysiological mechanism of Alzheimer's disease and its management using plant natural products","volume":"21","author":"Firdaus","year":"2021","journal-title":"Mini Rev. Med. Chem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"176","DOI":"10.2478\/s11536-012-0124-7","article-title":"Effects of Rhodiola rosea extract on passive avoidance tests in rats","volume":"8","author":"Getova","year":"2013","journal-title":"Cent. Eur. J. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"441","DOI":"10.3109\/14756366.2015.1036051","article-title":"Acetylcholinesterase and carbonic anhydrase isoenzymes I and II inhibition profiles of taxifolin","volume":"31","author":"Gocer","year":"2016","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.neulet.2008.09.022","article-title":"Neuroprotective effect of hydroxytyrosol and hydroxytyrosol acetate in rat brain slices subjected to hypoxia-reoxygenation","volume":"446","author":"Gonz\u00e1lez-Correa","year":"2008","journal-title":"Neurosci. Lett."},{"key":"B32","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s13311-014-0313-y","article-title":"\u03b2-Amyloid peptides and amyloid plaques in Alzheimer's disease","volume":"12","author":"Gouras","year":"2015","journal-title":"Neurotherapeutics"},{"key":"B33","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1039\/b715668p","article-title":"Scaffold diversity of natural products: inspiration for combinatorial library design","volume":"25","author":"Grabowski","year":"2008","journal-title":"Nat. Prod. Rep."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1698","DOI":"10.3109\/14756366.2015.1135914","article-title":"Rosmarinic acid inhibits some metabolic enzymes including glutathione S-transferase, lactoperoxidase, acetylcholinesterase, butyrylcholinesterase and carbonic anhydrase isoenzymes","volume":"31","author":"Gulcin","year":"2016","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e01831","DOI":"10.1002\/brb3.1831","article-title":"Memantine, donepezil, or combination therapy \u2013 what is the best therapy for Alzheimer's disease? A network meta-analysis","volume":"10","author":"Guo","year":"2020","journal-title":"Brain Behav."},{"key":"B36","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.neulet.2016.04.045","article-title":"Preventive effects of Salvia officinalis L. against learning and memory deficit induced by diabetes in rats: possible hypoglycaemic and antioxidant mechanisms","volume":"622","author":"Hasanein","year":"2016","journal-title":"Neurosci. Lett."},{"key":"B37","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.jep.2004.02.012","article-title":"Galanthamine from snowdrop \u2013 the development of a modern drug against Alzheimer's disease from local Caucasian knowledge","volume":"92","author":"Heinrich","year":"2004","journal-title":"J. Ethnopharmacol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"373","DOI":"10.3389\/fncel.2018.00373","article-title":"Phenolic compounds characteristic of the Mediterranean diet in mitigating microglia-mediated neuroinflammation","volume":"12","author":"Hornedo-Ortega","year":"2018","journal-title":"Front. Cell Neurosci."},{"key":"B39","first-page":"41","article-title":"The effect of oleuropein on working and passive avoidance memory in the pentylenetetrazole-induced seizure animal model","volume":"6","author":"Hosseini","year":"2019","journal-title":"J. Bas. Res. Med. Sci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1186\/s12906-021-03373-4","article-title":"Evaluation of cholinesterase inhibitory and antioxidant activity of Wedelia chinensis and isolation of apigenin as an active compound","volume":"21","author":"Islam","year":"2021","journal-title":"BMC Complement. Med. Ther."},{"key":"B41","doi-asserted-by":"publisher","first-page":"445","DOI":"10.31887\/DCNS.2013.15.4\/hjahn","article-title":"Memory loss in Alzheimer's disease","volume":"15","author":"Jahn","year":"2013","journal-title":"Dialogues Clin. Neurosci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1002\/ptr.2406","article-title":"Inhibition of cholinesterase and amyloid-beta aggregation by resveratrol oligomers from Vitis amurensis","volume":"22","author":"Jang","year":"2008","journal-title":"Phytother. Res."},{"key":"B43","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.ejmech.2009.09.041","article-title":"Structural aspects of flavonoids as inhibitors of human butyrylcholinesterase","volume":"45","author":"Katalini\u0107","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.3390\/biom10101401","article-title":"The role of natural compounds and their nanocarriers in the treatment of CNS inflammation","volume":"10","author":"Khadka","year":"2020","journal-title":"Biomolecules"},{"key":"B45","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.cbi.2009.06.024","article-title":"Cholinesterase inhibitory activities of some flavonoid derivatives and chosen xanthone and their molecular docking studies","volume":"181","author":"Khan","year":"2009","journal-title":"Chem. Biol. Interact."