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Although levodopa-induced dyskinesia, characterized by tic-like abnormal involuntary movements, has no clinical treatment for Parkinson\u2019s disease patients, animal studies indicate that Riluzole, which interferes with glutamatergic neurotransmission, can improve the phenotype. The rat model of Levodopa-Induced Dyskinesia is a unilateral lesion with 6-hydroxydopamine in the medial forebrain bundle, followed by the repeated administration of levodopa. The molecular pathomechanism of Levodopa-Induced Dyskinesia is still not deciphered; however, the implication of epigenetic mechanisms was suggested. In this study, we investigated the striatum for DNA methylation alterations under chronic levodopa treatment with or without co-treatment with Riluzole. Our data show that the lesioned and contralateral striata have nearly identical DNA methylation profiles. Chronic levodopa and levodopa + Riluzole treatments led to DNA methylation loss, particularly outside of promoters, in gene bodies and CpG poor regions. We observed that several genes involved in the Levodopa-Induced Dyskinesia underwent methylation changes. Furthermore, the Riluzole co-treatment, which improved the phenotype, pinpointed specific methylation targets, with a more than 20% methylation difference relative to levodopa treatment alone. These findings indicate potential new druggable targets for Levodopa-Induced Dyskinesia.<\/jats:p>","DOI":"10.3390\/cells10061442","type":"journal-article","created":{"date-parts":[[2021,6,9]],"date-time":"2021-06-09T14:16:04Z","timestamp":1623248164000},"page":"1442","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Riluzole Administration to Rats with Levodopa-Induced Dyskinesia Leads to Loss of DNA Methylation in Neuronal Genes"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5539-4789","authenticated-orcid":false,"given":"Luca","family":"Pagliaroli","sequence":"first","affiliation":[{"name":"Department of Molecular Biology, Semmelweis University, H-1094 Budapest, Hungary"},{"name":"Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7398-9700","authenticated-orcid":false,"given":"Abel","family":"Fothi","sequence":"additional","affiliation":[{"name":"Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester","family":"Nespoli","sequence":"additional","affiliation":[{"name":"CNS Department, Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany"},{"name":"Department of Child and Adolescent Psychiatry\/Psychotherapy, University of Ulm, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7668-4726","authenticated-orcid":false,"given":"Istvan","family":"Liko","sequence":"additional","affiliation":[{"name":"Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borbala","family":"Veto","sequence":"additional","affiliation":[{"name":"Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piroska","family":"Devay","sequence":"additional","affiliation":[{"name":"Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2572-6820","authenticated-orcid":false,"given":"Flora","family":"Szeri","sequence":"additional","affiliation":[{"name":"Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary"},{"name":"Department of Biochemistry, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7811-9795","authenticated-orcid":false,"given":"Bastian","family":"Hengerer","sequence":"additional","affiliation":[{"name":"CNS Department, Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach an der Riss, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4350-8838","authenticated-orcid":false,"given":"Csaba","family":"Barta","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Semmelweis University, H-1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamas","family":"Aranyi","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Semmelweis University, H-1094 Budapest, Hungary"},{"name":"Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1002\/mds.23088","article-title":"Definition and classification of hyperkinetic movements in childhood","volume":"25","author":"Sanger","year":"2010","journal-title":"Mov. 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