{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T21:28:46Z","timestamp":1781126926983,"version":"3.54.1"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Fundaci\u00f3n Primafr\u00edo","award":["39747"],"award-info":[{"award-number":["39747"]}]},{"DOI":"10.13039\/100007801","name":"Fundaci\u00f3n S\u00e9neca","doi-asserted-by":"publisher","award":["19540\/PI\/14"],"award-info":[{"award-number":["19540\/PI\/14"]}],"id":[{"id":"10.13039\/100007801","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["FIS PI13\/01293"],"award-info":[{"award-number":["FIS PI13\/01293"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004687","name":"Universidad de Murcia","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004687","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neurotox Res"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>This study investigates the effects of an acute 1-metil 4-fenil 1,2,3,6-tetraidro-piridina (MPTP) treatment, a known inducer of parkinsonism, on oxidative stress and epigenetic changes in the mouse ventral midbrain (VM) and striatum. Key markers were analyzed at 4, 8, 24, and 48 h post-injections: the hydroxylated form of the purine guanine (8-hydroxy-2'-deoxyguanosine; 8-OHdG), a marker of oxidative stress; the methylated form of cytosine (5-methylcytosine; 5-mC), associated with gene silencing; the hydroxy methylated form of cytosine (5-hydroxymethylcytosine; 5-hmC), involved in demethylation and gene regulation. The results showed a pronounced decrease in 8-OHdG levels in the VM, suggesting a rapid oxidative stress response, whereas the striatum exhibited a less pronounced response, reflecting regional differences in oxidative stress vulnerability DNA methylation patterns revealed complex and biphasic changes in 5-mC levels in the VM, contrasted with a less pronounced response in the striatum, suggesting disrupted methylation homeostasis and regional epigenetic variability. MPTP treatment also significantly reduced in 5-hmC levels in the VM, pointing to impaired active DNA demethylation and compromised epigenetic flexibility. In contrast, the striatum maintained consistently high 5-hmC levels, reflecting compensatory hydroxymethylation mechanisms specific to this region. These findings highlight pronounced regional differences in oxidative stress vulnerability and epigenetic regulation, with the VM showing heightened sensitivity to oxidative damage and impaired epigenetic flexibility. This underscores the importance of understanding the role of oxidative and epigenetic mechanisms in Parkinson\u2019s disease pathophysiology, The changes pave the way for novel therapeutic strategies targeting oxidative DNA damage and epigenetic homeostasis.<\/jats:p>","DOI":"10.1007\/s12640-025-00748-0","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T04:13:38Z","timestamp":1751602418000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dynamic Changes in Oxidative Stress and Epigenetic Modifications in the Ventral Mesencephalon and Striatum of MPTP-Treated Mice: Implications for Parkinson's Disease Pathogenesis"],"prefix":"10.1007","volume":"43","author":[{"given":"Pablo","family":"Gallo-Soljancic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Egle","family":"De Stefano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana-Maria","family":"Gonzalez-Cuello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emiliano","family":"Fernandez-Villalba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lode","family":"Godderis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Trinidad","family":"Herrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,4]]},"reference":[{"key":"748_CR1","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.exger.2014.09.014","volume":"68","author":"R Abdullah","year":"2015","unstructured":"Abdullah R, Basak I, Patil KS, Alves GW, Larsen JP, M\u00f8ller SG (2015) Parkinson\u2019s disease and age: The obvious but largely unexplored link. Exp Gerontol 68:33\u201338. https:\/\/doi.org\/10.1016\/j.exger.2014.09.014","journal-title":"Exp