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While immune\u2010modulating drugs can prevent new lesions by targeting lymphocyte activity, treating relapse\u2010independent disease progression remains challenging. Persisting CNS inflammation, leading to axonal and neuronal injury along with failure of compensatory mechanisms, such as brain plasticity and remyelination, drives disease progression. Thus, identifying neuroprotective and\/or remyelination\u2010promoting compounds is urgently needed.<\/jats:p>\n                  <jats:p>We developed an in\u00a0vitro platform utilizing human\u2010induced pluripotent stem cell (iPSC)\u2010derived neurons and oligodendrocytes to assess neuroprotective and potentially promyelinating effects of selected compounds. We established assays mimicking MS pathophysiologies, such as neuronal loss and axonal injury. Proteomic analysis revealed modulation of molecular mechanisms. Findings were validated in an acute cuprizone (CPZ) mouse model.<\/jats:p>\n                  <jats:p>We demonstrated that pioglitazone and minocycline protected against glutamate\u2010induced axonal injury, rotenone\u2010induced neuronal death and promoted oligodendrocyte differentiation. Proteomic analyses suggest that pioglitazone's neuroprotective effect may involve reducing mitochondrial reactive oxygen species (ROS) production via PGC\u20101\u03b1 and stabilizing axonal transport through GSK3\u03b2 phosphorylation. Minocycline mainly impacted glutathione metabolism. In the cuprizone model, both compounds displayed neuroprotective effects but did not reduce demyelination or oligodendroglial loss. In summary, our findings demonstrate that human preclinical IPSC platforms can be used to characterize the neuroprotective properties of compounds and thus may aid the selection of drugs for clinical trials. Moreover, the platform's flexibility allows for the easy incorporation of additional disease\u2010specific phenotypic assays.<\/jats:p>","DOI":"10.1111\/ejn.70328","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T07:34:32Z","timestamp":1763969672000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Development of a Human Preclinical Platform for the Identification of Neuroprotective Compounds"],"prefix":"10.1111","volume":"62","author":[{"given":"Raquel\u00a0Guerrero","family":"Gonz\u00e1lez","sequence":"first","affiliation":[{"name":"Institute of Neuropathology University Hospital M\u00fcnster  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif\u00a0Nur","family":"Yilmaz","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology University Hospital M\u00fcnster  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6121-9960","authenticated-orcid":false,"given":"Stefanie","family":"Albrecht","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology University Hospital M\u00fcnster  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurine","family":"Fucito","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology G. d'Annunzio University of Chieti\u2010Pescara  Chieti Italy"},{"name":"Department of Innovative Technologies in Medicine and Dentistry University \u2018G. d'Annunzio\u2019 of Chieti\u2010Pescara  Chieti Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damiana","family":"Pieragostino","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology G. d'Annunzio University of Chieti\u2010Pescara  Chieti Italy"},{"name":"Department of Innovative Technologies in Medicine and Dentistry University \u2018G. d'Annunzio\u2019 of Chieti\u2010Pescara  Chieti Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology University Hospital M\u00fcnster  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Core Unit Proteomics, Interdisciplinary Centre for Clinical Research, Medical Faculty University of M\u00fcnster  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8019-6546","authenticated-orcid":false,"given":"Una","family":"FitzGerald","sequence":"additional","affiliation":[{"name":"Science Foundation Ireland (SFI) Centre for Research in Medical Devices (C\u00daRAM) &amp; Galway Neuroscience Centre University of Galway  Galway Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Kuhlmann","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology University Hospital M\u00fcnster  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,23]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox12051075"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jgar.2020.01.022"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI126381"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2017.10.002"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3900"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.13013"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20031336"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12405"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(24)00027-9"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-128"},{"key":"e_1_2_12_12_1","first-page":"299","article-title":"Activating Akt and the Brain's Resources to Drive Cellular Survival and Prevent Inflammatory Injury","volume":"20","author":"Chong Z. 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