{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T11:44:55Z","timestamp":1785930295999,"version":"3.56.0"},"reference-count":71,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T00:00:00Z","timestamp":1772668800000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["F31\u2010NS137783"],"award-info":[{"award-number":["F31\u2010NS137783"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01\u2010NS113912\u201005"],"award-info":[{"award-number":["R01\u2010NS113912\u201005"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["TL1\u2010TR002016"],"award-info":[{"award-number":["TL1\u2010TR002016"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011594","name":"Penn State College of Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011594","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, a region within the ventral midbrain known to accumulate iron. While L\u20103,4\u2010dihydroxyphenylalanine (L\u2010DOPA) remains the gold standard treatment for PD, its impact on brain iron homeostasis, particularly under varying systemic iron conditions, remains poorly understood. In this study, we investigate how dietary iron status and anti\u2010PD treatments influence brain iron accumulation and regulation in the ventral midbrain, with a focus on sex\u2010specific differences. Male and female Long\u2010Evans rats were placed on iron\u2010adequate (IA), iron\u2010deficient (ID), or iron\u2010repletion (IR) diets from postnatal day (PND) 21 for eight weeks. In the final three weeks, animals received daily subcutaneous injections of L\u2010DOPA, selegiline, or vehicle. Our findings revealed that L\u2010DOPA treatment in IR males significantly increased brain iron levels in the ventral midbrain, whereas females showed no such effect. This sex\u2010specific accumulation was accompanied by the upregulation of iron uptake protein transferrin receptor 1 (TfR1), increased ferroportin (FPN1), and reduced expression of the iron storage protein ferritin heavy chain (FTH1), indicating disrupted iron homeostasis. Furthermore, L\u2010DOPA\u2010treated males on the IR diet exhibited elevated glial fibrillary acidic protein (GFAP) and lipocalin\u20102 (LCN2), suggesting enhanced oxidative stress and astrocyte activation. Consistent with this, antioxidant enzymes catalase (CAT) and superoxide dismutase 2 (SOD2) were significantly decreased in L\u2010DOPA\u2010treated males on the IR diet, highlighting increased vulnerability to oxidative damage. In contrast, selegiline did not significantly alter brain iron levels or iron\u2010regulatory protein expression, regardless of diet or sex. These findings demonstrate that systemic iron repletion after deficiency sensitizes the male brain to L\u2010DOPA\u2010induced iron accumulation, potentially increasing susceptibility to neurodegeneration. This study highlights the importance of considering that both dietary iron status and biological sex may impact PD treatment strategies.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70389-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70389","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T19:07:25Z","timestamp":1772996845000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Sex and Diet Biased Effect of L\u2010\n                    <scp>DOPA<\/scp>\n                    on Iron Accumulation in the Ventral Midbrain"],"prefix":"10.1111","volume":"170","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5232-9172","authenticated-orcid":false,"given":"Rebecka O.","family":"Serpa","sequence":"first","affiliation":[{"name":"Department of Neurosurgery The Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"},{"name":"Department of Neuroscience and Experimental Therapeutics Sciences The Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"},{"name":"Penn State Neuroscience Institute The Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Tufano","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kondaiah","family":"Palsa","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7002-5997","authenticated-orcid":false,"given":"Timothy B.","family":"Helmuth","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Mills\u2010Huffnagle","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Experimental Therapeutics Sciences The Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"},{"name":"Penn State Neuroscience Institute The Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Kant","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R.","family":"Connor","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"},{"name":"Department of Neuroscience and Experimental Therapeutics Sciences The Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"},{"name":"Penn State Neuroscience Institute The Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.23.020102.075739"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13570"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471\u20104159.2008.05358.x"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14676"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2015.82"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2024.106506"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.3233\/jpd\u2010191683"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14834"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276\u2010021\u201000646\u20103"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471\u20104159.1995.65020717.x"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.61.6.886"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.curtheres.2020.100612"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2021.101414"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2016.11.007"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010023\u201001353\u20103"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(18)30295\u20103"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40035\u2010023\u201000368\u20108"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.29062"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.25303"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.3758\/BRM.41.4.1149"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.685822"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2017.95"},{"issue":"10","key":"e_1_2_11_24_1","first-page":"590","article-title":"Medical Management of Parkinson's Disease","volume":"33","author":"Goldenberg M. M.","year":"2008","journal-title":"P t"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2009.06.006"},{"issue":"3","key":"e_1_2_11_26_1","first-page":"517","article-title":"Iron Deficiency Alters H\u2010 and L\u2010Ferritin Expression in Rat Brain","volume":"46","author":"Han J.","year":"2000","journal-title":"Cellular and Molecular Biology (Noisy\u2010le\u2010Grand, France)"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep29651"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420\u2010021\u201000547\u20104"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.5114\/pm.2022.119634"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2018.00097"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.4261\u201015.2016"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci11050623"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2021.108800"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2006.10.002"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010019\u201047026\u20106"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2011.10.016"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380\u2010023\u201002399\u2010z"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2024.103342"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531\u2010025\u201000911\u20106"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.3945\/jn.110.131169"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2015.09.023"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/1742\u20102094\u201010\u2010130"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1179\/1351000214y.0000000119"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1097\/wnf.0000000000000343"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00702\u2010012\u20100905\u20109"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2019.00176"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102868"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202301596RR"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.04.007"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010024\u201003990\u20103"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/130.2.254"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/123.11.1939"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2019.03.010"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181bd80c1"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1229885"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2020.08.010"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2017.00306"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.647168"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2012.11.010"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu14214671"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2024.04.015"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311\u2010020\u201000929\u2010z"},{"key":"e_1_2_11_63_1","first-page":"419","volume-title":"Progress in Molecular Biology and Translational Science","author":"Trancikova A.","year":"2011"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102010\u201004\u2010278614"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/8360627"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2022.105920"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep07506"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1097\u20102765(02)00710\u20104"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010022\u201005043\u2010w"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnha.2024.100212"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10571-024-01459-4"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2010.09.010"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.70389","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jnc.70389","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.70389","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T06:12:05Z","timestamp":1778307125000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.70389"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3]]},"references-count":71,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1111\/jnc.70389"],"URL":"https:\/\/doi.org\/10.1111\/jnc.70389","archive":["Portico"],"relation":{},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3]]},"assertion":[{"value":"2025-09-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70389"}}