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/antiox11010001","article-title":"Anti-amnesic effects of epigallocatechin gallate on scopolamine\u2013induced learning and memory dysfunction in Sprague\u2013Dawley rats","volume":"11","author":"Kim","year":"2021","journal-title":"Antioxidants (Basel)"},{"key":"B47","doi-asserted-by":"publisher","first-page":"748212","DOI":"10.1155\/2015\/748212","article-title":"Working memory and executive function decline across normal aging, mild cognitive impairment, and Alzheimer's disease","volume":"2015","author":"Kirova","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"B48","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.ijbiomac.2016.11.062","article-title":"Combining in silico and in vitro approaches to evaluate the acetylcholinesterase inhibitory profile of some commercially available flavonoids in the management of Alzheimer's disease","volume":"95","author":"Kuppusamy","year":"2017","journal-title":"Int. J. Biol. Macromol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1987","DOI":"10.3945\/jn.109.109785","article-title":"Green tea (-)-epigallocatechin-3-gallate inhibits beta-amyloid-induced cognitive dysfunction through modification of secretase activity via inhibition of ERK and NF-kappaB pathways in mice","volume":"139","author":"Lee","year":"2009","journal-title":"J. Nutr."},{"key":"B50","doi-asserted-by":"publisher","first-page":"2442","DOI":"10.1016\/j.ijbiomac.2018.09.014","article-title":"Cholinesterases inhibition studies of biological active compounds from the rhizomes of Alpinia officinarum Hance and in silico molecular dynamics","volume":"120","author":"Lee","year":"2018","journal-title":"Int. J. Biol. Macromol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"7225","DOI":"10.3390\/ijms22137225","article-title":"EVOO polyphenols relieve synergistically autophagy dysregulation in a cellular model of Alzheimer\u2019s disease","volume":"22","author":"Leri","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B52","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.addr.2012.09.019","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"64","author":"Lipinski","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"B53","doi-asserted-by":"publisher","first-page":"6336","DOI":"10.1016\/j.bmcl.2013.09.071","article-title":"Gallic acid is the major component of grape seed extract that inhibits amyloid fibril formation","volume":"23","author":"Liu","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"B54","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/B978-0-12-804766-8.00009-1","article-title":"Epidemiology of aging and associated cognitive disorders: prevalence and incidence of Alzheimer's disease and other dementias","volume":"167","author":"Lopez","year":"2019","journal-title":"Handb. Clin. Neurol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1016\/j.foodchem.2012.11.022","article-title":"Neuroprotective effects of oral gallic acid against oxidative stress induced by 6-hydroxydopamine in rats","volume":"138","author":"Mansouri","year":"2013","journal-title":"Food Chem."},{"key":"B56","doi-asserted-by":"publisher","first-page":"2131","DOI":"10.1007\/s11064-021-03351-9","article-title":"Oleuropein protects against cerebral ischemia injury in rats: molecular docking, biochemical and histological findings","volume":"46","author":"Mnafgui","year":"2021","journal-title":"Neurochem. Res."},{"key":"B57","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1176\/ajp.142.1.28","article-title":"Oral physostigmine treatment of patients with Alzheimer's disease","volume":"142","author":"Mohs","year":"1985","journal-title":"Am. J. Psychiatry"},{"key":"B58","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1017\/S1092852920002229","article-title":"Galantamine beyond Alzheimer's disease \u2013 a fact or artefact?","volume":"27","author":"Naguy","year":"2022","journal-title":"CNS Spectr."},{"key":"B59","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.3233\/JAD-171124","article-title":"Diet supplementation with hydroxytyrosol ameliorates brain pathology and restores cognitive functions in a mouse model of amyloid-\u03b2 deposition","volume":"63","author":"Nardiello","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"B60","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1016\/j.nrl.2016.02.016","article-title":"Prevalence and incidence of Alzheimer's disease in Europe: a meta-analysis","volume":"32","author":"Niu","year":"2017","journal-title":"Neurologia"},{"key":"B61","doi-asserted-by":"publisher","first-page":"1090","DOI":"10.3390\/nu12041090","article-title":"Comparative kinetics of acetyl- and butyryl-cholinesterase inhibition by green tea catechins: relevance to the symptomatic treatment of Alzheimer's disease","volume":"12","author":"Okello","year":"2020","journal-title":"Nutrients"},{"key":"B62","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.fitote.2018.05.011","article-title":"Biophenols: enzymes (\u03b2-secretase, cholinesterases, histone deacetylase and tyrosinase) inhibitors from olive (Olea europaea