Gerontol"},{"key":"748_CR2","doi-asserted-by":"publisher","first-page":"934442","DOI":"10.1155\/2022\/7934442","volume":"2022","author":"AT Aborode","year":"2022","unstructured":"Aborode AT, Pustake M, Awuah WA, Alwerdani M, Shah P, Yarlagadda R, Ahmad S, Silva Correia IF, Chandra A, Nansubuga EP, Abdul-Rahman T, Mehta A, Ali O, Amaka SO, Zuniga Y, Shkodina A, Inya OC, Shen B, Alexiou A (2022) Targeting Oxidative Stress Mechanisms to Treat Alzheimer\u2019s and Parkinson\u2019s Disease: A Critical Review. Oxid Med Cell Longev 2022:934442. https:\/\/doi.org\/10.1155\/2022\/7934442","journal-title":"Oxid Med Cell Longev"},{"key":"748_CR3","doi-asserted-by":"publisher","first-page":"397","DOI":"10.3389\/fnins.2014.00397","volume":"8","author":"S Al-Mahdawi","year":"2014","unstructured":"Al-Mahdawi S, Virmouni SA, Pook MA (2014) The emerging role of 5-hydroxymethylcytosine in neurodegenerative diseases. Front Neurosci 8:397. https:\/\/doi.org\/10.3389\/fnins.2014.00397","journal-title":"Front Neurosci"},{"key":"748_CR4","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1111\/j.1365-2990.2012.01271.x","volume":"39","author":"V Annese","year":"2013","unstructured":"Annese V, Barcia C, Ros-Bernal F, G\u00f3mez A, Ros CM, De Pablos V, Fern\u00e1ndez-Villalba E, De Stefano ME, Herrero MT (2013) Evidence of oligodendrogliosis in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. Neuropathol Appl Neurobiol 39:132\u2013143. https:\/\/doi.org\/10.1111\/j.1365-2990.2012.01271.x","journal-title":"Neuropathol Appl Neurobiol"},{"key":"748_CR5","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1007\/s00429-014-0718-8","volume":"220","author":"V Annese","year":"2015","unstructured":"Annese V, Herrero MT, Di Pentima M, Gomez A, Lombardi L, Ros CM, De Pablos V, Fernandez-Villalba E, De Stefano ME (2015) Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. Brain Struct Funct 220:703\u2013727. https:\/\/doi.org\/10.1007\/s00429-014-0718-8","journal-title":"Brain Struct Funct"},{"key":"748_CR6","doi-asserted-by":"publisher","first-page":"e142","DOI":"10.1038\/cddis.2011.17","volume":"2","author":"C Barcia","year":"2011","unstructured":"Barcia C, Ros CM, Annese V, G\u00f3mez A, Ros-Bernal F, Aguado-Yera D, Mart\u00ednez-Pag\u00e1n ME, de Pablos V, Fernandez-Villalba E, Herrero MT (2011) IFN-\u03b3 signaling, with the synergistic contribution of TNF-\u03b1, mediates cell specific microglial and astroglial activation in experimental models of Parkinson\u2019s disease. Cell Death Dis 2:e142. https:\/\/doi.org\/10.1038\/cddis.2011.17","journal-title":"Cell Death Dis"},{"key":"748_CR7","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1038\/srep00809","volume":"2","author":"C Barcia","year":"2012","unstructured":"Barcia C, Ros CM, Annese V, Carrillo-de Sauvage MA, Ros-Bernal F, G\u00f3mez A, Yuste JE, Campuzano CM, de Pablos V, 1 Fernandez-Villalba E, Herrero MT, (2012) ROCK\/Cdc42-mediated microglial motility and gliapse formation lead to phagocytosis of degenerating dopaminergic neurons in vivo. Sci Rep 2:809. https:\/\/doi.org\/10.1038\/srep00809","journal-title":"Sci Rep"},{"key":"748_CR8","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.jneuroim.2013.05.001","volume":"261","author":"C Barcia","year":"2013","unstructured":"Barcia C, Ros CM, Ros-Bernal F, G\u00f3mez A, Annese V, Carrillo-de Sauvage MA, Yuste JE, Campuzano CM, de Pablos V, Fern\u00e1ndez-Villalba E, Herrero MT (2013) Persistent phagocytic characteristics of microglia in the substantia nigra of long-term Parkinsonian macaques. J Neuroimmunol 261:60\u201366. https:\/\/doi.org\/10.1016\/j.jneuroim.2013.05.001","journal-title":"J Neuroimmunol"},{"key":"748_CR9","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/845618","volume":"2012","author":"J Blesa","year":"2012","unstructured":"Blesa J, Phani S, Jackson-Lewis V, Przedborski S (2012) Classic and new animal models of Parkinson\u2019s disease. J Biomed Biotechnol 2012:845618. https:\/\/doi.org\/10.1155\/2012\/845618","journal-title":"J Biomed Biotechnol"},{"key":"748_CR10","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1093\/brain\/awm304","volume":"131","author":"MB Bogdanov","year":"2008","unstructured":"Bogdanov