{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T19:26:26Z","timestamp":1786994786193,"version":"build-2736575974"},"reference-count":50,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2021,1,1]],"date-time":"2021-01-01T00:00:00Z","timestamp":1609459200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2021,1,1]],"date-time":"2021-01-01T00:00:00Z","timestamp":1609459200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"funder":[{"DOI":"10.13039\/501100010218","name":"Department of Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010218","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Neuroscience Letters"],"published-print":{"date-parts":[[2021,1]]},"DOI":"10.1016\/j.neulet.2020.135426","type":"journal-article","created":{"date-parts":[[2020,10,16]],"date-time":"2020-10-16T16:48:18Z","timestamp":1602866898000},"page":"135426","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":40,"special_numbering":"C","title":["Hesperidin downregulates kinases lrrk2 and gsk3\u03b2 in a 6-OHDA induced Parkinson\u2019s disease model"],"prefix":"10.1016","volume":"740","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1163-7042","authenticated-orcid":false,"given":"Swathi","family":"Kesh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6846-5777","authenticated-orcid":false,"given":"Rajaretinam Rajesh","family":"Kannan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8449-3951","authenticated-orcid":false,"given":"Kalaiarasi","family":"Sivaji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anandan","family":"Balakrishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.neulet.2020.135426_bib0005","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1186\/s40478-014-0176-9","article-title":"Models of \u03b1-synuclein aggregation in Parkinson\u2019s disease","volume":"2","author":"Gir\u00e1ldez-P\u00e9rez","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"10.1016\/j.neulet.2020.135426_bib0010","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1749-6632.2003.tb07458.x","article-title":"Description of Parkinson\u2019s disease as a clinical syndrome","volume":"991","author":"Fahn","year":"2003","journal-title":"Ann. N. Y. Acad. Sci."},{"issue":"1","key":"10.1016\/j.neulet.2020.135426_bib0015","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ncl.2014.09.010","article-title":"Pathogenic mechanisms of neurodegeneration in Parkinson disease","volume":"33","author":"Mullin","year":"2015","journal-title":"Neurol. Clin."},{"issue":"3","key":"10.1016\/j.neulet.2020.135426_bib0020","doi-asserted-by":"crossref","first-page":"259","DOI":"10.31887\/DCNS.2004.6.3\/galexander","article-title":"Biology of Parkinson\u2019s disease: pathogenesis and pathophysiology of a multisystem neurodegenerative disorder","volume":"6","author":"Alexander","year":"2004","journal-title":"Dialogues Clin. Neurosci."},{"issue":"3","key":"10.1016\/j.neulet.2020.135426_bib0025","doi-asserted-by":"crossref","first-page":"190","DOI":"10.4103\/aian.AIAN_239_17","article-title":"Levodopa-induced dyskinesia: clinical features, pathophysiology, and medical management","volume":"20","author":"Pandey","year":"2017","journal-title":"Ann. Indian Acad. Neurol."},{"issue":"1","key":"10.1016\/j.neulet.2020.135426_bib0030","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a008888","article-title":"Genetics of Parkinson\u2019s disease","volume":"2","author":"Klein","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"issue":"2","key":"10.1016\/j.neulet.2020.135426_bib0035","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1136\/jmedgenet-2017-105047","article-title":"Genetics of Parkinson\u2019s disease and related disorders","volume":"55","author":"Zhang","year":"2018","journal-title":"J. Med. Genet."},{"key":"10.1016\/j.neulet.2020.135426_bib0040","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.neulet.2018.04.004","article-title":"Multiple pathways for mitophagy: a neurodegenerative conundrum for Parkinson\u2019s disease","volume":"697","author":"Chu","year":"2019","journal-title":"Neurosci. Lett."},{"key":"10.1016\/j.neulet.2020.135426_bib0045","doi-asserted-by":"crossref","DOI":"10.1016\/j.phymed.2019.152954","article-title":"Multiple pathways for natural product treatment of Parkinson\u2019s disease: a mini review","volume":"60","author":"Li","year":"2019","journal-title":"Phytomedicine"},{"issue":"57","key":"10.1016\/j.neulet.2020.135426_bib0050","article-title":"Parkinson\u2019s disease-implicated kinases in the brain; insights into disease pathogenesis","volume":"7","author":"Dzamko","year":"2014","journal-title":"Front. Mol. Neurosci."