{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T04:07:01Z","timestamp":1742270821131,"version":"3.40.1"},"reference-count":51,"publisher":"PeerJ","license":[{"start":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T00:00:00Z","timestamp":1742169600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:sec>\n               <jats:title>Background<\/jats:title>\n               <jats:p>Valproic acid (VPA) is known for its broad-spectrum antiepileptic effects and is recommended for generalized epilepsy, in contrast to phenytoin, which has a more limited spectrum. This study investigated the cytotoxic and inflammatory responses to phenytoin and VPA in peripheral blood mononuclear cells (PBMCs), with and without bacterial lipopolysaccharide (LPS) stimulation.<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Methods<\/jats:title>\n               <jats:p>PBMCs from healthy donors were divided into 12 groups: control (Ctrl), phenytoin (Phy), and four concentrations of VPA (Val-50, Val-75, Val-100, Val-200), with and without LPS. Assessments were conducted on days 1 and 3, including total, live, and dead cell counts, cell viability, and lactic acid dehydrogenase (LDH) cytotoxicity assays. Inflammatory mediators (IL-6, IL-1\u03b2) and immune markers (IL-18, IgA) were measured using enzyme-linked immunosorbent assay (ELISA) on day 3. Statistical analysis involved two-way ANOVA, Tukey\u2019s HSD tests, and paired <jats:italic>t<\/jats:italic>-tests.<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Results<\/jats:title>\n               <jats:p>All treatment groups showed significant declines in cell counts and viability from day 1 to day 3, which were exacerbated by LPS. Val-50 + LPS maintained higher cell counts compared to Ctrl + LPS and Phy + LPS. Elevated LDH levels were primarily observed in the Val-100 and Val-200 groups, with and without LPS. In the absence of LPS, the Val-75 and Val-100 groups showed notable reductions in IL-18 and IgA levels, while all VPA treatments reduced IL-6 levels compared to controls. This effect was enhanced under LPS exposure, although IL-1\u03b2 reductions in the Val-75, Val-100, and Val-200 groups were reversed in the presence of LPS. Val-75 demonstrated lower cytotoxic and inflammatory responses compared to Phy and higher VPA doses, showing moderate LDH increases and reduced IL-18, IgA, IL-1\u03b2, and IL-6 levels, particularly under LPS challenge.<\/jats:p>\n            <\/jats:sec>\n            <jats:sec>\n               <jats:title>Conclusion<\/jats:title>\n               <jats:p>Phenytoin and VPA induced significant cytotoxic and inflammatory responses, influenced by dosage and LPS exposure. Val-75 exhibited a dose-specific immunomodulatory effect, reducing both pro-inflammatory and immune markers.<\/jats:p>\n            <\/jats:sec>","DOI":"10.7717\/peerj.19102","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T08:25:26Z","timestamp":1742199926000},"page":"e19102","source":"Crossref","is-referenced-by-count":0,"title":["Impact of phenytoin and valproic acid on cytotoxicity and inflammatory mediators in human mononuclear cells: with and without lipopolysaccharide stimulation"],"prefix":"10.7717","volume":"13","author":[{"given":"Aminah","family":"Alesawy","sequence":"first","affiliation":[{"name":"Department of Preventive Dental Sciences, College of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norah","family":"Alotaibi","sequence":"additional","affiliation":[{"name":"Department of Preventive Dental Sciences, College of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marwa","family":"Alalshaikh","sequence":"additional","affiliation":[{"name":"Department of Preventive Dental Sciences, College of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faisal E.","family":"Aljofi","sequence":"additional","affiliation":[{"name":"Department of Preventive Dental Sciences, College of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nada","family":"Aldossary","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam,  Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nada","family":"Al-Zahrani","sequence":"additional","affiliation":[{"name":"Blood Bank, Laboratory Medicine, King Fahad University Hospital, Al Khobar, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omar","family":"Omar","sequence":"additional","affiliation":[{"name":"Department of Biomedical Dental Sciences, College of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marwa","family":"Madi","sequence":"additional","affiliation":[{"name":"Department of Preventive Dental Sciences, College of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"4443","published-online":{"date-parts":[[2025,3,17]]},"reference":[{"key":"10.7717\/peerj.19102\/ref-1","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1212\/CON.0000000000000715","article-title":"Update on antiepileptic drugs 2019","volume":"25","author":"Abou-Khalil","year":"2019","journal-title":"CONTINUUM: Lifelong Learning in Neurology"},{"key":"10.7717\/peerj.19102\/ref-2","first-page":"65","article-title":"Effect of anti-epileptic drugs on serum immunoglobulin levels in children","volume":"110","author":"Ashrafi","year":"2010","journal-title":"Acta Neurologica Belgica"},{"issue":"7","key":"10.7717\/peerj.19102\/ref-3","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.3324\/haematol.2009.008870","article-title":"Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation","volume":"95","author":"Bartels","year":"2010","journal-title":"Haematologica"},{"issue":"6","key":"10.7717\/peerj.19102\/ref-4","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.1084\/jem.169.6.2133","article-title":"Interleukins and IgA synthesis. 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