MB, Matson WR, Wang L, Matson T, Saunders-Pullman R, Bressman S, Flint Beal M (2008) Metabolomic profiling to develop blood biomarkers for Parkinson\u2019s disease. Brain 131:389\u2013396. https:\/\/doi.org\/10.1093\/brain\/awm304","journal-title":"Brain"},{"key":"748_CR11","first-page":"859","volume":"57","author":"A Bolner","year":"2011","unstructured":"Bolner A, Pilleri M, De Riva V, Nordera G (2011) Plasma and urinary HPLC-ED determination of the ratio of 8-OHdG\/2-dG in Parkinson\u2019s disease. Clin Lab 57:859\u2013866","journal-title":"Clin Lab"},{"key":"748_CR12","doi-asserted-by":"publisher","unstructured":"Bourdenx M, Nioche A, Dovero S, Arotcarena ML, Camus S, Porras G, Thiolat ML, Rougier NP, Prigent A, Aubert P, Bohic S, Sandt C, Laferri\u00e8re F, Doudnikoff E, Kruse N, Mollenhauer B, Novello S, Morari M, Leste-Lasserre T, Damas IT, Goillandeau M, Perier C, Estrada C, Garcia-Carrillo N, Recasens A, Vaikath NN, El-Agnaf OMA, Herrero MT, Derkinderen P, Vila M, Obeso JA, Dehay B, Bezard E. (2020) Identification of distinct pathological signatures induced by patient-derived \u03b1-synuclein structures in nonhuman primates. Sci. Adv 6:eaaz9165. https:\/\/doi.org\/10.1126\/sciadv.aaz9165.","DOI":"10.1126\/sciadv.aaz9165"},{"key":"748_CR13","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/s0197-4580(02)00065-9","volume":"24","author":"H Braak","year":"2003","unstructured":"Braak H, Del Tredici K, R\u00fcb U, de Vos RA, Steur ENJ, Braak E (2003) Staging of brain pathology related to sporadic Parkinson\u2019s disease. Neurobiol Aging 24:197\u2013211. https:\/\/doi.org\/10.1016\/s0197-4580(02)00065-9","journal-title":"Neurobiol Aging"},{"key":"748_CR14","doi-asserted-by":"publisher","first-page":"18536","DOI":"10.1074\/jbc.m413224200","volume":"280","author":"J Callio","year":"2005","unstructured":"Callio J, Oury TD, Chu CT (2005) Manganese superoxide dismutase protects against 6-Hydroxydopamine Injury in mouse brains. J Biol Chem 280:18536\u201318542. https:\/\/doi.org\/10.1074\/jbc.m413224200","journal-title":"J Biol Chem"},{"key":"748_CR15","doi-asserted-by":"publisher","first-page":"955","DOI":"10.3390\/antiox12040955","volume":"12","author":"S Chakrabarti","year":"2023","unstructured":"Chakrabarti S, Bisaglia M (2023) Oxidative stress and neuroinflammation in Parkinson\u2019s disease: the role of dopamine oxidation products. Antioxidants 12:955. https:\/\/doi.org\/10.3390\/antiox12040955","journal-title":"Antioxidants"},{"key":"748_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s40801-023-00410-1","volume":"11","author":"KR Chaudhuri","year":"2024","unstructured":"Chaudhuri KR, Azulay J, Odin P, Lindvall S, Domingos JA, Alobaidi A, Kandukuri PL, Chaudhari VS, Parra JC, Yamazaki T, Oddsdottir J, Wright J, Mart\u00ednez-Mart\u00edn P (2024) Economic burden of Parkinson\u2019s dsease: a multinational, real-world, cost-of-illness study. Drugs Real World Outcomes 11:1\u201311. https:\/\/doi.org\/10.1007\/s40801-023-00410-1","journal-title":"Drugs Real World Outcomes"},{"key":"748_CR17","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1186\/s13073-017-0466-5","volume":"9","author":"YH Chuang","year":"2017","unstructured":"Chuang YH, Paul KC, Bronstein JM, Bordelon Y, Horvath S, Ritz B (2017) Parkinson\u2019s disease is associated with DNA methylation levels in human blood and saliva. Genome Med 9:76. https:\/\/doi.org\/10.1186\/s13073-017-0466-5","journal-title":"Genome Med"},{"key":"748_CR18","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1007\/s11481-020-09925-8","volume":"16","author":"T Costa","year":"2021","unstructured":"Costa T, Fernandez-Villalba E, Izura V, Lucas-Ochoa AM, Menezes-Filho NJ, Santana RC, de Oliveira MD, Ara\u00fajo FM, Estrada C, Silva V, Costa SL, Herrero MT (2021) Combined 1-deoxynojirimyein and ibuprofen treatment decreases microglia activation, phagocytosis and dopaminergic degeneration in MPTP-treated mice. J Neuroimm Pharmacol 16:390\u2013402. https:\/\/doi.org\/10.1007\/s11481-020-09925-8","journal-title":"J Neuroimm Pharmacol"},{"key":"748_CR19","doi-asserted-by":"publisher","unstructured":"Cuenca