{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:51:19Z","timestamp":1791075079076,"version":"4.1.0"},"reference-count":109,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,10,2]],"date-time":"2021-10-02T00:00:00Z","timestamp":1633132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Neurodegenerative diseases (NDDs) are one of the leading causes of death and disability in humans. From a mechanistic perspective, the complexity of pathophysiological mechanisms contributes to NDDs. Therefore, there is an urgency to provide novel multi-target agents towards the simultaneous modulation of dysregulated pathways against NDDs. Besides, their lack of effectiveness and associated side effects have contributed to the lack of conventional therapies as suitable therapeutic agents. Prevailing reports have introduced plant secondary metabolites as promising multi-target agents in combating NDDs. Polydatin is a natural phenolic compound, employing potential mechanisms in fighting NDDs. It is considered an auspicious phytochemical in modulating neuroinflammatory\/apoptotic\/autophagy\/oxidative stress signaling mediators such as nuclear factor-\u03baB (NF-\u03baB), NF-E2\u2013related factor 2 (Nrf2)\/antioxidant response elements (ARE), matrix metalloproteinase (MMPs), interleukins (ILs), phosphoinositide 3-kinases (PI3K)\/protein kinase B (Akt), and the extracellular regulated kinase (ERK)\/mitogen-activated protein kinase (MAPK). Accordingly, polydatin potentially counteracts Alzheimer\u2019s disease, cognition\/memory dysfunction, Parkinson\u2019s disease, brain\/spinal cord injuries, ischemic stroke, and miscellaneous neuronal dysfunctionalities. The present study provides all of the neuroprotective mechanisms of polydatin in various NDDs. Additionally, the novel delivery systems of polydatin are provided regarding increasing its safety, solubility, bioavailability, and efficacy, as well as developing a long-lasting therapeutic concentration of polydatin in the central nervous system, possessing fewer side effects.<\/jats:p>","DOI":"10.3390\/molecules26195985","type":"journal-article","created":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T21:23:55Z","timestamp":1633728235000},"page":"5985","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["The Neuroprotective Role of Polydatin: Neuropharmacological Mechanisms, Molecular Targets, Therapeutic Potentials, and Clinical Perspective"],"prefix":"10.3390","volume":"26","author":[{"given":"Sajad","family":"Fakhri","sequence":"first","affiliation":[{"name":"Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Mehdi","family":"Gravandi","sequence":"additional","affiliation":[{"name":"Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah 6714415153, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5680-0806","authenticated-orcid":false,"given":"Sadaf","family":"Abdian","sequence":"additional","affiliation":[{"name":"Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah 6714415153, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5829-7869","authenticated-orcid":false,"given":"Esra K\u00fcpeli","family":"Akkol","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7081-6521","authenticated-orcid":false,"given":"Mohammad Hosein","family":"Farzaei","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2790-2544","authenticated-orcid":false,"given":"Eduardo","family":"Sobarzo-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain"},{"name":"Instituto de Investigaci\u00f3n y Postgrado, Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago 8330507, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1146\/annurev.neuro.30.051606.094313","article-title":"Multiple sclerosis: An immune or neurodegenerative disorder?","volume":"31","author":"Trapp","year":"2008","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/s41583-018-0055-7","article-title":"Inflammasome signalling in brain function and neurodegenerative disease","volume":"19","author":"Heneka","year":"2018","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.molmed.2005.02.009","article-title":"Alzheimer\u2019s disease: A\u03b2, tau and synaptic dysfunction","volume":"11","author":"LaFerla","year":"2005","journal-title":"Trends Mol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1093\/brain\/awx133","article-title":"Inflammasomes in neurological diseases: Emerging pathogenic and therapeutic concepts","volume":"140","author":"Mamik","year":"2017","journal-title":"Brain"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"105069","DOI":"10.1016\/j.phrs.2020.105069","article-title":"Targeting apoptosis and autophagy following spinal cord injury: Therapeutic ap-proaches to polyphenols and candidate phytochemicals","volume":"160","author":"Abbaszadeh","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1046\/j.1525-1373.1999.d01-140.x","article-title":"Antioxidants, Oxidative Stress, and Degenerative Neurological Disorders","volume":"222","author":"Floyd","year":"1999","journal-title":"Proc. Soc. Exp. Boil. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.2174\/1381612824666180327170632","article-title":"The Role of Inflammation in Neurological Disorders","volume":"24","author":"Degan","year":"2018","journal-title":"Curr. Pharm. Des."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.mito.2019.07.003","article-title":"Mitochondrial dysfunction in neurodegenerative diseases and drug targets via apoptotic signaling","volume":"49","author":"Wu","year":"2019","journal-title":"Mitochondrion"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.phrs.2018.08.012","article-title":"Astaxanthin: A mechanistic review on its biological activities and health benefits","volume":"136","author":"Fakhri","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"111563","DOI":"10.1016\/j.biopha.2021.111563","article-title":"On the therapeutic targets and pharmacological treatments for pain relief following spinal cord injury: A mechanistic review","volume":"139","author":"Fakhri","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"111714","DOI":"10.1016\/j.fct.2020.111714","article-title":"Astaxanthin targets PI3K\/Akt signaling pathway toward potential therapeutic applications","volume":"145","author":"Zarneshan","year":"2020","journal-title":"Food. Chem. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1007\/s11011-021-00750-3","article-title":"Flavonoids modulate AMPK\/PGC-1\u03b1 and inter-connected pathways toward potential neuroprotective activities","volume":"36","author":"Gravandi","year":"2021","journal-title":"Metab. Brain Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"153664","DOI":"10.1016\/j.phymed.2021.153664","article-title":"Natural products attenuate PI3K\/Akt\/mTOR signaling pathway: A promising strategy in regulating neurodegeneration","volume":"91","author":"Fakhri","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.phrs.2017.08.002","article-title":"Anti-inflammatory activity of natural stilbenoids: A review","volume":"124","author":"Dvorakova","year":"2017","journal-title":"Pharmacol. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/S1572-5995(08)80032-4","article-title":"Stilbenoids: Chemistry and bioactivities","volume":"Volume 34","author":"Attaur","year":"2008","journal-title":"Bioactive Natural Products (Part L)"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1021\/jf048909e","article-title":"Cellular uptake and efflux of trans-piceid and its aglycone trans-resveratrol on the apical membrane of human intestinal Caco-2 cells","volume":"53","author":"Henry","year":"2005","journal-title":"J. Agric. Food Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1007\/s00394-006-0609-8","article-title":"Transport, deglycosylation, and metabolism of trans-piceid by small intestinal epithelial cells","volume":"45","author":"Girard","year":"2006","journal-title":"Eur. J. Nutr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.redox.2018.07.002","article-title":"Polydatin prevents fructose-induced liver inflammation and lipid deposition through increasing miR-200a to regulate Keap1\/Nrf2 pathway","volume":"18","author":"Zhao","year":"2018","journal-title":"Redox Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.ejphar.2018.10.039","article-title":"The protective mechanisms of polydatin in cerebral ischemia","volume":"842","author":"Tang","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"127","DOI":"10.2174\/1570159X18666200611144825","article-title":"Protective Effects of Polydatin Against Dementia-Related Disorders","volume":"19","author":"Tang","year":"2020","journal-title":"Curr. Neuropharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.3109\/13880209.2013.792849","article-title":"Polydatin: A review of pharmacology and pharmacokinetics","volume":"51","author":"Du","year":"2013","journal-title":"Pharm. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2666","DOI":"10.1021\/jf9900884","article-title":"Determination of stilbenes (trans-astringin, cis- and trans- piceid, and cis- and trans- resveratrol) in Portuguese wines","volume":"47","author":"Teissedre","year":"1999","journal-title":"J. Agric. Food Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1017\/S0007114507882997","article-title":"Concentrations of resveratrol and derivatives in foods and estimation of dietary intake in a Spanish population: European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain cohort","volume":"100","author":"Berenguer","year":"2008","journal-title":"Br. J. