{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T04:03:13Z","timestamp":1784952193195,"version":"3.55.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T00:00:00Z","timestamp":1753228800000},"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. Neurosci."],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a devastating neurodegenerative disorder characterized by cognitive decline and neuronal damage. Cadmium exposure has been implicated in AD pathogenesis. This study aimed to investigate the potential therapeutic effects of Ebixa (memantine), <jats:italic>Ginkgo biloba<\/jats:italic>, and selenium in a cadmium-induced rat model of AD. Adult male Wistar rats were divided into six groups: control, control + Ginkgo-treated, cadmium chloride (CdCl2), CdCl2\u202f+\u202fEbixa-treated, CdCl2\u202f+\u202fGinkgo, and CdCl2\u202f+\u202fGinkgo + Selenium. Behavioral tests, including the Morris water maze and passive avoidance learning, were conducted. Additionally, biochemical analysis of acetylcholine (Ach), choline acetyltransferase (AchT), and acetylcholinesterase (AChE) levels in brain homogenates was performed. Histological sections of the cerebral cortex, cerebellum, and medulla were examined. Apoptotic assessment was conducted using the TUNEL assay. CdCl2 exposure resulted in cognitive deficits, reduced Ach levels, and neuronal damage, mirroring AD-like characteristics. Ebixa treatment improved spatial memory behavior as well as Ach, AchT and AChE levels in the brain. <jats:italic>Ginkgo biloba<\/jats:italic> and selenium co-administration increased the number of crossings in the Morris water maze test, suggesting memory preservation. Additionally, <jats:italic>Ginkgo biloba<\/jats:italic> exhibited potential cholinergic system protective effects. Histological analysis revealed neuroprotection in the cerebral cortex, cerebellum, and medulla. TUNEL assays demonstrated anti-apoptotic effects of both Ebixa and the combination of Ginkgo and selenium. Ebixa, <jats:italic>Ginkgo biloba<\/jats:italic>, and selenium showed promise in mitigating cognitive deficits and preserving neuronal structures in a CdCl2-induced AD manifestation in rats. These findings provide insights into potential therapeutic strategies for AD and warrant further investigation.<\/jats:p>","DOI":"10.3389\/fnins.2025.1634601","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T13:08:26Z","timestamp":1753276106000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Potential therapeutic effects of Ebixa, Ginkgo biloba, and selenium in a cadmium chloride-induced Alzheimer\u2019s disease manifestations in rats"],"prefix":"10.3389","volume":"19","author":[{"given":"Afaf","family":"Alrikabi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wasayf","family":"Allahyani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amjad","family":"Shaghath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jawaher","family":"Alrashdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reem","family":"Almoqhem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fawaz","family":"Alasmari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walid","family":"Al-Qerem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gadah","family":"Albasher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,23]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"5104","DOI":"10.1007\/s12011-021-03073-7","article-title":"Resveratrol-selenium nanoparticles alleviate neuroinflammation and neurotoxicity in a rat model of Alzheimer\u2019s disease by regulating Sirt1\/miRNA-134\/GSK3\u03b2 expression","volume":"200","author":"Abozaid","year":"2022","journal-title":"Biol. Trace Elem. Res."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"100331","DOI":"10.1016\/j.prmcm.2023.100331","article-title":"Ginkgo biloba: an updated review on pharmacological, ethnobotanical, and phytochemical studies","volume":"9","author":"Akaberi","year":"2023","journal-title":"Pharmacol. Res. Mod. Chin. Med."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1007\/s40610-022-00148-9","article-title":"Significance of choline acetyltransferase enzyme in tackling neurodegenerative diseases","volume":"8","author":"Bagwe","year":"2022","journal-title":"Curr. Mol. Biol. Rep."