L, Gil-Martinez AL, Cano-Fernandez L, S\u00e1nchez-Rodrigo C, Estrada C, Fern\u00e1ndez-Villalba E, Herrero MT (2019) Parkinson's disease: a short story of 200 years. Histol Histopathol 34:573\u2013591. https:\/\/doi.org\/10.14670\/hh-18-073","DOI":"10.14670\/hh-18-073"},{"key":"748_CR20","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1016\/s0896-6273(03)00568-3","volume":"39","author":"WT Dauer","year":"2003","unstructured":"Dauer WT, Przedborski S (2003) Parkinson\u2019s disease mechanisms and models. Neuron 39:889\u2013909. https:\/\/doi.org\/10.1016\/s0896-6273(03)00568-3","journal-title":"Neuron"},{"key":"748_CR21","doi-asserted-by":"publisher","unstructured":"de Ara\u00fajo FM, Cuenca-Bermejo L, Fern\u00e1ndez-Villalba E, Costa SL, Silva VDA, Herrero MT (2022) Role of Microgliosis and NLRP3 inflammasome in Parkinson's disease pathogenesis and therapy. J Neuroimm Pharmacol l16:390\u2013402. https:\/\/doi.org\/10.1007\/s12640-022-00616-1.","DOI":"10.1007\/s12640-022-00616-1"},{"key":"748_CR22","doi-asserted-by":"publisher","first-page":"101263","DOI":"10.1016\/j.arr.2021.101263","volume":"67","author":"PA Dionisio","year":"2021","unstructured":"Dionisio PA, Amaral JD, Rodrigues CPM (2021) Oxidative stress and regulated cell death in Parkinson\u2019s disease. Ageing Res Rev 67:101263. https:\/\/doi.org\/10.1016\/j.arr.2021.101263","journal-title":"Ageing Res Rev"},{"key":"748_CR23","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s40035-023-00368-8","volume":"12","author":"A Dovonou","year":"2023","unstructured":"Dovonou A, Bolduc C, Soto Linan V, Gora C, PeraltaMR LM (2023) Animal models of Parkinson\u2019s disease: bridging the gap between disease hallmarks and research questions. Trans Neurodeg 12:36. https:\/\/doi.org\/10.1186\/s40035-023-00368-8","journal-title":"Trans Neurodeg"},{"key":"748_CR24","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1159\/000513678","volume":"28","author":"R Du","year":"2021","unstructured":"Du R, Bu W (2021) Simvastatin prevents neurodegeneration in the MPTP mouse Model of Parkinson\u2019s disease via inhibition of A1 reactive astrocytes. NeuroImmunoModulation 28:82\u201389. https:\/\/doi.org\/10.1159\/000513678","journal-title":"NeuroImmunoModulation"},{"key":"748_CR25","doi-asserted-by":"publisher","first-page":"14669","DOI":"10.1073\/pnas.251341998","volume":"98","author":"Y Du","year":"2001","unstructured":"Du Y, Ma Z, Lin S, Dodel R, Gao F, Bales KR, Triarhou LC, Chernet E, Perry KW, Nelson DL, Luecke S, Phebus L, Bymaster FP, Paul SM (2001) Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson\u2019s disease. Proc Natl Acad Sci USA 98:14669\u201314674. https:\/\/doi.org\/10.1073\/pnas.251341998","journal-title":"Proc Natl Acad Sci USA"},{"key":"748_CR26","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/0006-8993(95)00629-5","volume":"691","author":"BA Faucheux","year":"1995","unstructured":"Faucheux BA, Herrero MT, Villares J, Levy R, Javoy-Agid F, Obeso JA, Hauw JJ, Agid Y, Hirsch EC (1995) Autoradiographic localization and density of [125I]ferrotransferrin binding sites in the basal ganglia of control subjects, patients with Parkinson\u2019s disease and MPTP-lesioned monkeys. Brain Res 691:115\u2013124. https:\/\/doi.org\/10.1016\/0006-8993(95)00629-5","journal-title":"Brain Res"},{"key":"748_CR27","doi-asserted-by":"publisher","first-page":"451","DOI":"10.3389\/fncel.2018.00451","volume":"12","author":"AL Gil-Martinez","year":"2018","unstructured":"Gil-Martinez AL, Cuenca L, Estrada C, S\u00e1nchez-Rodrigo C, Fern\u00e1ndez-Villalba E, Herrero MT (2018) Unexpected exacerbation of neuroinflammatory response after a combined therapy in old Parkinsonian mice. Front Cell Neurosci 12:451. https:\/\/doi.org\/10.3389\/fncel.2018.00451","journal-title":"Front Cell Neurosci"},{"key":"748_CR28","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1007\/s12640-019-0010-z","volume":"35","author":"AL Gil-Martinez","year":"2019","unstructured":"Gil-Martinez AL, Estrada C, Cuenca L, Cano JA, Valiente M, Mart\u00ednez-C\u00e1ceres CM, Fern\u00e1ndez-Villalba E, Herrero MT (2019) Local gastrointestinal