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1021\/jf903009f","article-title":"Preformulation Stability of trans-Resveratrol and trans-Resveratrol Glucoside (Piceid)","volume":"58","author":"Jensen","year":"2010","journal-title":"J. Agric. Food Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3110","DOI":"10.1002\/jssc.200700285","article-title":"Isocratic chromatography of resveratrol and piceid after previous generation of fluorescent photoproducts: Wine analysis without sample preparation","volume":"30","year":"2007","journal-title":"J. Sep. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.phymed.2015.03.014","article-title":"Comparative studies of polydatin and resveratrol on mutual transformation and antioxidative effect in vivo","volume":"22","author":"Wang","year":"2015","journal-title":"Phytomedicine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.jchromb.2007.04.035","article-title":"Quantitative determination of trans-polydatin, a natural strong anti-oxidative compound, in rat plasma and cellular environment of a human colon ade-nocarcinoma cell line for pharmacokinetic studies","volume":"855","author":"He","year":"2007","journal-title":"J. Chromatogr. B"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.jep.2011.05.049","article-title":"Pharmacokinetics and tissue distribution of 2,3,5,4\u2032-tetrahydroxystilbene-2-O-\u03b2-d-glucoside from traditional Chinese medicine Polygonum multiflorum following oral ad-ministration to rats","volume":"137","author":"Lv","year":"2011","journal-title":"J. Ethnopharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1007\/s10753-011-9310-z","article-title":"Anti-inflammatory Effect of Resveratrol and Polydatin by In Vitro IL-17 Modulation","volume":"35","author":"Lanzilli","year":"2011","journal-title":"Inflammation"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4545","DOI":"10.1039\/C6FO01057A","article-title":"Polydatin attenuates D-galactose-induced liver and brain damage through its anti-oxidative, anti-inflammatory and anti-apoptotic effects in mice","volume":"7","author":"Xu","year":"2016","journal-title":"Food Funct."},{"key":"ref_31","first-page":"55","article-title":"Assessment of in vitro antioxidant activity study of polydatin","volume":"8","author":"Jayalakshmi","year":"2019","journal-title":"J. Pharm. Phytochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.jss.2015.05.041","article-title":"Polydatin: A new therapeutic agent against multiorgan dysfunction","volume":"198","author":"Zeng","year":"2015","journal-title":"J. Surg. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"362158","DOI":"10.1155\/2015\/362158","article-title":"Nephroprotective effects of polydatin against ischemia\/reperfusion injury: A role for the PI3K\/Akt signal pathway","volume":"2015","author":"Liu","year":"2015","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.lfs.2018.11.053","article-title":"Polydatin attenuates spinal cord injury in rats by inhibiting oxidative stress and microglia apoptosis via Nrf2\/HO-1 pathway","volume":"217","author":"Lv","year":"2019","journal-title":"Life Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/aps.2016.123","article-title":"Polydatin ameliorates Staphylo-coccus aureus-induced mastitis in mice via inhibiting TLR2-mediated activation of the p38 MAPK\/NF-\u03baB pathway","volume":"38","author":"Jiang","year":"2017","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1196\/annals.1427.015","article-title":"The Role of Mitochondria in Reactive Oxygen Species Metabolism and Signaling","volume":"1147","author":"Starkov","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5481","DOI":"10.3892\/mmr.2016.5936","article-title":"Neuroprotective effects of polydatin against mitochondrial-dependent apoptosis in the rat cerebral cortex following ischemia\/reperfusion injury","volume":"14","author":"Gao","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1080\/14728222.2016.1177023","article-title":"Polydatin ameliorates injury to the small intestine induced by hemorrhagic shock via SIRT3 activation-mediated mitochondrial protection","volume":"20","author":"Zeng","year":"2016","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/s41586-019-1195-2","article-title":"Single-cell transcriptomic analysis of Alzheimer\u2019s disease","volume":"570","author":"Mathys","year":"2019","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.redox.2017.10.014","article-title":"Oxidative stress and the amyloid beta peptide in Alzheimer\u2019s disease","volume":"14","author":"Cheignon","year":"2018","journal-title":"Redox Boil."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s11904-017-0361-0","article-title":"Differentiating HIV-Associated Neurocognitive Disorders From Alzheimer\u2019s Disease: An Emerging Issue in Geriatric NeuroHIV","volume":"14","author":"Milanini","year":"2017","journal-title":"Curr. HIV\/AIDS Rep."