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Its mechanism of action is not fully understood, and there is a need to characterize whether DMF or its bioactive metabolite monomethyl fumarate (MMF) exerts neuroprotective properties. Moreover, the combination of adjuvant agents such as cannabidiol (CBD) could be relevant to enhance neuroprotection. The aim of this study was to compare the neuroprotective and immunomodulatory effects of DMF, MMF, and CBD in neurons and microglia in vitro. We found that DMF and CBD, but not MMF, activated the Nrf2 antioxidant pathway in neurons. Similarly, only DMF and CBD, but not MMF, prevented the LPS-induced activation of the inflammatory pathway NF-kB in microglia. Additionally, the three drugs inhibited the production of nitric oxide in microglia and protected neurons against apoptosis. Transcriptomically, DMF modulated a greater number of inflammatory and Nrf2-related genes compared to MMF and CBD in both neurons and microglia. Our results show that DMF and MMF, despite being structurally related, present differences in their mechanisms of action that could be relevant for the achievement of neuroprotection in MS patients. Additionally, CBD shows potential as a neuroprotective agent.<\/jats:p>","DOI":"10.3390\/ijms252313082","type":"journal-article","created":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T06:24:44Z","timestamp":1733379884000},"page":"13082","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Neuroprotective and Anti-Inflammatory Effects of Dimethyl Fumarate, Monomethyl Fumarate, and Cannabidiol in Neurons and Microglia"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1155-081X","authenticated-orcid":false,"given":"Alicia","family":"S\u00e1nchez-Sanz","sequence":"first","affiliation":[{"name":"Neuroimmunology Unit, Instituto de Investigaci\u00f3n Sanitaria Puerta de Hierro-Segovia de Arana, 28222 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jos\u00e9","family":"Coronado-Albi","sequence":"additional","affiliation":[{"name":"Confocal Microscopy Core Facility, Instituto de Investigaci\u00f3n Sanitaria Puerta de Hierro-Segovia de Arana, 28222 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1363-6978","authenticated-orcid":false,"given":"Rafael","family":"Mu\u00f1oz-Viana","sequence":"additional","affiliation":[{"name":"Bioinformatics Unit, Instituto de Investigaci\u00f3n Sanitaria Puerta de Hierro-Segovia de Arana, 28222 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Garc\u00eda-Merino","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Instituto de Investigaci\u00f3n Sanitaria Puerta de Hierro-Segovia de Arana, 28222 Madrid, Spain"},{"name":"Department of Neurology, Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain"},{"name":"Department of Medicine, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM), 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7168-6175","authenticated-orcid":false,"given":"Antonio J.","family":"S\u00e1nchez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Instituto de Investigaci\u00f3n Sanitaria Puerta de Hierro-Segovia de Arana, 28222 Madrid, Spain"},{"name":"Red Espa\u00f1ola de Esclerosis M\u00faltiple (REEM), 08028 Barcelona, Spain"},{"name":"Biobank, Instituto de Investigaci\u00f3n Sanitaria Puerta de Hierro-Segovia de Arana, 28222 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1002\/med.21567","article-title":"Dimethyl fumarate, a two-edged drug: Current status and future directions","volume":"39","author":"Saidu","year":"2019","journal-title":"Med. 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