injury exacerbates inflammation and dopaminergic cell death in Parkinsonian mice. Neurotox Res 35:918\u2013930. https:\/\/doi.org\/10.1007\/s12640-019-0010-z","journal-title":"Neurotox Res"},{"key":"748_CR29","doi-asserted-by":"publisher","unstructured":"Gil-Martinez AL, Cuenca-Bermejo L, Gallo-Soljancic P, S\u00e1nchez-Rodrigo C, Izura V, Steinbusch HW, Fern\u00e1ndez-Villalba E, Herrero MT (2020a) Study of the link between neuronal death, glial response, and MAPK pathway in old Parkinsonian mice. Front Aging Neurosci 12:214. https:\/\/doi.org\/10.3389\/fnagi.2020.00214","DOI":"10.3389\/fnagi.2020.00214"},{"key":"748_CR30","doi-asserted-by":"publisher","unstructured":"Gil-Martinez AL, Cuenca-Bermejo L, Gonzalez-Cuello AM, Sanchez-Rodrig C, Parrado A, Vyas S, Fernandez-Villalba E, Herrero MT (2020b) Identification of differentially expressed genes profiles in a combined mouse model of Parkinsonism and colitis. Sci Rep 10:13147. https:\/\/doi.org\/10.1038\/s41598-020-69695-4","DOI":"10.1038\/s41598-020-69695-4"},{"key":"748_CR31","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1159\/000237221","volume":"6","author":"K Gmitterov\u00e1","year":"2009","unstructured":"Gmitterov\u00e1 K, Heinemann U, Gawinecka J, Varges D, Ciesielczyk B, Valkovi\u010d P, Benetin J, Zerr I (2009) 8-OHdG in cerebrospinal fluid as a marker of oxidative stress in various neurodegenerative diseases. Neurodegener Dis 6:263\u2013269. https:\/\/doi.org\/10.1159\/000237221","journal-title":"Neurodegener Dis"},{"key":"748_CR32","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1097\/wco.0000000000000112","volume":"27","author":"JG Goldman","year":"2014","unstructured":"Goldman JG, Postuma RB (2014) Premotor and nonmotor features of Parkinson\u2019s disease. Curr Opin Neurol 27:434\u2013441. https:\/\/doi.org\/10.1097\/wco.0000000000000112","journal-title":"Curr Opin Neurol"},{"key":"748_CR33","doi-asserted-by":"publisher","first-page":"4777","DOI":"10.3390\/ijms21134777","volume":"21","author":"F He","year":"2020","unstructured":"He F, Ru X, Wen T (2020) NRF2, a transcription factor for stress response and beyond. Int J Mol Sci 21:4777. https:\/\/doi.org\/10.3390\/ijms21134777","journal-title":"Int J Mol Sci"},{"key":"748_CR34","doi-asserted-by":"publisher","first-page":"787771","DOI":"10.3389\/fphar.2021.787771","volume":"12","author":"D He","year":"2022","unstructured":"He D, Hu G, Zhou A, Liu Y, Huang B, Su Y, Wang H, Ye B, He Y, Gao X, Fu S, Liu D (2022) Echinocystic acid inhibits inflammation and exerts neuroprotective effects in MPTP-induced Parkinson\u2019s disease model mice. Front Pharmacol 12:787771. https:\/\/doi.org\/10.3389\/fphar.2021.787771","journal-title":"Front Pharmacol"},{"key":"748_CR35","doi-asserted-by":"publisher","first-page":"640266","DOI":"10.3389\/fgene.2021.640266","volume":"12","author":"AR Henderson","year":"2021","unstructured":"Henderson AR, Matta S, Smeyne RJ, Marras C, Visanji NP, Lang AE, Brotchie JM, Hazrati LN (2021) DNA methylation and expression profiles of whole blood in Parkinson\u2019s disease. Front Genet 12:640266. https:\/\/doi.org\/10.3389\/fgene.2021.640266","journal-title":"Front Genet"},{"key":"748_CR36","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/s1474-4422(09)70062-6","volume":"8","author":"EC Hirsch","year":"2009","unstructured":"Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson\u2019s disease: a target for neuroprotection? Lancet Neurol 8:382\u2013397. https:\/\/doi.org\/10.1016\/s1474-4422(09)70062-6","journal-title":"Lancet Neurol"},{"key":"748_CR37","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/nrn.2017.46","volume":"18","author":"JY Hwang","year":"2017","unstructured":"Hwang JY, Aromolaran KA, Zukin RS (2017) The emerging field of epigenetics in neurodegeneration and neuroprotection. Nat Rev Neurosci 18:347\u2013361. https:\/\/doi.org\/10.1038\/nrn.2017.46","journal-title":"Nat Rev Neurosci"},{"key":"748_CR38","doi-asserted-by":"publisher","first-page":"2666","DOI":"10.2174\/0929867323666160812151356","volume":"23","author":"FJ Jim\u00e9nez-Jim\u00e9nez","year":"2016","unstructured":"Jim\u00e9nez-Jim\u00e9nez