},{"key":"ref_42","first-page":"200","article-title":"The neuropathology of probable Alzheimer disease and mild cognitive impairment","volume":"66","author":"Schneider","year":"2009","journal-title":"Ann. Neurol. Off. J. Am. Neurol. Assoc. Child Neurol. Soc."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Fakhri, S., Pesce, M., Patruno, A., Moradi, S.Z., Iranpanah, A., Farzaei, M.H., and Sobarzo-S\u00e1nchez, E. (2020). Attenuation of Nrf2\/Keap1\/ARE in Alzheimer\u2019s disease by plant secondary metabolites: A mechanistic review. Molecules, 25.","DOI":"10.3390\/molecules25214926"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.phymed.2012.03.002","article-title":"Polydatin protects learning and memory impair-ments in a rat model of vascular dementia","volume":"19","author":"Li","year":"2012","journal-title":"Phytomedicine"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1080\/09168451.2020.1722057","article-title":"Polydatin ameliorates chemotherapy-induced cognitive impairment (chemobrain) by inhibiting oxidative stress, inflammatory response, and apoptosis in rats","volume":"84","author":"Tong","year":"2020","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Cauli, O. (2021). Oxidative Stress and Cognitive Alterations Induced by Cancer Chemotherapy Drugs: A Scoping Review. Antioxidants, 10.","DOI":"10.3390\/antiox10071116"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.3892\/mmr.2014.2577","article-title":"Protective effect of polydatin on learning and memory impairments in neonatal rats with hypoxic-ischemic brain injury by up-regulating brain-derived neurotrophic factor","volume":"10","author":"Sun","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_48","first-page":"11116","article-title":"Beneficial effects of polydatin on learning and memory in rats with chronic ethanol exposure","volume":"8","author":"Zhang","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1016\/j.bmc.2006.09.069","article-title":"Inhibitory activity of stilbenes on Alzheimer\u2019s \u03b2-amyloid fibrils in vitro","volume":"15","author":"Richard","year":"2007","journal-title":"Bioorg. Med. Chem."},{"key":"ref_50","first-page":"1120","article-title":"The Polyphenol Piceid Destabilizes Preformed Amyloid Fibrils and Oligomers In Vitro: Hypothesis on Possible Molecular Mechanisms","volume":"34","author":"Delaunay","year":"2008","journal-title":"Neurochem. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"356","DOI":"10.3109\/13880209.2013.837078","article-title":"Membrane permeability-guided identification of neuroprotective components fromPolygonum cuspidatun","volume":"52","author":"Xiao","year":"2013","journal-title":"Pharm. Biol."},{"key":"ref_52","first-page":"213","article-title":"[Effect of polydatin on learning and memory and expression of NR2B in the prefrontal cortex of rats with chronic alcoholism]","volume":"27","author":"Xu","year":"2011","journal-title":"Chin. J. Appl. Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/S1474-4422(06)70471-9","article-title":"Epidemiology of Parkinson\u2019s disease","volume":"5","author":"Breteler","year":"2006","journal-title":"Lancet Neurol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1097\/WCO.0b013e3283550c0d","article-title":"Biomarkers in Parkinson\u2019s disease","volume":"25","author":"Shtilbans","year":"2012","journal-title":"Curr. Opin. Neurol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pneurobio.2016.07.005","article-title":"Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson\u2019s disease and Alzheimer\u2019s disease","volume":"147","author":"Jiang","year":"2016","journal-title":"Prog. Neurobiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1038\/nn.4660","article-title":"Synuclein and dopamine: The Bonnie and Clyde of Parkinson\u2019s disease","volume":"20","author":"Roy","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"104671","DOI":"10.1016\/j.neuint.2020.104671","article-title":"Polydatin protects SH-SY5Y in models of Parkinson\u2019s disease by promoting Atg5-mediated but parkin-independent autophagy","volume":"134","author":"Bai","year":"2020","journal-title":"Neurochem. Int."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"117244","DOI":"10.1016\/j.lfs.2019.117244","article-title":"Parkin and Nrf2 prevent oxidative stress-induced apoptosis in intervertebral endplate chondrocytes via inducing mitophagy and anti-oxidant defenses","volume":"243","author":"Kang","year":"2020","journal-title":"Life Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/s41591-018-0051-5","article-title":"Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson\u2019s disease","volume":"24","author":"Yun","year":"2018","journal-title":"Nat. Med."