L.)","volume":"128","author":"Omar","year":"2018","journal-title":"Fitoterapia"},{"key":"B63","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.2174\/1570159X18666201119153807","article-title":"Cholinesterase inhibitory potential of quercetin towards Alzheimer's disease \u2013 a promising natural molecule or fashion of the day? A narrowed review","volume":"19","author":"Orhan","year":"2021","journal-title":"Curr. Neuropharmacol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.jep.2008.12.026","article-title":"Appraisal of scopolamine-induced antiamnesic effect in mice and in vitro antiacetylcholinesterase and antioxidant activities of some traditionally used Lamiaceae plants","volume":"122","author":"Orhan","year":"2009","journal-title":"J. Ethnopharmacol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/j.fitote.2013.09.012","article-title":"Rosmarinus officinalis L. leaf extract improves memory impairment and affects acetylcholinesterase and butyrylcholinesterase activities in rat brain","volume":"91","author":"Ozarowski","year":"2013","journal-title":"Fitoterapia"},{"key":"B66","doi-asserted-by":"publisher","first-page":"493","DOI":"10.3233\/JAD-180802","article-title":"Understanding the amyloid hypothesis in Alzheimer's disease","volume":"68","author":"Paroni","year":"2019","journal-title":"J. Alzheimers Dis."},{"key":"B67","doi-asserted-by":"publisher","first-page":"1681","DOI":"10.1111\/jphp.12081","article-title":"Nature as a source of metabolites with cholinesterase-inhibitory activity: an approach to Alzheimer's disease treatment","volume":"65","author":"Pinho","year":"2013","journal-title":"J. Pharm. Pharmacol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1023\/A:1015810312465","article-title":"Predicting skin permeability","volume":"9","author":"Potts","year":"1992","journal-title":"Pharm. Res."},{"key":"B69","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1007\/s12576-016-0437-4","article-title":"Neuroprotective effects of oleuropein against cognitive dysfunction induced by colchicine in hippocampal CA1 area in rats","volume":"66","author":"Pourkhodadad","year":"2016","journal-title":"J. Physiol. Sci."},{"key":"B70","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.1111\/jphp.12807","article-title":"Antioxidant activity of oleuropein and semisynthetic acetyl-derivatives determined by measuring malondialdehyde in rat brain","volume":"69","author":"Rizzo","year":"2017","journal-title":"J. Pharm. Pharmacol."},{"key":"B71","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.bbagen.2009.01.007","article-title":"Olive phenols efficiently inhibit the oxidation of serum albumin-bound linoleic acid and butyrylcholine esterase","volume":"1790","author":"Roche","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"B72","doi-asserted-by":"publisher","first-page":"4353","DOI":"10.3390\/ijms24054353","article-title":"Molecular mechanisms of the protective effects of olive leaf polyphenols against Alzheimer's disease","volume":"24","author":"Romero-M\u00e1rquez","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B73","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.22038\/ijbms.2018.31230.7523","article-title":"Effect of gallic acid on chronic restraint stress-induced anxiety and memory loss in male BALB\/c mice","volume":"21","author":"Salehi","year":"2018","journal-title":"Iran. J. Basic Med. Sci."},{"key":"B74","doi-asserted-by":"publisher","first-page":"978","DOI":"10.3923\/pjbs.2014.978.990","article-title":"Gallic acid improves cognitive, hippocampal long-term potentiation deficits and brain damage induced by chronic cerebral hypoperfusion in rats","volume":"17","author":"Sarkaki","year":"2014","journal-title":"Pak. J. Biol. Sci."},{"key":"B75","doi-asserted-by":"publisher","first-page":"264","DOI":"10.2174\/1568026619666190128125912","article-title":"Target enzyme in Alzheimer's disease: acetylcholinesterase inhibitors","volume":"19","author":"Saxena","year":"2019","journal-title":"Curr. Top. Med. Chem."},{"key":"B76","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.phytochem.2016.10.012","article-title":"Selective in vitro and in silico butyrylcholinesterase inhibitory activity of diterpenes and rosmarinic acid isolated from Perovskia atriplicifolia Benth. and Salvia glutinosa L","volume":"133","author":"Senol","year":"2017","journal-title":"Phytochemistry"},{"key":"B77","doi-asserted-by":"publisher","first-page":"123452","DOI":"10.1016\/j.saa.2023.123452","article-title":"Inhibition mechanism of fisetin on acetylcholinesterase and its synergistic effect with galantamine","volume":"305","author":"Shi","year":"2024","journal-title":"Spectrochim. Acta A Mol. Biomol. Spectrosc."