FJ, Alonso-Navarro H, Herrero MT, Garc\u00eda-Mart\u00edn E, Ag\u00fandez JA (2016) An update on the role of nitric oxide in the neurodegenerative processes of Parkinson\u2019s disease. Curr Med Chem 23:2666\u20132679. https:\/\/doi.org\/10.2174\/0929867323666160812151356","journal-title":"Curr Med Chem"},{"key":"748_CR39","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1002\/ana.410360213","volume":"36","author":"A Kastner","year":"1994","unstructured":"Kastner A, Herrero MT, Hirsch EC, Guillen J, Luquin MR, Javoy-Agid F, Obeso JA, Agid Y (1994) Decreased tyrosine hydroxylase content in the dopaminergic neurons of MPTP-intoxicated monkeys: effect of levodopa and GM1 ganglioside therapy. Ann Neurol 36:206\u2013214. https:\/\/doi.org\/10.1002\/ana.410360213","journal-title":"Ann Neurol"},{"key":"748_CR40","doi-asserted-by":"publisher","first-page":"502","DOI":"10.3390\/life12040502","volume":"12","author":"O Kaut","year":"2022","unstructured":"Kaut O, Schmitt I, Tost J, Busato F, Liu Y, Hofmann P, Witt SH, Rietschel M, Fr\u00f6hlich H, W\u00fcllner U (2022) Epigenome-wide analysis of DNA methylation in Parkinson\u2019s disease cortex. Life 12:502. https:\/\/doi.org\/10.3390\/life12040502","journal-title":"Life"},{"key":"748_CR41","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1093\/toxsci\/kfz069","volume":"169","author":"J Kochmanski","year":"2019","unstructured":"Kochmanski J, VanOeveren SE, Patterson JR, Bernstein AI (2019) Developmental dieldrin exposure alters DNA methylation at genes related to dopaminergic neuron development and Parkinson\u2019s disease in mouse midbrain. Toxicol Sci 169:2. https:\/\/doi.org\/10.1093\/toxsci\/kfz069","journal-title":"Toxicol Sci"},{"key":"748_CR42","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1038\/s41531-022-00355-2","volume":"8","author":"J Kochmanski","year":"2022","unstructured":"Kochmanski J, Kuhn NC, Bernstein AI (2022) Parkinson\u2019s disease-associated, sex-specific changes in DNA methylation at PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2\u03b2), and NR4A2 (NURR1) in cortical neurons. NPJ Parkinsons Dis 8:120. https:\/\/doi.org\/10.1038\/s41531-022-00355-2","journal-title":"NPJ Parkinsons Dis"},{"key":"748_CR43","doi-asserted-by":"publisher","first-page":"176819","DOI":"10.1016\/j.ejphar.2024.176819","volume":"980","author":"R Lal","year":"2024","unstructured":"Lal R, Singh A, Watts S, Chopra K (2024) Experimental models of Parkinson\u2019s disease: challenges and opportunities. Eur J Pharmacol 980:176819. https:\/\/doi.org\/10.1016\/j.ejphar.2024.176819","journal-title":"Eur J Pharmacol"},{"key":"748_CR44","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/s41418-018-0124-5","volume":"26","author":"E Lee","year":"2019","unstructured":"Lee E, Hwang I, Park S, Hong S, Hwang B, Cho Y, Son J, Yu JW (2019) MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration. Cell Death Differ 26:213\u2013228. https:\/\/doi.org\/10.1038\/s41418-018-0124-5","journal-title":"Cell Death Differ"},{"key":"748_CR45","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1007\/s11064-011-0471-9","volume":"36","author":"RB Mythri","year":"2011","unstructured":"Mythri RB, Venkateshappa C, Harish G, Mahadevan A, Muthane UB, Yasha TC, Srinivas Bharath MM, Shankar SK (2011) Evaluation of markers of oxidative stress, antioxidant function and astrocytic proliferation in the striatum and frontal cortex of Parkinson\u2019s disease brains. Neurochem Res 36:1452\u20131463. https:\/\/doi.org\/10.1007\/s11064-011-0471-9","journal-title":"Neurochem Res"},{"key":"748_CR46","doi-asserted-by":"publisher","first-page":"1687","DOI":"10.3390\/cells9071687","volume":"9","author":"M Pajares","year":"2020","unstructured":"Pajares M, Rojo AI, Manda G, Bosc\u00e1 L, Cuadrado A (2020) Inflammation in Parkinson\u2019s disease: mechanisms and therapeutic implications. Cells 9:1687. https:\/\/doi.org\/10.3390\/cells9071687","journal-title":"Cells"},{"key":"748_CR47","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/0006-8993(92)91201-o","volume":"1585","author":"I Perez-Otano","year":"1992","unstructured":"Perez-Otano