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Kujawska, M., and Jodynis-Liebert, J. (2018). Polyphenols in Parkinson\u2019s Disease: A Systematic Review of In Vivo Studies. Nutrients, 10.","DOI":"10.3390\/nu10050642"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1750-1326-10-4","article-title":"Anti-oxidant polydatin (piceid) protects against substantia nigral motor degeneration in multiple rodent models of Parkinson\u2019s disease","volume":"10","author":"Chen","year":"2015","journal-title":"Mol. Neurodegener."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.3389\/fimmu.2018.02527","article-title":"Polydatin prevents lipopolysaccharide (LPS)-induced Parkinson\u2019s disease via regulation of the AKT\/GSK3\u03b2-Nrf2\/NF-\u03baB signaling axis","volume":"9","author":"Huang","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"488","DOI":"10.3389\/fncel.2018.00488","article-title":"Microglia in neurological diseases: A road map to brain-disease dependent-inflammatory response","volume":"12","author":"Bachiller","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"25344","DOI":"10.1038\/srep25344","article-title":"Meclizine-induced enhanced glycolysis is neuroprotective in Parkinson disease cell models","volume":"6","author":"Hong","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"104815","DOI":"10.1016\/j.neuint.2020.104815","article-title":"Polydatin alleviates parkinsonism in MPTP-model mice by enhancing glycolysis in dopaminergic neurons","volume":"139","author":"Zhang","year":"2020","journal-title":"Neurochem. Int."},{"key":"ref_66","first-page":"2003","article-title":"Oxidative stress, mitochondrial damage and neurodegenerative diseases","volume":"8","author":"Guo","year":"2013","journal-title":"Neural Regen. Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1007\/s00204-017-2073-z","article-title":"Protective effects of the resveratrol analog piceid in dopaminergic SH-SY5Y cells","volume":"92","author":"Potdar","year":"2018","journal-title":"Arch. Toxicol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"584","DOI":"10.4067\/S0717-95022018000200584","article-title":"Neuroprotective Potential of Polydatin Against Motor Abnormalities and Dopaminergic Neuronal Loss in Rotenone Induced Parkinson Model","volume":"36","author":"Ahmed","year":"2018","journal-title":"Int. J. Morphol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Fakhri, S., Tomas, M., Capanoglu, E., Hussain, Y., Abbaszadeh, F., Lu, B., Hu, X., Wu, J., Zou, L., and Smeriglio, A. (2021). Antioxidant and anticancer potentials of edible flowers: Where do we stand?. Crit. Rev. Food Sci. Nutr., 1\u201357.","DOI":"10.1080\/10408398.2021.1931022"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/s41423-019-0213-5","article-title":"Dissemination of brain inflammation in traumatic brain injury","volume":"16","author":"Shi","year":"2019","journal-title":"Cell. Mol. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"621099","DOI":"10.3389\/fphar.2020.621099","article-title":"Targeting neurological manifestations of coronaviruses by candidate phytochemicals: A mechanistic approach","volume":"11","author":"Fakhri","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Nouri, Z., Fakhri, S., Nouri, K., Wallace, C.E., Farzaei, M.H., and Bishayee, A. (2020). Targeting multiple signaling pathways in cancer: The rutin therapeutic approach. Cancers, 12.","DOI":"10.3390\/cancers12082276"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"6687212","DOI":"10.1155\/2021\/6687212","article-title":"Polydatin Attenuates OGD\/R-Induced Neuronal Injury and Spinal Cord Ischemia\/Reperfusion Injury by Protecting Mitochondrial Function via Nrf2\/ARE Signaling Pathway","volume":"2021","author":"Zhan","year":"2021","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"5317","DOI":"10.1111\/jcmm.15187","article-title":"Polydatin promotes the neuronal differentiation of bone marrow mesenchymal stem cells in vitro and in vivo: Involvement of Nrf2 signalling pathway","volume":"24","author":"Zhan","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"9394150","DOI":"10.1155\/2016\/9394150","article-title":"Polydatin Protects Bone Marrow Stem Cells against Oxidative Injury: Involvement of Nrf 2\/ARE Pathways","volume":"2016","author":"Chen","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.bbrc.2021.03.108","article-title":"Polydatin alleviates traumatic brain injury: Role of inhibiting ferroptosis","volume":"556","author":"Huang","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/nm.4043","article-title":"Targeted stimulation of the spinal cord to restore locomotor activity","volume":"22","author":"Prochazka","year":"2016","journal-title":"Nat. Med."