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1369373","DOI":"10.3389\/fnut.2024.1369373","article-title":"The effect of selenium supplementation on oxidative stress, clinical and physiological symptoms in patients with migraine: a double-blinded randomized clinical trial","volume":"11","author":"Balali","year":"2024","journal-title":"Front. Nutr."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"3993","DOI":"10.3390\/molecules28103993","article-title":"The potential of Ginkgo biloba as a source of biologically active compounds\u2014a review of the recent literature and patents","volume":"28","author":"Biernacka","year":"2023","journal-title":"Molecules"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1080\/10590500701569414","article-title":"Ginkgo biloba leave extract: biological, medicinal, and toxicological effects","volume":"25","author":"Chan","year":"2007","journal-title":"J. Environ. Sci. Health C"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"e16050","DOI":"10.14814\/phy2.16050","article-title":"Anti-oxidative and anti-inflammatory effects of Ginkgo biloba extract (EGb761) on hindlimb skeletal muscle ischemia\u2013reperfusion injury in rats","volume":"12","author":"Chen","year":"2024","journal-title":"Physiol. Rep."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"8288818","DOI":"10.1155\/2022\/8288818","article-title":"Ginkgo biloba: a treasure of functional phytochemicals with multimedicinal applications","volume":"2022","author":"Das","year":"2022","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"159950","DOI":"10.1016\/j.scitotenv.2022.159950","article-title":"Long-term cadmium exposure impairs cognitive function by activating lnc-Gm10532\/m6A\/FIS1 axis-mediated mitochondrial fission and dysfunction","volume":"858","author":"Deng","year":"2023","journal-title":"Sci. Total Environ."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"279","DOI":"10.3390\/antiox9040279","article-title":"Ginkgo biloba prevents oxidative stress-induced apoptosis blocking p53 activation in neuroblastoma cells","volume":"9","author":"Di Meo","year":"2020","journal-title":"Antioxidants"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"835","DOI":"10.2174\/1568026615666150827094936","article-title":"Potential roles of selenium and selenoproteins in the prevention of Alzheimer's disease","volume":"16","author":"Du","year":"2016","journal-title":"Curr. Top. Med. Chem."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1177\/1091581820930651","article-title":"Cadmium chloride induces memory deficits and hippocampal damage by activating the JNK\/p66Shc\/NADPH oxidase axis","volume":"39","author":"El-Kott","year":"","journal-title":"Int. J. Toxicol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1007\/s11064-019-02911-4","article-title":"Kaempferol protects against cadmium chloride-induced memory loss and hippocampal apoptosis by increased intracellular glutathione stores and activation of PTEN\/AMPK induced inhibition of Akt\/mTOR signaling","volume":"45","author":"El-Kott","year":"","journal-title":"Neurochem. Res."},{"key":"ref14","first-page":"233","article-title":"Neuroprotective effects of selenium and Ginkgo biloba extract (EGb761) against ischemia and reperfusion injury in rat brain","volume":"13","author":"Erbil","year":"2008","journal-title":"Neurosciences"},{"key":"ref15","first-page":"1471","article-title":"Ginkgo biloba extract improves cognitive function and increases neurogenesis by reducing a\u03b2 pathology in 5\u00d7 FAD mice","volume":"13","author":"Ge","year":"2021","journal-title":"Am. J. Transl. Res."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.jneumeth.2005.06.009","article-title":"ELISA methods to measure cholinergic markers and nerve growth factor receptors in cortex, hippocampus, prefrontal cortex, and basal forebrain from rat brain","volume":"150","author":"Gearhart","year":"2006","journal-title":"J. Neurosci. Methods"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"121","DOI":"10.5681\/bi.2011.016","article-title":"Effect of vitamin e and selenium supplement on paraoxonase-1 activity, oxidized low density lipoprotein and antioxidant defense in diabetic rats","volume":"1","author":"Ghaffari","year":"2011","journal-title":"Bioimpacts"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"272","DOI":"10.3109\/01480545.2015.1092042","article-title":"Cadmium exposure during lactation causes learning and memory-impairment in F1 generation mice: amelioration by quercetin","volume":"39","author":"Halder","year":"2016","journal-title":"Drug Chem. Toxicol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"111636","DOI":"10.1016\/j.fct.2020.111636","article-title":"Caffeic acid phenethyl ester reversed cadmium-induced cell death in hippocampus and cortex and subsequent cognitive disorders in mice: involvements of AMPK\/SIRT1 pathway and amyloid-tau-neuroinflammation axis","volume":"144","author":"Hao","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.bbr.2019.03.001","article-title":"Neuroprotective effect of tanshinone IIA-incubated mesenchymal stem cells on A\u03b225-35-induced neuroinflammation","volume":"365","author":"Huang","year":"2019","journal-title":"Behav. Brain Res."