I, Herrero MT, Luquin MR, Obeso JA, Del Rio J, J, (1992) Chronic MPTP treatment reduces substance P and met-enkephalin content in the basal ganglia of the marmoset. Brain Res 1585:156\u2013160. https:\/\/doi.org\/10.1016\/0006-8993(92)91201-o","journal-title":"Brain Res"},{"key":"748_CR48","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1016\/s0166-2236(03)00144-9","volume":"26","author":"C Perier","year":"2003","unstructured":"Perier C, Bov\u00e9 J, Vila M, Przedborski S (2003) The rotenone model of Parkinson\u2019s disease. Trends Neurosci 26:345\u2013346. https:\/\/doi.org\/10.1016\/s0166-2236(03)00144-9","journal-title":"Trends Neurosci"},{"key":"748_CR49","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.1002\/mds.25945","volume":"29","author":"TM Pringsheim","year":"2014","unstructured":"Pringsheim TM, Jett\u00e9 N, Frolkis AD, Steeves TD (2014) The prevalence of Parkinson\u2019s disease: A systematic review and meta-analysis. Mov Disord 29:1583\u20131590. https:\/\/doi.org\/10.1002\/mds.25945","journal-title":"Mov Disord"},{"key":"748_CR50","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1046\/j.1471-4159.2001.00183.x","volume":"76","author":"S Przedborski","year":"2001","unstructured":"Przedborski S, Jackson-Lewis VR, Naini AB, Jakowec MW, Petzinger GM, Miller R, Akram M (2001) The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a technical review of its utility and safety. J Neurochem 76:1265\u20131274. https:\/\/doi.org\/10.1046\/j.1471-4159.2001.00183.x","journal-title":"J Neurochem"},{"key":"748_CR51","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13041-017-0340-9","volume":"10","author":"L Puspita","year":"2017","unstructured":"Puspita L, Chung SY, Shim JW (2017) Oxidative stress and cellular pathologies in Parkinson\u2019s disease. Mol Brain 10:1\u201312. https:\/\/doi.org\/10.1186\/s13041-017-0340-9","journal-title":"Mol Brain"},{"key":"748_CR52","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1093\/toxsci\/kfi304","volume":"88","author":"JR Richardson","year":"2005","unstructured":"Richardson JR, Quan Y, Sherer T, Greenamyre JT, Miller GW (2005) Paraquat neurotoxicity is distinct from that of MPTP and rotenone. Toxicol Sci 88:193\u2013201. https:\/\/doi.org\/10.1093\/toxsci\/kfi304","journal-title":"Toxicol Sci"},{"key":"748_CR53","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.brainresbull.2019.12.013","volume":"156","author":"P Sinha","year":"2020","unstructured":"Sinha P, Chakrabarti N, Ghosh N, Mitra S, Dalui S, Bhattacharyya A (2020) Alterations of thyroidal status in brain regions and hypothalamo-pituitary-blood-thyroid-axis associated with dopaminergic depletion in substantia nigra and ROS formation in different brain regions after MPTP treatment in adult male mice. Brain Res Bull 156:131\u2013140. https:\/\/doi.org\/10.1016\/j.brainresbull.2019.12.013","journal-title":"Brain Res Bull"},{"key":"748_CR54","doi-asserted-by":"publisher","unstructured":"Tan AH, Chuah K, Beh YY, Schee JP, Mahadeva S, Lim S (2023) Gastrointestinal dysfunction in Parkinson's disease: neuro-gastroenterology perspectives on a multifaceted problem. J Mov Disord 16:138\u2013151. https:\/\/doi.org\/10.14802\/jmd.22220.","DOI":"10.14802\/jmd.22220"},{"key":"748_CR55","doi-asserted-by":"publisher","first-page":"134","DOI":"10.3390\/neurosci4020013","volume":"4","author":"G Torres-Pasillas","year":"2023","unstructured":"Torres-Pasillas G, Chi-Casta\u00f1eda D, Carrillo-Castilla P, Mar\u00edn G, Hern\u00e1ndez-Aguilar ME, Aranda-Abreu GE, Manzo J, Garc\u00eda LI (2023) Olfactory dysfunction in Parkinson\u2019s disease, its functional and neuroanatomical correlates. NeuroSci 4:134\u2013151. https:\/\/doi.org\/10.3390\/neurosci4020013","journal-title":"NeuroSci"},{"key":"748_CR56","doi-asserted-by":"publisher","first-page":"e13031","DOI":"10.1111\/acel.13031","volume":"18","author":"BG Trist","year":"2019","unstructured":"Trist BG, Hare DJ, Double KL (2019) Oxidative stress in the aging substantia nigra and the etiology of Parkinson\u2019s disease. Aging Cell 18:e13031. https:\/\/doi.org\/10.1111\/acel.13031","journal-title":"Aging