{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T11:11:06Z","timestamp":1784718666716,"version":"3.55.0"},"reference-count":35,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2019,6,18]],"date-time":"2019-06-18T00:00:00Z","timestamp":1560816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["5R01\u2010NS036692"],"award-info":[{"award-number":["5R01\u2010NS036692"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R01\u2010NS052634"],"award-info":[{"award-number":["R01\u2010NS052634"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA227149"],"award-info":[{"award-number":["R01CA227149"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2019,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Currently prescribed antiepileptic drugs (<jats:styled-content style=\"fixed-case\">AED<\/jats:styled-content>s) are ineffective in treating approximately 30% of epilepsy patients. Sulfasalazine (<jats:styled-content style=\"fixed-case\">SAS<\/jats:styled-content>) is an US Food and Drug Administration (<jats:styled-content style=\"fixed-case\">FDA)<\/jats:styled-content>\u2013approved drug for the treatment of Crohn disease that has been shown to inhibit the cystine\/glutamate antiporter system xc\u2010 (<jats:styled-content style=\"fixed-case\">SXC<\/jats:styled-content>) and decrease tumor\u2010associated seizures. This study evaluates the effect of <jats:styled-content style=\"fixed-case\">SAS<\/jats:styled-content> on distinct pharmacologically induced network excitability and determines whether it can further decrease hyperexcitability when administered with currently prescribed <jats:styled-content style=\"fixed-case\">AED<\/jats:styled-content>s.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using in vitro cortical mouse brain slices, whole\u2010cell patch\u2010clamp recordings were made from layer 2\/3 pyramidal neurons. Epileptiform activity was induced with bicuculline (bic), 4\u2010aminopyridine (4\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content>) and magnesium\u2010free (Mg<jats:sup>2+<\/jats:sup>\u2010free) solution to determine the effect of <jats:styled-content style=\"fixed-case\">SAS<\/jats:styled-content> on epileptiform events. In addition, voltage\u2010sensitive dye (<jats:styled-content style=\"fixed-case\">VSD<\/jats:styled-content>) recordings were performed to characterize the effect of <jats:styled-content style=\"fixed-case\">SAS<\/jats:styled-content> on the spatiotemporal spread of hyperexcitable network activity and compared to currently prescribed <jats:styled-content style=\"fixed-case\">AED<\/jats:styled-content>s.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">SAS<\/jats:styled-content> decreased evoked excitatory postsynaptic currents (<jats:styled-content style=\"fixed-case\">eEPSC<\/jats:styled-content>s) and increased the decay kinetics of evoked inhibitory postsynaptic currents (<jats:styled-content style=\"fixed-case\">eIPSC<\/jats:styled-content>s) in layer 2\/3 pyramidal neurons. Although application of <jats:styled-content style=\"fixed-case\">SAS<\/jats:styled-content> to bic and Mg<jats:sup>2+<\/jats:sup>\u2010free\u2013induced epileptiform activity caused a decrease in the duration of epileptiform events, <jats:styled-content style=\"fixed-case\">SAS<\/jats:styled-content> completely blocked 4\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content>\u2013induced epileptiform events. In <jats:styled-content style=\"fixed-case\">VSD<\/jats:styled-content> recordings, <jats:styled-content style=\"fixed-case\">SAS<\/jats:styled-content> decreased <jats:styled-content style=\"fixed-case\">VSD<\/jats:styled-content> optical signals induced by 4\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content>. Co\u2010application of <jats:styled-content style=\"fixed-case\">SAS<\/jats:styled-content> with the <jats:styled-content style=\"fixed-case\">AED<\/jats:styled-content> topiramate (<jats:styled-content style=\"fixed-case\">TPM<\/jats:styled-content>) caused a significantly further decrease in the spatiotemporal spread of <jats:styled-content style=\"fixed-case\">VSD<\/jats:styled-content> optical signals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Taken together this study provides evidence that inhibition of <jats:styled-content style=\"fixed-case\">SXC<\/jats:styled-content> by <jats:styled-content style=\"fixed-case\">SAS<\/jats:styled-content> can decrease network hyperexcitability induced by three distinct pharmacologic agents in the superficial layers of the cortex. Furthermore, <jats:styled-content style=\"fixed-case\">SAS<\/jats:styled-content> provided additional suppression of 4\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content>\u2013induced network activity when administered with the currently prescribed <jats:styled-content style=\"fixed-case\">AED TPM<\/jats:styled-content>. These findings may serve as a foundation to assess the potential for <jats:styled-content style=\"fixed-case\">SAS<\/jats:styled-content> or other compounds that selectively target <jats:styled-content style=\"fixed-case\">SXC<\/jats:styled-content> as an adjuvant treatment for epilepsy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.16073","type":"journal-article","created":{"date-parts":[[2019,6,18]],"date-time":"2019-06-18T13:15:49Z","timestamp":1560863749000},"page":"1365-1377","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Sulfasalazine decreases mouse cortical hyperexcitability"],"prefix":"10.1111","volume":"60","author":[{"given":"Oscar","family":"Alcoreza","sequence":"first","affiliation":[{"name":"Fralin Biomedical Research Institute Translational Biology, Medicine and Health, Virginia Tech Roanoke Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhanu P.","family":"Tewari","sequence":"additional","affiliation":[{"name":"Fralin Biomedical Research Institute Glial Biology in Health, Disease and Cancer, Virginia Tech Roanoke Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Bouslog","sequence":"additional","affiliation":[{"name":"Fralin Biomedical Research Institute Translational Biology, Medicine and Health, Virginia Tech Roanoke Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Savoia","sequence":"additional","affiliation":[{"name":"School of Neuroscience Virginia Tech Blacksburg Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Sontheimer","sequence":"additional","affiliation":[{"name":"Fralin Biomedical Research Institute Glial Biology in Health, Disease and Cancer, Virginia Tech Roanoke Virginia"},{"name":"School of Neuroscience Virginia Tech Blacksburg Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7775-8600","authenticated-orcid":false,"given":"Susan L.","family":"Campbell","sequence":"additional","affiliation":[{"name":"School of Neuroscience Virginia Tech Blacksburg Virginia"},{"name":"Animal and Poultry Sciences, Virginia Tech Blacksburg Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,6,18]]},"reference":[{"key":"e_1_2_8_2_1","unstructured":"Epilepsy: WHO;2018[updated February 8 2018. 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