},{"key":"10.1016\/j.neulet.2020.135426_bib0055","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.jns.2019.05.016","article-title":"Targeting kinases in Parkinson\u2019s disease: a mechanism shared by LRRK2, neurotrophins, exenatide, urate, nilotinib and lithium","volume":"402","author":"Guttuso","year":"2019","journal-title":"J. Neurol. Sci."},{"issue":"1","key":"10.1016\/j.neulet.2020.135426_bib0060","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/febs.12579","article-title":"Leucine-rich repeat kinase 2 regulates tau phosphorylation through direct activation of glycogen synthase kinase-3\u03b2","volume":"281","author":"Kawakami","year":"2014","journal-title":"FEBS J."},{"key":"10.1016\/j.neulet.2020.135426_bib0065","doi-asserted-by":"crossref","DOI":"10.1155\/2013\/891748","article-title":"Polyphenols: multipotent therapeutic agents in neurodegenerative diseases","volume":"2013","author":"Bhullar","year":"2013","journal-title":"Oxid. Med. Cell. Longev."},{"key":"10.1016\/j.neulet.2020.135426_bib0070","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3389\/fnut.2018.00087","article-title":"The role of polyphenols in human health and food systems: a mini-review","volume":"5","author":"Cory","year":"2018","journal-title":"Front. Nutr."},{"issue":"11","key":"10.1016\/j.neulet.2020.135426_bib0075","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.3390\/nu2111106","article-title":"Polyphenols and human health: prevention of disease and mechanisms of action","volume":"2","author":"Vauzour","year":"2010","journal-title":"Nutrients"},{"key":"10.1016\/j.neulet.2020.135426_bib0080","doi-asserted-by":"crossref","DOI":"10.1155\/2019\/2676307","article-title":"Benefits of hesperidin for cutaneous functions","volume":"2019","author":"Man","year":"2019","journal-title":"Evid. Based Complement. Altern. Med."},{"issue":"3","key":"10.1016\/j.neulet.2020.135426_bib0085","doi-asserted-by":"crossref","DOI":"10.3390\/molecules24030648","article-title":"Hesperidin as a neuroprotective agent: a review of animal and clinical evidence","volume":"24","author":"Hajialyani","year":"2019","journal-title":"Molecules"},{"issue":"1-2","key":"10.1016\/j.neulet.2020.135426_bib0090","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.lfs.2014.07.029","article-title":"Neuropharmacological properties and pharmacokinetics of the citrus flavonoids hesperidin and hesperetin--a mini-review","volume":"113","author":"Roohbakhsh","year":"2014","journal-title":"Life Sci."},{"key":"10.1016\/j.neulet.2020.135426_bib0095","doi-asserted-by":"crossref","DOI":"10.1177\/1759091418777438","article-title":"Neurotoxin-induced animal models of parkinson disease: pathogenic mechanism and assessment","volume":"10","author":"Zeng","year":"2018","journal-title":"ASN Neuro"},{"issue":"1","key":"10.1016\/j.neulet.2020.135426_bib0100","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s00441-004-0938-y","article-title":"Classic toxin-induced animal models of Parkinson\u2019s disease: 6-OHDA and MPTP","volume":"318","author":"Schober","year":"2004","journal-title":"Cell Tissue Res."},{"issue":"7446","key":"10.1016\/j.neulet.2020.135426_bib0105","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/nature12111","article-title":"The zebrafish reference genome sequence and its relationship to the human genome","volume":"496","author":"Howe","year":"2013","journal-title":"Nature"},{"issue":"24","key":"10.1016\/j.neulet.2020.135426_bib0110","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1056\/NEJMoa033447","article-title":"Levodopa and the progression of Parkinson\u2019s disease","volume":"351","author":"Fahn","year":"2004","journal-title":"N. Engl. J. Med."},{"issue":"3","key":"10.1016\/j.neulet.2020.135426_bib0115","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1179\/174329210X12650506623447","article-title":"Involvement of the mitochondrial apoptotic pathway and nitric oxide synthase in dopaminergic neuronal death induced by 6-hydroxydopamine and lipopolysaccharide","volume":"15","author":"Singh","year":"2010","journal-title":"Redox Rep."},{"issue":"1","key":"10.1016\/j.neulet.2020.135426_bib0120","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1021\/tx700210j","article-title":"Oxidative stress and neurotoxicity","volume":"21","author":"Sayre","year":"2008","journal-title":"Chem. Res. Toxicol."},{"issue":"1","key":"10.1016\/j.neulet.2020.135426_bib0125","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a009316","article-title":"A guide to neurotoxic animal models of Parkinson\u2019s disease","volume":"1","author":"Tieu","year":"2011","journal-title":"Cold Spring Harb. Perspect. Med."