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"781","DOI":"10.21608\/ejchem.2020.46027.2943","article-title":"Balanites aegyptiaca extract to treat risk factors of Alzheimer\u2019s disease: an in vitro study","volume":"64","author":"Ibrahim","year":"2021","journal-title":"Egypt. J. Chem."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1725638","DOI":"10.1155\/2023\/1725638","article-title":"Effects of Phoenix dactylifera against Streptozotocin-Aluminium chloride induced Alzheimer\u2019s rats and their in silico study","volume":"2023","author":"Ismail","year":"2023","journal-title":"Biomed. Res. Int."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"49","DOI":"10.3969\/j.issn.1673-5374.2013.01.006","article-title":"Chronic pre-treatment with memantine prevents amyloid-beta protein-mediated long-term potentiation disruption","volume":"8","author":"Li","year":"2013","journal-title":"Neural Regen. Res."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"123740","DOI":"10.1016\/j.ijbiomac.2023.123740","article-title":"Selenium supplementation enhanced the expression of selenoproteins in hippocampus and played a neuroprotective role in LPS-induced neuroinflammation","volume":"234","author":"Liang","year":"2023","journal-title":"Int. J. Biol. Macromol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"127599","DOI":"10.1016\/j.jtemb.2025.127599","article-title":"Selenium ameliorates cognitive impairment through activating BDNF\/TrkB pathway","volume":"88","author":"Liu","year":"2025","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1046\/j.1365-2125.1999.00026.x","article-title":"Acetylcholinesterase inhibitors in Alzheimer\u2019s disease","volume":"48","author":"Mcgleenon","year":"1999","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1016\/j.foodchem.2011.11.095","article-title":"The effects of pre-treatment with vitamin B6 on memory retrieval in rats","volume":"132","author":"Nassiri-Asl","year":"2012","journal-title":"Food Chem."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"156327","DOI":"10.1016\/j.phymed.2024.156327","article-title":"Ginkgo biloba extract EGb 761\u00ae ameliorates cognitive impairment and alleviates TNF\u03b1 response in 5xFAD Alzheimer\u2018s disease model mice","volume":"136","author":"Nguyen","year":"2025","journal-title":"Phytomedicine"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"775034","DOI":"10.3389\/fphar.2021.775034","article-title":"The use of Ginkgo biloba L. as a neuroprotective agent in the Alzheimer\u2019s disease","volume":"12","author":"Nowak","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1046\/j.1440-1827.1999.00977.x","article-title":"Choline acetyltransferase: the structure, distribution and pathologic changes in the central nervous system","volume":"49","author":"Oda","year":"1999","journal-title":"Pathol. Int."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.jalz.2012.11.007","article-title":"The global prevalence of dementia: a systematic review and metaanalysis","volume":"9","author":"Prince","year":"2013","journal-title":"Alzheimers Dement."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"e6958","DOI":"10.7759\/cureus.6958","article-title":"The neuroprotective effects of exercise on cognitive decline: a preventive approach to Alzheimer disease","volume":"12","author":"Rashid","year":"2020","journal-title":"Cureus"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1007\/s40120-022-00338-8","article-title":"Alzheimer\u2019s disease: epidemiology and clinical progression","volume":"11","author":"Tahami Monfared","year":"2022","journal-title":"Neurol. Ther."