{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T20:43:43Z","timestamp":1791665023753,"version":"4.3.4"},"reference-count":87,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T00:00:00Z","timestamp":1713830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Women and Gender Equality Bureau (FGB)"},{"name":"Mainz Research School of Translational Biomedicine (TransMed)"},{"name":"Deutsche Forschungsgemeinschaft"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The histone deacetylase inhibitor (HDACi) valproic acid (VPA) has neuroprotective and anti-inflammatory effects in experimental traumatic brain injury (TBI), which have been partially attributed to the epigenetic disinhibition of the transcription repressor RE1-Silencing Transcription Factor\/Neuron-Restrictive Silencer Factor (REST\/NRSF). Additionally, VPA changes post-traumatic brain injury (TBI) brain metabolism to create a neuroprotective environment. To address the interconnection of neuroprotection, metabolism, inflammation and REST\/NRSF after TBI, we subjected C57BL\/6N mice to experimental TBI and intraperitoneal VPA administration or vehicle solution at 15 min, 1, 2, and 3 days post-injury (dpi). At 7 dpi, TBI-induced an up-regulation of REST\/NRSF gene expression and HDACi function of VPA on histone H3 acetylation were confirmed. Neurological deficits, brain lesion size, blood\u2013brain barrier permeability, or astrogliosis were not affected, and REST\/NRSF target genes were only marginally influenced by VPA. However, VPA attenuated structural damage in the hippocampus, microgliosis and expression of the pro-inflammatory marker genes. Analyses of plasma lipidomic and polar metabolomic patterns revealed that VPA treatment increased lysophosphatidylcholines (LPCs), which were inversely associated with interleukin 1 beta (Il1b) and tumor necrosis factor (Tnf) gene expression in the brain. The results show that VPA has mild neuroprotective and anti-inflammatory effects likely originating from favorable systemic metabolic changes resulting in increased plasma LPCs that are known to be actively taken up by the brain and function as carriers for neuroprotective polyunsaturated fatty acids.<\/jats:p>","DOI":"10.3390\/cells13090734","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T12:20:30Z","timestamp":1713874830000},"page":"734","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Valproic Acid Treatment after Traumatic Brain Injury in Mice Alleviates Neuronal Death and Inflammation in Association with Increased Plasma Lysophosphatidylcholines"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7223-2703","authenticated-orcid":false,"given":"Regina","family":"Hummel","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, University Medical Center Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0383-3273","authenticated-orcid":false,"given":"Erika","family":"Dorochow","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, Medical Faculty, Goethe-University Frankfurt, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Zander","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Medical Center Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Ritter","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Medical Center Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0382-5695","authenticated-orcid":false,"given":"Lisa","family":"Hahnefeld","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, Medical Faculty, Goethe-University Frankfurt, 60596 Frankfurt am Main, Germany"},{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Fraunhofer Cluster of Excellence for Immune-Mediated Diseases, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Gurke","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, Medical Faculty, Goethe-University Frankfurt, 60596 Frankfurt am Main, Germany"},{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Fraunhofer Cluster of Excellence for Immune-Mediated Diseases, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7524-8025","authenticated-orcid":false,"given":"Irmgard","family":"Tegeder","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, Medical Faculty, Goethe-University Frankfurt, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6055-6244","authenticated-orcid":false,"given":"Michael K. E.","family":"Sch\u00e4fer","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Medical Center Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"},{"name":"Focus Program Translational Neurosciences (FTN), Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"},{"name":"Research Center for Immunotherapy (FZI), Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1089\/neu.2014.3352","article-title":"Long-Term Consequences of Traumatic Brain Injury: Current Status of Potential Mechanisms of Injury and Neurological Outcomes","volume":"32","author":"Bramlett","year":"2015","journal-title":"J. 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