{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T15:51:22Z","timestamp":1790265082697,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,29]],"date-time":"2022-10-29T00:00:00Z","timestamp":1667001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007414","name":"Deanship of Scientific Research, Qassim University, Saudi Arabia","doi-asserted-by":"publisher","award":["10223-pharmacy-2020-1-3-I"],"award-info":[{"award-number":["10223-pharmacy-2020-1-3-I"]}],"id":[{"id":"10.13039\/501100007414","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Cancer chemotherapy-induced cognitive impairment (chemobrain) is a major complication that affects the prognosis of therapy. Our study evaluates the nootropic-like activity of levetiracetam (LEVE) against doxorubicin (DOX)-induced memory defects using in vivo and molecular modelling. Rats were treated with LEVE (100 and 200 mg\/kg, 30 days) and chemobrain was induced by four doses of DOX (2 mg\/kg, i.p.). Spatial memory parameters were evaluated using an elevated plus maze (EPM) and Y-maze. Additionally, acetylcholinesterase (AChE) and the neuroinflammatory biomarkers cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), nuclear factor-\u03baB (NF-\u03baB), and tumor necrosis factor-alpha (TNF-\u03b1) were analyzed using brain homogenate. PharmMapper was used for inverse docking and AutoDock Vina was used for molecular docking. LEVE treatment significantly diminished the DOX-induced memory impairment parameters in both the EPM and Y-maze. In addition, the drug treatment significantly reduced AChE, COX-2, PGE2, NF-\u03baB, and TNF-\u03b1 levels compared to DOX-treated animals. The inverse docking procedures resulted in the identification of AChE as the potential target. Further molecular modelling studies displayed interactions with residues Gly118, Gly119, and Ser200, critical for the hydrolysis of ACh. Analysis of the results suggested that administration of LEVE improved memory-related parameters in DOX-induced animals. The \u2018nootropic-like\u2019 activity could be related to diminished AChE and neuroinflammatory mediator levels.<\/jats:p>","DOI":"10.3390\/molecules27217364","type":"journal-article","created":{"date-parts":[[2022,10,30]],"date-time":"2022-10-30T09:01:42Z","timestamp":1667120502000},"page":"7364","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Levetiracetam Ameliorates Doxorubicin-Induced Chemobrain by Enhancing Cholinergic Transmission and Reducing Neuroinflammation Using an Experimental Rat Model and Molecular Docking Study"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8440-8366","authenticated-orcid":false,"given":"Vasudevan","family":"Mani","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7255-5254","authenticated-orcid":false,"given":"Minhajul","family":"Arfeen","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Imam","family":"Rabbani","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Shariq","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5803-1227","authenticated-orcid":false,"given":"Palanisamy","family":"Amirthalingam","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk 47512, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1093\/annonc\/mdw604","article-title":"Causes of death among cancer patients","volume":"28","author":"Zaorsky","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13","DOI":"10.31557\/APJCP.2020.21.1.13","article-title":"Bibliographic analysis of oral precancer and cancer research papers from Saudi Arabia","volume":"21","author":"Patil","year":"2020","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.15537\/smj.2018.12.23348","article-title":"Trends in the incidence and mortality of cancer in Saudi Arabia","volume":"39","author":"Althubiti","year":"2018","journal-title":"Saudi Med. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1111\/jphp.12539","article-title":"Increasing role of the cancer chemotherapeutic doxorubicin in cellular metabolism","volume":"68","author":"Meredith","year":"2016","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"172818","DOI":"10.1016\/j.ejphar.2019.172818","article-title":"Effects of doxorubicin on the heart: From molecular mechanisms to intervention strategies","volume":"866","author":"Prathumsap","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s11064-020-03164-2","article-title":"C-phycocyanin mitigates cognitive impairment in doxorubicin-induced chemobrain: Impact on neuroinflammation, oxidative stress, and brain mitochondrial and synaptic alterations","volume":"46","author":"Wang","year":"2021","journal-title":"Neurochem. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"673340","DOI":"10.3389\/fonc.2021.673340","article-title":"Doxorubicin-induced cognitive impairment: The mechanistic insights","volume":"1","author":"Du","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/978-1-4419-6306-2_19","article-title":"Chemo brain (chemo fog) as a potential side effect of doxorubicin administration: Role of cytokine-induced, oxidative\/nitrosative stress in cognitive dysfunction","volume":"678","author":"Aluise","year":"2010","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"119078","DOI":"10.1016\/j.lfs.2021.119078","article-title":"Berberine ameliorates doxorubicin-induced cognitive impairment (chemobrain) in rats","volume":"269","author":"Shaker","year":"2021","journal-title":"Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1007\/s00280-019-03881-8","article-title":"Spatial memory deficits in mice induced by chemotherapeutic agents are prevented by acetylcholinesterase inhibitors","volume":"84","author":"Philpot","year":"2019","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"287","DOI":"10.2165\/11319230-000000000-00000","article-title":"Piracetam and piracetam-like drugs: From basic science to novel clinical applications to CNS disorders","volume":"70","author":"Malykh","year":"2010","journal-title":"Drugs"},{"key":"ref_12","first-page":"2174","article-title":"Investigating neuroprotective potential of berberine, levetiracetam and their combination in the management of Alzheimer\u2019s disease utilizing drug repurposing strategy","volume":"10","author":"Singh","year":"2021","journal-title":"Curr. Rev. Clin. Exp. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.nlm.2013.02.001","article-title":"Effects of levetiracetam, an antiepileptic drug, on memory impairments associated with aging and Alzheimer\u2019s disease in mice","volume":"102","author":"Devi","year":"2013","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.schres.2017.06.027","article-title":"Treatment with levetiracetam improves cognition in a ketamine rat model of schizophrenia","volume":"193","author":"Koh","year":"2018","journal-title":"Schizophr. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"108358","DOI":"10.1016\/j.yebeh.2021.108358","article-title":"Effect of valproate and add-on levetiracetam on inflammatory biomarkers in children with epilepsy","volume":"125","author":"Labh","year":"2021","journal-title":"Epilepsy Behav."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"113118","DOI":"10.1016\/j.expneurol.2019.113118","article-title":"Doxorubicin and cisplatin-induced cognitive impairment: The possible mechanisms and interventions","volume":"324","author":"Ongnok","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Yoshizaki, K., Asai, M., and Hara, T. (2020). High-fat diet enhances working memory in the Y-maze test in male C57BL\/6J mice with less anxiety in the elevated plus maze test. Nutrients, 12.","DOI":"10.3390\/nu12072036"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.lfs.2017.05.013","article-title":"Ciproxifan improves cholinergic transmission, attenuates neuroinflammation and oxidative stress but does not reduce amyloid level in transgenic mice","volume":"180","author":"Mani","year":"2017","journal-title":"Life Sci."},{"key":"ref_19","first-page":"9660","article-title":"Ameliorative effect of metformin on cyclophosphamide-induced memory impairment in mice","volume":"23","author":"Alhowail","year":"2019","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00280-019-03827-0","article-title":"Chemotherapy and cognition: Comprehensive review on doxorubicin-induced chemobrain","volume":"84","author":"Esmat","year":"2019","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"173078","DOI":"10.1016\/j.ejphar.2020.173078","article-title":"Doxorubicin chemotherapy-induced \u201cchemo-brain\u201d: Meta-analysis","volume":"881","author":"Eide","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuro.2021.04.003","article-title":"Protective effect of nanocurcumin against neurotoxicity induced by doxorubicin in rat\u2019s brain","volume":"85","author":"Khadrawy","year":"2021","journal-title":"Neurotoxicology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"613","DOI":"10.14348\/molcells.2017.0096","article-title":"Molecular and cellular basis of neurodegeneration in Alzheimer\u2019s disease","volume":"40","author":"Jeong","year":"2017","journal-title":"Mol. Cells."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1177\/0269881118805496","article-title":"Cognitive improvement of acetylcholinesterase inhibitors in schizophrenia","volume":"32","author":"Santos","year":"2018","journal-title":"J Psychopharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1186\/s12974-019-1575-4","article-title":"Poldip2 mediates blood-brain barrier disruption in a model of sepsis-associated encephalopathy","volume":"16","author":"Kikuchi","year":"2019","journal-title":"J. Neuroinflammation."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.neulet.2016.05.019","article-title":"Psychotropic drugs attenuate lipopolysaccharide-induced hypothermia by altering hypothalamic levels of inflammatory mediators in rats","volume":"626","author":"Nassar","year":"2016","journal-title":"Neurosci. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/s10571-019-00749-6","article-title":"Geniposide alleviates traumatic brain injury in rats via anti-inflammatory effect and MAPK\/NF-\u03baB inhibition","volume":"40","author":"Yuan","year":"2020","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_28","first-page":"5007","article-title":"Study on the mechanism of JAK2\/STAT3 signaling pathway-mediated inflammatory reaction after cerebral ischemia","volume":"17","author":"Wu","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9809","DOI":"10.3390\/ijms15069809","article-title":"Inhibitors of acetylcholinesterase and butyrylcholinesterase meet immunity","volume":"15","author":"Pohanka","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.neuropharm.2005.10.013","article-title":"Anti-inflammatory properties of cholinergic up-regulation: A new role for acetylcholinesterase inhibitors","volume":"50","author":"Nizri","year":"2006","journal-title":"Neuropharmacology"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"De Boer, D., Nguyen, N., Mao, J., Moore, J., and Sorin, E.J. (2021). A comprehensive review of cholinesterase modeling and simulation. Biomolecules, 11.","DOI":"10.3390\/biom11040580"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10572","DOI":"10.1021\/ja020243m","article-title":"Role of the catalytic triad and oxyanion hole in acetylcholinesterase catalysis:\u2009 An ab initio QM\/MM study","volume":"124","author":"Zhang","year":"2002","journal-title":"J. Am. Chem. Soc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.jsps.2022.03.016","article-title":"Sukkari dates seed improves type-2 diabetes mellitus-induced memory impairment by reducing blood glucose levels and enhancing brain cholinergic transmission: In vivo and molecular modeling studies","volume":"30","author":"Mani","year":"2022","journal-title":"Saudi Pharm. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2738","DOI":"10.1016\/j.sjbs.2021.12.060","article-title":"Aqueous Ajwa dates seeds extract improves memory impairment in type-2 diabetes mellitus rats by reducing blood glucose levels and enhancing brain cholinergic transmission","volume":"29","author":"Mani","year":"2022","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"101","DOI":"10.21315\/mjms2017.24.5.11","article-title":"Sample size calculation in animal studies using resource equation approach","volume":"24","author":"Arifin","year":"2017","journal-title":"Malays. J. Med. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5727","DOI":"10.1007\/s12035-017-0797-7","article-title":"Astaxanthin ameliorates doxorubicin-induced cognitive impairment (chemobrain) in experimental rat model: Impact on oxidative, inflammatory, and apoptotic machineries","volume":"55","author":"Wahdan","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_37","first-page":"FF01","article-title":"Add-on effect of levetiracetam on cognitive activity of carbamazepine and topiramate treated healthy rats","volume":"9","author":"Dhande","year":"2015","journal-title":"J. Clin. Diagn. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1249\/MSS.0000000000002294","article-title":"Effects of exercise training on anxious-depressive-like behavior in Alzheimer rat","volume":"52","author":"Wu","year":"2020","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"395","DOI":"10.3389\/fphar.2019.00395","article-title":"Apelin-13 suppresses neuroinflammation against cognitive deficit in a streptozotocin-induced rat model of Alzheimer\u2019s disease through activation of BDNF-TrkB signaling pathway","volume":"10","author":"Luo","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"103950","DOI":"10.1016\/j.arabjc.2022.103950","article-title":"Phytochemical profiling, molecular docking, and in vitro anti-hepatocellular carcinoid bioactivity of Suaeda vermiculata extracts","volume":"15","author":"Mohammed","year":"2022","journal-title":"Arab. J. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2578","DOI":"10.1080\/07391102.2015.1063457","article-title":"Molecular dynamics simulation studies of GSK-3\u03b2 ATP competitive inhibitors: Understanding the factors contributing to selectivity","volume":"33","author":"Arfeen","year":"2015","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"W356","DOI":"10.1093\/nar\/gkx374","article-title":"PharmMapper 2017 update: A web server for potential drug target identification with a comprehensive target pharmacophore database","volume":"45","author":"Wang","year":"2017","journal-title":"Nucleic Acids Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/21\/7364\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:05:49Z","timestamp":1760144749000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/21\/7364"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,29]]},"references-count":44,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["molecules27217364"],"URL":"https:\/\/doi.org\/10.3390\/molecules27217364","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,29]]}}}