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Iron accumulation in the substantia nigra (SN) occurs with Parkinson\u2019s disease (PD) progression and has been hypothesized to be an etiological mechanism.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Based on emerging clinical observations, we tested the hypothesis that iron accumulation in the SN is a consequence of levodopa administration and is treatment-related rather than an intrinsic etiological mechanism.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We used both unilaterally lesioned 6-OHDA and unlesioned rats. We administered levodopa to rats at doses that were allometrically calculated to be similar to those used in mid-stages of PD. Iron-sensitive MRI (R2*) was used to quantify iron in the brain. Both group and intra-subject analyses were done using paired t-tests and linear mixed models.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Experiment 1 used the unilateral 6-OHDA model to take advantage of the almost complete lack of dopamine neurons on the lesioned side. This permitted testing if levodopa-induced iron accumulation occurred in and\/or depended on dopamine neurons. Fifteen days of levodopa treatment caused a marked increase in Fe in both the lesioned (p = 0.042) and unlesioned sides (p = 0.005), showing that iron accumulation does not depend on the presence of dopamine neurons. Based on these data, in experiment 2 unlesioned rats were administered levodopa daily for four months, and iron (R2*) values were assessed at baseline, 1, 2, and 4 months. In these normal rats, the levodopa-treated group had significantly increased Fe (R2*) in the substantia nigra compared to the vehicle group (p = 0.013). Interestingly, these effects were limited to the striatum, with no increases seen in the striatum, ventral tegmental area, or frontal cortex<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Levodopa triggers processes that increase iron deposition in the substantia nigra, but this process may not depend on dopamine neurons. The underlying mechanisms and the effect on PD progression are important to elucidate and may transform how we understand PD and related neurodegenerative disorders<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.26.728066","type":"posted-content","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T17:30:14Z","timestamp":1780335014000},"source":"Crossref","is-referenced-by-count":0,"title":["Levodopa increases substantia nigra iron: implications for Parkinson\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8267-0301","authenticated-orcid":false,"given":"Guangwei","family":"Du","sequence":"first","affiliation":[{"name":"Department of Neurology, Penn State College of Medicine, Hershey, PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Bransom","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Experimental Therapeutics, Penn State College of Medicine, Hershey, PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neurology, Penn State College of Medicine, Hershey, PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9714-921X","authenticated-orcid":false,"given":"Christopher","family":"Sica","sequence":"additional","affiliation":[{"name":"Department of Radiology, Rush University, Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Virginia School of Medicine, Charlottesville VA 22902"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Experimental Therapeutics, Penn State College of Medicine, Hershey, PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1353-2738","authenticated-orcid":false,"given":"Richard B.","family":"Mailman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, University of Virginia School of Medicine, Charlottesville VA 22902"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026060410101960000_2026.05.26.728066v1.1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/114.5.2283"},{"key":"2026060410101960000_2026.05.26.728066v1.2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awt192"},{"key":"2026060410101960000_2026.05.26.728066v1.3","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/114.4.1953"},{"key":"2026060410101960000_2026.05.26.728066v1.4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1989.tb07264.x"},{"key":"2026060410101960000_2026.05.26.728066v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(87)91361-4"},{"key":"2026060410101960000_2026.05.26.728066v1.6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1991.tb02017.x"},{"key":"2026060410101960000_2026.05.26.728066v1.7","doi-asserted-by":"publisher","DOI":"10.1007\/BF01244786"},{"key":"2026060410101960000_2026.05.26.728066v1.8","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000286384.31050.b5"},{"key":"2026060410101960000_2026.05.26.728066v1.9","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.00180"},{"key":"2026060410101960000_2026.05.26.728066v1.10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2010.07132.x"},{"key":"2026060410101960000_2026.05.26.728066v1.11","doi-asserted-by":"publisher","DOI":"10.1021\/tx0497144"},{"key":"2026060410101960000_2026.05.26.728066v1.12","doi-asserted-by":"crossref","unstructured":"Ward, R.J. , Dexter, D.T. & Crichton, R.R. 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