{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T20:24:12Z","timestamp":1792614252365,"version":"4.5.0"},"reference-count":46,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T00:00:00Z","timestamp":1743033600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NINDS","award":["R61NS138063"],"award-info":[{"award-number":["R61NS138063"]}]},{"name":"NIH\/NINDS","award":["R01NS092823"],"award-info":[{"award-number":["R01NS092823"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Background: All the processes leading to neurodegeneration cannot be addressed with just one medication. Combinations of drugs affecting various disease mechanisms concurrently could demonstrate improved effect in slowing the course of Parkinson\u2019s disease (PD). Objective: This was a drug-repurposing experiment designed to assess several combinations of nine drugs for possible added or synergistic efficacy using in vitro models of PD. Methods: We evaluated 44 combinations of the nine medications (sodium phenylbutyrate, terazosin, exenatide, ambroxol, deferiprone, coenzyme-Q10, creatine, dasatinib and tauroursodeoxycholic acid) selected for their previously demonstrated evidence of their impact on different targets, showing neuroprotective properties in preclinical models of PD. We utilized wild-type induced pluripotent stem-cell-derived human dopaminergic neurons treated with 1-methyl-4-phenylpyridinium for initial screening. We retested some combinations using an idiopathic PD patient-derived induced pluripotent stem cell line and alpha-synuclein triplication line. We assessed anti-neuroinflammatory effects using human microglia cells. As metrics, we evaluated neurite length, number of branch points per mm2, the number of live neurons, neurofilament heavy chain and pro-inflammatory cytokines. Results: We have identified four combinations of two to three drugs that showed an additive protective effect in some endpoints. Only the combination of sodium phenylbutyrate, exenatide and tauroursodeoxycholic acid showed improvement in four endpoints studied. Conclusions: We demonstrated that some of the medications, used in combination, can exert an additive neuroprotective effect in preclinical models of PD that is superior to that of each of the compounds individually. This project can lead to the development of the first treatment for PD that can slow or prevent its progression.<\/jats:p>","DOI":"10.3390\/antiox14040396","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T04:36:48Z","timestamp":1743136608000},"page":"396","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Evaluation of Additive Neuroprotective Effect of Combination Therapy for Parkinson\u2019s Disease Using In Vitro Models"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3159-8637","authenticated-orcid":false,"given":"Alexander","family":"Shtilbans","sequence":"first","affiliation":[{"name":"Department of Neurology, Hospital for Special Surgery, New York, NY 10021, USA"},{"name":"Department of Neurology, Weill Cornell Medicine, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise","family":"Esneault","sequence":"additional","affiliation":[{"name":"Porsolt Research Laboratory, 53940 Le Genest-Saint-Isle, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Simon","sequence":"additional","affiliation":[{"name":"Porsolt Research Laboratory, 53940 Le Genest-Saint-Isle, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph R.","family":"Mazzulli","sequence":"additional","affiliation":[{"name":"Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Drew J.","family":"Quiriconi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dror","family":"Rom","sequence":"additional","affiliation":[{"name":"Prosoft Clinical, Chesterbrook, PA 19087, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang E.","family":"Reintsch","sequence":"additional","affiliation":[{"name":"The Neuro\u2019s Early Drug Discovery Unit (EDDU), McGill University, Montreal, QC H3A 2B4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7975-6489","authenticated-orcid":false,"given":"Andrea I.","family":"Krahn","sequence":"additional","affiliation":[{"name":"The Neuro\u2019s Early Drug Discovery Unit (EDDU), McGill University, Montreal, QC H3A 2B4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3942-1956","authenticated-orcid":false,"given":"Thomas M.","family":"Durcan","sequence":"additional","affiliation":[{"name":"The Neuro\u2019s Early Drug Discovery Unit (EDDU), McGill University, Montreal, QC H3A 2B4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41531-020-0117-1","article-title":"Current and projected future economic burden of Parkinson\u2019s disease in the U.S.","volume":"6","author":"Yang","year":"2020","journal-title":"npj Park. 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