{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T18:43:43Z","timestamp":1791053023942,"version":"4.1.0"},"reference-count":61,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2013,12,2]],"date-time":"2013-12-02T00:00:00Z","timestamp":1385942400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2014,1]]},"abstract":"Summary<\/jats:title>Purpose<\/jats:title>The contribution of glial cells, mainly astrocytes and microglia, to the pathophysiology of epilepsy is increasingly appreciated. Glia play a pivotal role in the initiation and maintenance of the central nervous system (CNS<\/jats:styled-content>) immune response and neuronal metabolic and trophic supply. Recent clinical and experimental evidence suggests a direct relationship between epileptic activity andCNS<\/jats:styled-content>inflammation, which is characterized by accumulation, activation, and proliferation of microglia and astrocytes. Concomitant glia\u2010mediated mechanisms of action of several antiepileptic drugs (AED<\/jats:styled-content>s) have been proposed. However, their direct effects on glial cells have been rarely investigated. We aimed to investigate the effect of commonly usedAED<\/jats:styled-content>s on glial viability, the gap junctional network, the microglial activation, and cytokine expression in an in vitro astroglia\/microglia co\u2010culture model.<\/jats:p><\/jats:sec>Methods<\/jats:title>Primary astrocytic cultures were prepared from brains of postnatal (P<\/jats:styled-content>0\u2013P<\/jats:styled-content>2)W<\/jats:styled-content>istar rats and co\u2010cultured with a physiologic amount of 5%, as well as 30% microglia in order to mimic inflammatory conditions. Co\u2010cultures were treated with valproic acid (VPA<\/jats:styled-content>), carbamazepine (CBZ<\/jats:styled-content>), phenytoin (PHE<\/jats:styled-content>), and gabapentin (GBT<\/jats:styled-content>). Viability and proliferation were measured using the tetrazolium (MTT<\/jats:styled-content>) assay. The microglial activation state was determined by immunocytochemical labeling. The astroglial connexin 43 (C<\/jats:styled-content>x43) expression was measured byW<\/jats:styled-content>estern blot analysis. The transforming growth factor\u2010\u03b21 (TGF<\/jats:styled-content>\u2010\u03b21) and tumor necrosis factor\u2010\u03b1 (TNF<\/jats:styled-content>\u2010\u03b1) cytokine levels were measured by the quantitative sandwich enzyme immunosorbent assay (ELISA<\/jats:styled-content>).<\/jats:p><\/jats:sec>Key Findings<\/jats:title>Astrocytes, co\u2010cultured with 5% microglia (M5 co\u2010cultures), showed a dose\u2010dependent, significant reduction in glial viability after incubation withPHE<\/jats:styled-content>andCBZ<\/jats:styled-content>. Furthermore,VPA<\/jats:styled-content>led to highly significant microglial activation at all doses examined. The antiinflammatory cytokineTGF<\/jats:styled-content>\u2010\u03b21 release was induced by high doses ofGBT<\/jats:styled-content>andPHE<\/jats:styled-content>.<\/jats:p>Astrocytes co\u2010cultured with 30% microglia (M30 co\u2010cultures) revealed a dose\u2010dependent significant reduction in glial viability after incubation withPHE<\/jats:styled-content>, accompanied by increasedTGF<\/jats:styled-content>\u2010\u03b21 andTNF<\/jats:styled-content>\u2010\u03b1 levels. However,CBZ<\/jats:styled-content>significantly reduced the amount of activated microglial cells and increased the total number of inactivated microglia. Finally,CBZ<\/jats:styled-content>resulted in reduced viability at all doses examined.<\/jats:p><\/jats:sec>Significance<\/jats:title>CNS<\/jats:styled-content>inflammation is characterized by a disturbance of glial cell functions. Strong microglial activation, a typical hallmark of inflammation, was induced byVPA<\/jats:styled-content>inM<\/jats:styled-content>5 and continued inM<\/jats:styled-content>30 co\u2010cultures. With regard to the direct relation betweenCNS<\/jats:styled-content>inflammation and seizures,VPA<\/jats:styled-content>seems to be unsuitable for reducing inflammatory conditions. The reverse effect was achieved afterCBZ<\/jats:styled-content>. We noticed significant microglial inactivation, after incubation of theM<\/jats:styled-content>30 co\u2010cultures. In conclusion, we suggest thatAED<\/jats:styled-content>s with antiinflammatory glial features are beneficial for seizures caused by persistent brain inflammation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.12473","type":"journal-article","created":{"date-parts":[[2013,12,2]],"date-time":"2013-12-02T16:51:16Z","timestamp":1386003076000},"page":"184-192","source":"Crossref","is-referenced-by-count":86,"title":["Glia and epilepsy: Experimental investigation of antiepileptic drugs in an astroglia\/microglia co\u2010culture model of inflammation"],"prefix":"10.1111","volume":"55","author":[{"given":"Hannes","family":"Dambach","sequence":"first","affiliation":[{"name":"Department of Neuroanatomy and Molecular Brain Research Ruhr University Bochum Bochum Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Hinkerohe","sequence":"additional","affiliation":[{"name":"Department of Neurology Ruhr\u2010University Bochum Knappschafts Hospital Bochum 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