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"922","DOI":"10.3390\/molecules30040922","article-title":"Promising natural remedies for Alzheimer\u2019s disease therapy","volume":"30","author":"Thawabteh","year":"2025","journal-title":"Molecules"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1186\/s12877-024-05000-6","article-title":"Association of dietary selenium intake and all-cause mortality of Parkinson\u2019s disease and its interaction with blood cadmium level: a retrospective cohort study","volume":"24","author":"Tu","year":"2024","journal-title":"BMC Geriatr."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"11795735211029113","DOI":"10.1177\/11795735211029113","article-title":"The state of the art on acetylcholinesterase inhibitors in the treatment of Alzheimer\u2019s disease","volume":"13","author":"Vecchio","year":"2021","journal-title":"J. Cent. Nerv. Syst. Dis."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1038\/nprot.2006.116","article-title":"Morris water maze: procedures for assessing spatial and related forms of learning and memory","volume":"1","author":"Vorhees","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/0091-3057(91)90597-U","article-title":"Effects of an extract of Ginkgo biloba on learning and memory in mice","volume":"38","author":"Winter","year":"1991","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"30557","DOI":"10.1021\/acsami.2c06283","article-title":"Multifunctional selenium nanoparticles with different surface modifications ameliorate neuroinflammation through the gut microbiota-NLRP3 inflammasome-brain Axis in APP\/PS1 mice","volume":"14","author":"Yang","year":"2022","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1016\/j.bbadis.2007.09.004","article-title":"Selenium effectively inhibits ROS-mediated apoptotic neural precursor cell death in vitro and in vivo in traumatic brain injury","volume":"1772","author":"Yeo","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"106168","DOI":"10.1016\/j.jff.2024.106168","article-title":"Ginkgo biloba extract (EGb761) inhibits autophagy and apoptosis in a rat model of vascular dementia via the AMPK-mTOR signalling pathway","volume":"116","author":"Yin","year":"2024","journal-title":"J. Funct. Foods"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"2746","DOI":"10.3390\/pharmaceutics15122746","article-title":"Ginkgo biloba extract drives gut flora and microbial metabolism variation in a mouse model of Alzheimer\u2019s disease","volume":"15","author":"Yu","year":"2023","journal-title":"Pharmaceutics"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"578101","DOI":"10.1016\/j.jneuroim.2023.578101","article-title":"Ginkgo biloba extract (EGb-761) confers neuroprotection against ischemic stroke by augmenting autophagic\/lysosomal signaling pathway","volume":"382","author":"Zang","year":"2023","journal-title":"J. Neuroimmunol."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1197459","DOI":"10.3389\/fnhum.2023.1197459","article-title":"The cerebellum and cognitive neural networks","volume":"17","author":"Zhang","year":"2023","journal-title":"Front. Hum. Neurosci."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2022\/2408598","article-title":"Ginkgo Biloba extract reduces cardiac and brain inflammation in rats fed a HFD and exposed to chronic mental stress through NF-\u03baB inhibition","volume":"2022","author":"Zhang","year":"2022","journal-title":"Mediat. Inflamm."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"390","DOI":"10.5607\/en.2019.28.3.390","article-title":"Memantine improves cognitive function and alters hippocampal and cortical proteome in triple transgenic mouse model of Alzheimer's disease","volume":"28","author":"Zhou","year":"2019","journal-title":"Exp. Neurobiol."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"4003","DOI":"10.1038\/s41467-024-48376-0","article-title":"Cerebellar Purkinje cells combine sensory and motor information to predict the sensory consequences of active self-motion in macaques","volume":"15","author":"Zobeiri","year":"2024","journal-title":"Nat. Commun."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2025.1634601\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T13:08:28Z","timestamp":1753276108000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2025.1634601\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,23]]},"references-count":47,"alternative-id":["10.3389\/fnins.2025.1634601"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2025.1634601","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,23]]},"article-number":"1634601"}}