},{"issue":"8","key":"10.1016\/j.neulet.2020.135426_bib0130","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.nrl.2015.06.011","article-title":"The 6-hydroxydopamine model and parkinsonian pathophysiology: novel findings in an older model","volume":"32","author":"Hernandez-Baltazar","year":"2017","journal-title":"Neurologia"},{"key":"10.1016\/j.neulet.2020.135426_bib0135","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.yrtph.2019.04.001","article-title":"Acute and sub-chronic oral toxicity studies of hesperidin isolated from orange peel extract in Sprague Dawley rats","volume":"105","author":"Li","year":"2019","journal-title":"Regul. Toxicol. Pharmacol."},{"issue":"5","key":"10.1016\/j.neulet.2020.135426_bib0140","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.tins.2008.02.008","article-title":"The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?","volume":"31","author":"Fukui","year":"2008","journal-title":"Trends Neurosci."},{"issue":"4","key":"10.1016\/j.neulet.2020.135426_bib0145","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.ajme.2017.09.001","article-title":"First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): their fundamental role in the entire antioxidant defence grid","volume":"54","author":"Ighodaro","year":"2018","journal-title":"Alexandria J. Med."},{"issue":"6","key":"10.1016\/j.neulet.2020.135426_bib0150","doi-asserted-by":"crossref","first-page":"4094","DOI":"10.1007\/s12035-015-9337-5","article-title":"Oxidative stress in neurodegenerative diseases","volume":"53","author":"Niedzielska","year":"2016","journal-title":"Mol. Neurobiol."},{"issue":"1-2","key":"10.1016\/j.neulet.2020.135426_bib0155","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.brainres.2003.12.034","article-title":"The role of oxidative stress, impaired glycolysis and mitochondrial respiratory redox failure in the cytotoxic effects of 6-hydroxydopamine in vitro","volume":"1004","author":"Mazzio","year":"2004","journal-title":"Brain Res."},{"issue":"3-4","key":"10.1016\/j.neulet.2020.135426_bib0160","first-page":"329","article-title":"Inhibition of mitochondrial complexes I and IV by 6-hydroxydopamine","volume":"292","author":"Glinka","year":"1995","journal-title":"Eur. J. Pharmacol."},{"key":"10.1016\/j.neulet.2020.135426_bib0165","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.brainres.2015.12.035","article-title":"Neuroprotection of inositol hexaphosphate and changes of mitochondrion mediated apoptotic pathway and \u03b1-synuclein aggregation in 6-OHDA induced parkinson\u2019s disease cell model","volume":"1633","author":"Zhang","year":"2016","journal-title":"Brain Res."},{"issue":"1","key":"10.1016\/j.neulet.2020.135426_bib0170","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41420-018-0109-7","article-title":"Zebrafish: an emerging real-time model system to study Alzheimer\u2019s disease and neurospecific drug discovery","volume":"4","author":"Saleem","year":"2018","journal-title":"Cell Death Discov."},{"issue":"347","key":"10.1016\/j.neulet.2020.135426_bib0175","article-title":"Zebrafish as an animal model for drug discovery in parkinson\u2019s disease and other movement disorders: a systematic review","volume":"9","author":"Vaz","year":"2018","journal-title":"Front. Neurol."},{"issue":"2","key":"10.1016\/j.neulet.2020.135426_bib0180","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1111\/j.1471-4159.2004.02190.x","article-title":"Neurochemical and behavioural changes in zebrafish Danio rerio after systemic administration of 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine","volume":"88","author":"Anichtchik","year":"2004","journal-title":"J. Neurochem."},{"issue":"3","key":"10.1016\/j.neulet.2020.135426_bib0185","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1089\/zeb.2013.0950","article-title":"Effects of 6-hydroxydopamine exposure on motor activity and biochemical expression in zebrafish (Danio rerio) larvae","volume":"11","author":"Feng","year":"2014","journal-title":"Zebrafish"},{"issue":"6","key":"10.1016\/j.neulet.2020.135426_bib0190","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.mcp.2016.11.001","article-title":"Genetics of Parkinson\u2019s disease","volume":"30","author":"Lill","year":"2016","journal-title":"Mol. Cell. Probes"},{"issue":"5","key":"10.1016\/j.neulet.2020.135426_bib0195","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s11910-018-0829-3","article-title":"Mitochondrial dysfunction in parkinson\u2019s disease: new mechanistic insights and therapeutic perspectives","volume":"18","author":"Park","year":"2018","journal-title":"Curr. Neurol. Neurosci. Rep."