},{"key":"B78","doi-asserted-by":"publisher","first-page":"mfac018","DOI":"10.1093\/mtomcs\/mfac018","article-title":"Copper-mediated \u03b2-amyloid toxicity and its chelation therapy in Alzheimer's disease","volume":"14","author":"Singh","year":"2022","journal-title":"Metallomics"},{"key":"B79","doi-asserted-by":"publisher","first-page":"2722","DOI":"10.3390\/ijms24032722","article-title":"Natural inhibitors of cholinesterases: chemistry, structure\u2013activity and methods of their analysis","volume":"24","author":"Smyrska-Wieleba","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B80","doi-asserted-by":"publisher","first-page":"0125","DOI":"10.5560\/ZNC.2013.68c0125","article-title":"Anticholinesterase activity of phenolic acids and their derivatives","volume":"68","author":"Szwajgier","year":"2013","journal-title":"Z. Naturforsch C"},{"key":"B81","doi-asserted-by":"publisher","first-page":"690","DOI":"10.5604\/12321966.1185777","article-title":"Anticholinesterase activity of selected phenolic acids and flavonoids \u2013 interaction testing in model solutions","volume":"22","author":"Szwajgier","year":"2015","journal-title":"Ann. Agric. Environ. Med."},{"key":"B82","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1016\/j.ejmech.2017.07.026","article-title":"Structure\u2013activity relations of rosmarinic acid derivatives for the amyloid \u03b2 aggregation inhibition and antioxidant properties","volume":"138","author":"Taguchi","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"B83","doi-asserted-by":"publisher","first-page":"12877","DOI":"10.1074\/jbc.RA118.002038","article-title":"Epigallocatechin-3-gallate remodels apolipoprotein A-I amyloid fibrils into soluble oligomers in the presence of heparin","volume":"293","author":"Townsend","year":"2018","journal-title":"J. Biol. Chem."},{"key":"B84","doi-asserted-by":"publisher","first-page":"196","DOI":"10.5114\/fn.2023.126893","article-title":"Protective effects of fisetin in an A\u03b21\u201342-induced rat model of Alzheimer's disease","volume":"61","author":"Wang","year":"2023","journal-title":"Folia Neuropathol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1016\/j.pharep.2017.03.018","article-title":"The mechanism of neuroprotective action of natural compounds","volume":"69","author":"Wasik","year":"2017","journal-title":"Pharmacol. Rep."},{"key":"B86","doi-asserted-by":"publisher","first-page":"111497","DOI":"10.1016\/j.foodres.2022.111497","article-title":"The inhibition mechanism of polyphenols from Phyllanthus emblica Linn. fruit on acetylcholinesterase: an interaction, kinetic, spectroscopic, and molecular simulation study","volume":"158","author":"Wu","year":"2022","journal-title":"Food Res. Int."},{"key":"B87","doi-asserted-by":"publisher","first-page":"2582","DOI":"10.1039\/c4fo00287c","article-title":"Inhibition of flavonoids on acetylcholine esterase: binding and structure\u2013activity relationship","volume":"5","author":"Xie","year":"2014","journal-title":"Food Funct."},{"key":"B88","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1002\/med.21745","article-title":"Structure and therapeutic uses of butyrylcholinesterase: application in detoxification, Alzheimer's disease, and fat metabolism","volume":"41","author":"Xing","year":"2021","journal-title":"Med. Res. Rev."},{"key":"B89","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/j.fshw.2021.12.006","article-title":"Multifaceted neuroprotective effects of (-)-epigallocatechin-3-gallate (EGCG) in Alzheimer\u2019s disease: an overview of pre-clinical studies focused on beta-amyloid peptide","volume":"11","author":"Youn","year":"2022","journal-title":"Food Sci. Hum. Wellness"},{"key":"B90","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1017\/S0007114515000884","article-title":"Hydroxytyrosol improves mitochondrial function and reduces oxidative stress in the brain of db\/db mice: role of AMP-activated protein kinase activation","volume":"113","author":"Zheng","year":"2015","journal-title":"Br. J. Nutr."},{"key":"B91","doi-asserted-by":"publisher","first-page":"112719","DOI":"10.1016\/j.biopha.2022.112719","article-title":"Therapeutic targets of neuroprotection and neurorestoration in ischemic stroke: applications for natural compounds from medicinal herbs","volume":"148","author":"Zhu","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"B92","first-page":"1187","article-title":"Induced-fit docking and virtual screening for 8-hydroxy-3-methoxy-5H-pyrido[2,1-c]pyrazin-5-one derivatives as inducible nitric oxide synthase inhibitors","volume":"6","author":"Zou","year":"2014","journal-title":"J. Chem. Pharm. Res."},{"key":"B93","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.niox.2022.07.007","article-title":"Epigallocatechin gallate is a potent inhibitor of cystathionine beta-synthase: structure\u2013activity relationship and mechanism of action","volume":"128","author":"Zuhra","year":"2022","journal-title":"Nitric Oxide"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1640034\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T05:34:36Z","timestamp":1759815276000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1640034\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,7]]},"references-count":93,"alternative-id":["10.3389\/fphar.2025.1640034"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1640034","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,7]]},"article-number":"1640034"}}