Cell"},{"key":"748_CR57","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1038\/s41531-023-00568-z","volume":"9","author":"M Tsalenchuk","year":"2023","unstructured":"Tsalenchuk M, Gentleman SM, Marzi SJ (2023) Linking environmental risk factors with epigenetic mechanisms in Parkinson\u2019s disease. NPJ Parkinsons Dis 9:123. https:\/\/doi.org\/10.1038\/s41531-023-00568-z","journal-title":"NPJ Parkinsons Dis"},{"key":"748_CR58","doi-asserted-by":"publisher","first-page":"2285","DOI":"10.1007\/s11064-023-03904-0","volume":"48","author":"SM Vastegani","year":"2023","unstructured":"Vastegani SM, Nasrolahi A, Ghaderi S, Belali R, Rashno M, Farzaneh M, Khoshnam SE (2023) Mitochondrial dysfunction and Parkinson\u2019s disease: pathogenesis and therapeutic strategies. Neurochem Res 48:2285\u20132308. https:\/\/doi.org\/10.1007\/s11064-023-03904-0","journal-title":"Neurochem Res"},{"key":"748_CR59","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1007\/s11064-011-0619-7","volume":"37","author":"C Venkateshappa","year":"2012","unstructured":"Venkateshappa C, Harish G, Mythri RB, Mahadevan A, Srinivas Bharath MM, Shankar SK (2012) Increased oxidative damage and decreased antioxidant function in aging human substantia nigra compared to striatum: implications for Parkinson\u2019s disease. Neurochem Res 37:358\u2013369. https:\/\/doi.org\/10.1007\/s11064-011-0619-7","journal-title":"Neurochem Res"},{"key":"748_CR60","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1111\/neup.12691","volume":"40","author":"K Wakabayashi","year":"2020","unstructured":"Wakabayashi K (2020) Where and how alpha-synuclein pathology spreads in Parkinson\u2019s disease. Neuropathology 40:415\u2013425. https:\/\/doi.org\/10.1111\/neup.12691","journal-title":"Neuropathology"},{"key":"748_CR61","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1007\/s11910-019-0995-y","volume":"19","author":"M Xylaki","year":"2019","unstructured":"Xylaki M, Atzler B, Outeiro TF (2019) Epigenetics of the synapse in neurodegeneration. Curr Neurol Neurosci Rep 19:72. https:\/\/doi.org\/10.1007\/s11910-019-0995-y","journal-title":"Curr Neurol Neurosci Rep"},{"key":"748_CR62","doi-asserted-by":"publisher","unstructured":"Younesian S, Yousefi AM, Momeny M, Ghaffari SH, Bashash D et al\u00a0(2022)\u00a0The DNA methylation in neurological diseases. Cells 11(21):3439. https:\/\/doi.org\/10.3390\/cells11213439","DOI":"10.3390\/cells11213439"},{"key":"748_CR63","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/j.tins.2024.04.003","volume":"47","author":"W Zhang","year":"2024","unstructured":"Zhang W, Sun H-S, Wang X, Dumont AS, Liu Q (2024) Cellular senescence, DNA damage, and neuroinflammation in the aging brain. Trends Neurosci 47:461\u2013474. https:\/\/doi.org\/10.1016\/j.tins.2024.04.003","journal-title":"Trends Neurosci"}],"container-title":["Neurotoxicity Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12640-025-00748-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12640-025-00748-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12640-025-00748-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T16:02:06Z","timestamp":1756224126000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12640-025-00748-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,4]]},"references-count":63,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["748"],"URL":"https:\/\/doi.org\/10.1007\/s12640-025-00748-0","relation":{},"ISSN":["1029-8428","1476-3524"],"issn-type":[{"value":"1029-8428","type":"print"},{"value":"1476-3524","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,4]]},"assertion":[{"value":"7 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 April 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 May 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 July 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The author(s) declared no potential conflicts of interest with respect to the research, authorship, and\/or publication of this article.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicting Interests"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"30"}}