},{"issue":"6","key":"10.1016\/j.neulet.2020.135426_bib0200","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1007\/s00401-019-01995-0","article-title":"LRRK2 modifies \u03b1-syn pathology and spread in mouse models and human neurons","volume":"137","author":"Bieri","year":"2019","journal-title":"Acta Neuropathol."},{"key":"10.1016\/j.neulet.2020.135426_bib0205","doi-asserted-by":"crossref","DOI":"10.1016\/j.nbd.2019.104720","article-title":"Glycogen synthase kinase 3 \u03b2 activity is essential for Polo-like kinase 2- and Leucine-rich repeat kinase 2-mediated regulation of \u03b1-synuclein","volume":"136","author":"Kofoed","year":"2020","journal-title":"Neurobiol. Dis."},{"issue":"3","key":"10.1016\/j.neulet.2020.135426_bib0210","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.nbd.2010.07.010","article-title":"Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice","volume":"40","author":"Melrose","year":"2010","journal-title":"Neurobiol. Dis."},{"issue":"5","key":"10.1016\/j.neulet.2020.135426_bib0215","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1002\/ana.20831","article-title":"Early-onset familial parkinsonism due to POLG mutations","volume":"59","author":"Davidzon","year":"2006","journal-title":"Ann. Neurol."},{"issue":"Pt 2","key":"10.1016\/j.neulet.2020.135426_bib0220","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1042\/bj3480425","article-title":"Increase of mitochondria and mitochondrial DNA in response to oxidative stress in human cells","volume":"348 Pt 2","author":"Lee","year":"2000","journal-title":"Biochem. J."},{"key":"10.1016\/j.neulet.2020.135426_bib0225","doi-asserted-by":"crossref","DOI":"10.1155\/2013\/754946","article-title":"High glucose-induced oxidative stress increases the copy number of mitochondrial DNA in human mesangial cells","volume":"2013","author":"Al-Kafaji","year":"2013","journal-title":"Biomed Res. Int."},{"issue":"4","key":"10.1016\/j.neulet.2020.135426_bib0230","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1023\/A:1016167228059","article-title":"Initiator caspases in apoptosis signaling pathways","volume":"7","author":"Chen","year":"2002","journal-title":"Apoptosis"},{"issue":"24","key":"10.1016\/j.neulet.2020.135426_bib0235","doi-asserted-by":"crossref","first-page":"9519","DOI":"10.1523\/JNEUROSCI.21-24-09519.2001","article-title":"Caspase-9 activation results in downstream caspase-8 activation and bid cleavage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson\u2019s disease","volume":"21","author":"Viswanath","year":"2001","journal-title":"J. Neurosci."},{"key":"10.1016\/j.neulet.2020.135426_bib0240","doi-asserted-by":"crossref","first-page":"73","DOI":"10.3389\/fnins.2018.00073","article-title":"The role of Insulin\/IGF-1\/PI3K\/Akt\/GSK3\u03b2 signaling in Parkinson\u2019s disease dementia","volume":"12","author":"Yang","year":"2018","journal-title":"Front. Neurosci."},{"key":"10.1016\/j.neulet.2020.135426_bib0245","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.pharmthera.2014.11.016","article-title":"Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases","volume":"148","author":"Beurel","year":"2015","journal-title":"Pharmacol. Ther."},{"issue":"8","key":"10.1016\/j.neulet.2020.135426_bib0250","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0070951","article-title":"Activation of GSK-3\u03b2 and caspase-3 occurs in Nigral dopamine neurons during the development of apoptosis activated by a striatal injection of 6-hydroxydopamine","volume":"8","author":"Hernandez-Baltazar","year":"2013","journal-title":"PLoS One"}],"container-title":["Neuroscience Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0304394020306960?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0304394020306960?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T20:34:51Z","timestamp":1759610091000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0304394020306960"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1]]},"references-count":50,"alternative-id":["S0304394020306960"],"URL":"https:\/\/doi.org\/10.1016\/j.neulet.2020.135426","relation":{},"ISSN":["0304-3940"],"issn-type":[{"value":"0304-3940","type":"print"}],"subject":[],"published":{"date-parts":[[2021,1]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Hesperidin downregulates kinases lrrk2 and gsk3\u03b2 in a 6-OHDA induced Parkinson\u2019s disease model","name":"articletitle","label":"Article Title"},{"value":"Neuroscience Letters","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.neulet.2020.135426","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2020 Published by Elsevier B.V.","name":"copyright","label":"Copyright"}],"article-number":"135426"}}