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Fakhri, S., Kiani, A., Jalili, C., Abbaszadeh, F., Piri, S., Farzaei, M.H., Rastegari-Pouyani, M., Mohammadi-Noori, E., and Khan, H. (2020). Intrathecal Administration of Melatonin Ameliorates the Neuroinflammation-mediated Sensory and Motor Dysfunction in a rat Model of Compression Spinal Cord Injury. Curr. Mol. Pharmacol.","DOI":"10.2174\/1874467213666201230101811"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"107699","DOI":"10.1016\/j.intimp.2021.107699","article-title":"Polydatin alleviates severe traumatic brain injury induced acute lung injury by inhibiting S100B mediated NETs formation","volume":"98","author":"Gu","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1258\/0007142001903120","article-title":"The impact of stroke","volume":"56","author":"Wolfe","year":"2000","journal-title":"Br. Med Bull."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/s10571-018-00646-4","article-title":"MALAT1 up-regulator poly-datin protects brain microvascular integrity and ameliorates stroke through C\/EBP\u03b2\/MALAT1\/CREB\/PGC-1\u03b1\/PPAR\u03b3 path-way","volume":"39","author":"Ruan","year":"2019","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"663","DOI":"10.3389\/fphar.2019.00663","article-title":"Polydatin attenuates neu-ronal loss via reducing neuroinflammation and oxidative stress in rat MCAO models","volume":"10","author":"Shah","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.brainresbull.2011.09.021","article-title":"Polydatin modulates inflammation by decreasing NF-\u03baB activation and oxidative stress by increasing Gli1, Ptch1, SOD1 expression and ameliorates blood\u2013brain barrier permeability for its neuroprotective effect in pMCAO rat brain","volume":"87","author":"Ji","year":"2012","journal-title":"Brain Res. Bull."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Bheereddy, P., Yerra, V.G., Kalvala, A.K., Sherkhane, B., and Kumar, A. (2020). SIRT1 activation by polydatin alleviates oxidative damage and elevates mitochondrial biogenesis in experimental diabetic neuropathy. Cell Mol. Neurobiol., 1\u201315.","DOI":"10.1007\/s10571-020-00923-1"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.brainres.2006.06.065","article-title":"Involvement of cell adhesion molecules in polydatin protection of brain tissues from ischemia\u2013reperfusion injury","volume":"1110","author":"Cheng","year":"2006","journal-title":"Brain Res."},{"key":"ref_86","first-page":"133","article-title":"Effect of polydatin on expression of p53 and Notch1 in brain tissue of ischemic cerebrovascular disease","volume":"32","author":"Chen","year":"2018","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_87","first-page":"629","article-title":"Establishment of cell-based neu-roglobin promoter reporter assay for neuroprotective compounds screening","volume":"15","author":"Liu","year":"2016","journal-title":"CNS Neurol. Disord.-Drug Targets (Former. Curr. Drug Targets-CNS Neurol. Disord.)"},{"key":"ref_88","first-page":"1041","article-title":"[Protective effect of polydatin on a PC12 cell model of oxygen-glucose deprivation]","volume":"30","author":"Xu","year":"2010","journal-title":"Nan fang yi ke da xue xue bao J. South. Med Univ."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1042\/BJ20111856","article-title":"Transcriptional regulation mechanisms of hypoxia-induced neuroglobin gene expression","volume":"443","author":"Liu","year":"2012","journal-title":"Biochem. J."},{"key":"ref_90","first-page":"3038","article-title":"Effect of polydatin on dynamic changes of excitatory amino acids in cerebrospinal fluid of cerebral hemorrhage rats","volume":"35","author":"Liu","year":"2010","journal-title":"China J. Chin. Mater. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1744806919900717","DOI":"10.1177\/1744806919900717","article-title":"Anxiolytic effects of polydatin through the blockade of neuroinflammation in a chronic pain mouse model","volume":"16","author":"Guan","year":"2020","journal-title":"Mol. Pain"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.neulet.2012.11.025","article-title":"Transcriptional regulation of mouse neuroglobin gene by cyclic AMP responsive element binding protein (CREB) in N2a cells","volume":"534","author":"Liu","year":"2013","journal-title":"Neurosci. Lett."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.4103\/1673-5374.255972","article-title":"Polydatin prevents the induction of secondary brain injury after traumatic brain injury by protecting neuronal mitochondria","volume":"14","author":"Li","year":"2019","journal-title":"Neural Regen. Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.intimp.2019.02.006","article-title":"Polydatin alleviates traumatic spinal cord injury by reducing microglial inflammation via regulation of iNOS and NLRP3 inflammasome pathway","volume":"70","author":"Lv","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1007\/s12031-020-01546-3","article-title":"Effect of Polydatin on Neurological Function and the Nrf2 Pathway during Intracerebral Hemorrhage","volume":"70","author":"Zhao","year":"2020","journal-title":"J. Mol. Neurosci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1021\/acsnano.6b06040","article-title":"Diverse Applications of Nanomedicine","volume":"11","author":"Pelaz","year":"2017","journal-title":"ACS Nano"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"111027","DOI":"10.1016\/j.biopha.2020.111027","article-title":"Polydatin mitigates pancreatic \u03b2-cell damage through its antioxidant activity","volume":"133","author":"Yousef","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1016\/j.ijbiomac.2019.11.031","article-title":"Novel polydatin-loaded chitosan nanoparticles for safe and efficient type 2 diabetes therapy: In silico, in vitro and in vivo approaches","volume":"154","author":"Yousef","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1080\/16583655.2020.1860504","article-title":"Ameliorative effect of polydatin and poly-datin-loaded chitosan nanoparticles against diabetes-induced pulmonary disorders in rats","volume":"15","author":"Mostafa","year":"2021","journal-title":"J. Taibah Univ. Sci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.bpc.2008.03.005","article-title":"Antioxidant properties of resveratrol and piceid on lipid peroxidation in micelles and monolamellar liposomes","volume":"135","author":"Fabris","year":"2008","journal-title":"Biophys. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1903138","DOI":"10.1002\/advs.201903138","article-title":"Nanodrug with ROS and pH Dual-Sensitivity Ameliorates Liver Fibrosis via Multicellular Regulation","volume":"7","author":"Lin","year":"2020","journal-title":"Adv. Sci."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.2147\/DDDT.S77615","article-title":"Novel nanoliposomal delivery system for polydatin: Preparation, characterization, and in vivo evaluation","volume":"9","author":"Guan","year":"2015","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/01635581.2019.1673451","article-title":"The effects of anticancer medicinal herbs on vascular endothelial growth factor based on pharmacological aspects: A review study","volume":"73","author":"Fakhri","year":"2021","journal-title":"Nutr. Cancer"},{"key":"ref_104","first-page":"1874","article-title":"Dietary Flavonoid Aglycones and Their Glycosides: Which Show Better Biological Significance?","volume":"57","author":"Xiao","year":"2017","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Vijayalakshmi, S., Mariadoss, A.V.A., Ramachandran, V., Shalini, V., Agilan, B., Sangeetha, C.C., Balupillai, A., Kotakadi, V.S., Karthikkumar, V., and Ernest, D. (2019). Polydatin Encapsulated Poly [Lactic-co-glycolic acid] Nanoformulation Counteract the 7,12-Dimethylbenz[a] Anthracene Mediated Experimental Carcinogenesis through the Inhibition of Cell Proliferation. Antioxidants, 8.","DOI":"10.3390\/antiox8090375"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1111\/apt.13958","article-title":"Randomised clinical trial: The analgesic properties of dietary supplementation with palmitoylethanolamide and polydatin in irritable bowel syndrome","volume":"45","author":"Cremon","year":"2017","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"107382","DOI":"10.1016\/j.biotechadv.2019.04.004","article-title":"Advances in phytochemical delivery systems for improved anticancer activity","volume":"38","author":"Lagoa","year":"2020","journal-title":"Biotechnol. Adv."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.semcancer.2019.08.014","article-title":"Natural product-based nanoformulations for cancer therapy: Opportunities and challenges","volume":"69","author":"Kashyap","year":"2021","journal-title":"Semin. Cancer Biol."},{"key":"ref_109","first-page":"1","article-title":"Modulation of dysregulated cancer metabolism by plant secondary me-tabolites: A mechanistic review","volume":"74","author":"Fakhri","year":"2020","journal-title":"Semin. Cancer Biol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/19\/5985\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:08:51Z","timestamp":1760166531000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/19\/5985"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,2]]},"references-count":109,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["molecules26195985"],"URL":"https:\/\/doi.org\/10.3390\/molecules26195985","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,2]]}}}