{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:33:38Z","timestamp":1791290018851,"version":"4.3.0"},"reference-count":36,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2013,7,19]],"date-time":"2013-07-19T00:00:00Z","timestamp":1374192000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Epilepsy Foundation to Nicola Marchi","award":["HD057256"],"award-info":[{"award-number":["HD057256"]}]},{"name":"Epilepsy Foundation to Nicola Marchi","award":["NS074621"],"award-info":[{"award-number":["NS074621"]}]},{"name":"Epilepsy Foundation to Nicola Marchi","award":["MH093302"],"award-info":[{"award-number":["MH093302"]}]},{"name":"Epilepsy Foundation to Nicola Marchi","award":["UH2NS080701"],"award-info":[{"award-number":["UH2NS080701"]}]},{"name":"and NARSAD"},{"name":"AHA","award":["13SDG13950015"],"award-info":[{"award-number":["13SDG13950015"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2013,9]]},"abstract":"Summary<\/jats:title>Purpose<\/jats:title>Brain drug bioavailability is regulated by the blood\u2013brain barrier (BBB<\/jats:styled-content>). It was recently suggested that cytochromeP<\/jats:styled-content>450 (CYP<\/jats:styled-content>) enzymes could act in concert with multidrug transporter proteins to regulate drug penetration and distribution into the diseased brain. The possibility thatp<\/jats:styled-content>haseII<\/jats:styled-content>metabolic enzymes could be expressed in the epileptic brain has been not evaluated. PhaseII<\/jats:styled-content>enzymes are involved in the metabolism of common antiepileptic drugs (AED<\/jats:styled-content>s).<\/jats:p><\/jats:sec>Methods<\/jats:title>PhaseII<\/jats:styled-content>enzymeUGT<\/jats:styled-content>1A<\/jats:styled-content>4 brain expression was evaluated in temporal lobe resections from patients with epilepsy.UGT<\/jats:styled-content>1A<\/jats:styled-content>4 expression was determined by western blot and immunocytochemistry in primary cultures of human drug\u2010resistant brain endothelial human brain epileptic endothelial cells (EPI<\/jats:styled-content>\u2010EC<\/jats:styled-content>)s and commercially available control cells human brain microvascular endothelial cells (HBMEC<\/jats:styled-content>s). Lack ofDNA<\/jats:styled-content>condensation measured by 4\u2032,6\u2010diamidino\u20102\u2010phenylindole(DAPI<\/jats:styled-content>) was used as a surrogate marker of cell viability and was correlated toUGT<\/jats:styled-content>1A<\/jats:styled-content>4 expression high performance liquid chromatography ultraviolet detection(HPLC<\/jats:styled-content>\u2010UV<\/jats:styled-content>) was used to quantify lamotrigine metabolism byEPI<\/jats:styled-content>\u2010EC<\/jats:styled-content>andHBMEC<\/jats:styled-content>. The appearance of the specific lamotrigine metabolite, 2\u2010n glucuronide (MET<\/jats:styled-content>\u20101), was also evaluated. Lamotrigine andMET<\/jats:styled-content>\u20101 levels were measured in selected surgical brain and matched blood samples.<\/jats:p><\/jats:sec>Key Findings<\/jats:title>UGT<\/jats:styled-content>1A<\/jats:styled-content>4 expression was observed inBBB<\/jats:styled-content>endothelial cells and neurons. Our quantification study revealed variable levels ofUGT<\/jats:styled-content>1A<\/jats:styled-content>4 expression across the brain specimens analyzed. Neurons devoid ofUGT<\/jats:styled-content>1A<\/jats:styled-content>4 expression displayed nuclearDAPI<\/jats:styled-content>condensation, a sign of cellular distress.UGT<\/jats:styled-content>1A<\/jats:styled-content>4 overexpression inEPI<\/jats:styled-content>\u2010EC<\/jats:styled-content>, as compared toHBMEC<\/jats:styled-content>, was reflected by a proportional increase in lamotrigine metabolism. The lamotrigine metabolite,MET<\/jats:styled-content>\u20101, was formed in vitro byEPI<\/jats:styled-content>\u2010EC<\/jats:styled-content>and, to a lesser extent, byHBMEC<\/jats:styled-content>.HPLC<\/jats:styled-content>\u2010UV<\/jats:styled-content>measurements of brain and blood samples obtained from patients receiving lamotrigine prior to surgery revealed the presence of lamotrigine and its metabolites in the brain.<\/jats:p><\/jats:sec>Significance<\/jats:title>These initial results suggest the presence of a phaseII<\/jats:styled-content>enzyme in the epileptic brain. Further studies are required to fully describe the pattern of brainUGT<\/jats:styled-content>1A<\/jats:styled-content>4 expression in relation to clinical variables and drug resistance.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.12318","type":"journal-article","created":{"date-parts":[[2013,7,19]],"date-time":"2013-07-19T10:11:13Z","timestamp":1374228673000},"page":"1562-1570","source":"Crossref","is-referenced-by-count":41,"title":["Expression and functional relevance ofUGT<\/scp>1A<\/scp>4 in a cohort of human drug\u2010resistant epileptic brains"],"prefix":"10.1111","volume":"54","author":[{"given":"Chaitali","family":"Ghosh","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Medicine Cerebrovascular Research, Cleveland Clinic Cleveland Ohio U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Hossain","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine Cerebrovascular Research, Cleveland Clinic Cleveland Ohio U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikram","family":"Puvenna","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine Cerebrovascular Research, Cleveland Clinic Cleveland Ohio U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Martinez\u2010Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Cleveland Clinic Cleveland Ohio U.S.A"},{"name":"Epilepsy Center Cleveland Clinic Cleveland Ohio U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Alexopolous","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Cleveland Clinic Cleveland Ohio U.S.A"},{"name":"Epilepsy Center Cleveland Clinic Cleveland Ohio U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damir","family":"Janigro","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine Cerebrovascular Research, Cleveland Clinic Cleveland Ohio U.S.A"},{"name":"Department of Neurosurgery Cleveland Clinic Cleveland Ohio U.S.A"},{"name":"Molecular Medicine Cleveland Clinic Lerner College of Medicine, Cleveland Clinic Cleveland Ohio U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Marchi","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine Cerebrovascular Research, Cleveland Clinic Cleveland Ohio U.S.A"},{"name":"Molecular Medicine Cleveland Clinic Lerner College of Medicine, Cleveland Clinic Cleveland Ohio 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