{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:25:32Z","timestamp":1791300332168,"version":"4.1.0"},"reference-count":45,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2016,3,25]],"date-time":"2016-03-25T00:00:00Z","timestamp":1458864000000},"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":[[2016,5]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>During critical periods of brain development, both seizures and anticonvulsant medications can affect neurodevelopmental outcomes. In rodent models, many anticonvulsants trigger neuronal apoptosis. However, white matter apoptosis (<jats:styled-content style=\"fixed-case\">WMA<\/jats:styled-content>) has not been examined after anticonvulsant drug treatment. Herein, we sought to determine if anticonvulsant drugs induced apoptosis in the developing white matter (<jats:styled-content style=\"fixed-case\">WM<\/jats:styled-content>) in a rodent model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Postnatal day (P)7 rats were treated with phenobarbital (<jats:styled-content style=\"fixed-case\">PB<\/jats:styled-content>\u201075), MK\u2010801 (dizocilpine, 0.5), lamotrigine (<jats:styled-content style=\"fixed-case\">LTG<\/jats:styled-content>\u201020), carbamazepine (<jats:styled-content style=\"fixed-case\">CBZ<\/jats:styled-content>\u2010100), phenytoin (<jats:styled-content style=\"fixed-case\">PHT<\/jats:styled-content>\u201050), levetiracetam (<jats:styled-content style=\"fixed-case\">LEV<\/jats:styled-content>\u2010250), or saline; all doses are mg\/kg. Brain tissue collected 24 h after treatment was stained using the terminal deoxynucleotidyl transferase dUTP nick end labeling method. The number of degenerating cells within <jats:styled-content style=\"fixed-case\">WM<\/jats:styled-content>, that is, anterior commissure (<jats:styled-content style=\"fixed-case\">AC<\/jats:styled-content>), corpus callosum, cingulum, and hippocampus\u2010associated <jats:styled-content style=\"fixed-case\">WM<\/jats:styled-content> tracts, was quantified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Saline\u2010treated rats showed low baseline level of apoptosis in developing <jats:styled-content style=\"fixed-case\">WM<\/jats:styled-content> on P8 in all the areas examined. <jats:styled-content style=\"fixed-case\">PB<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> PHT<\/jats:styled-content>, and <jats:styled-content style=\"fixed-case\">MK<\/jats:styled-content>\u2010801 significantly increased apoptosis in all four brain areas examined. Exposure to <jats:styled-content style=\"fixed-case\">CBZ<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> LTG<\/jats:styled-content>, or <jats:styled-content style=\"fixed-case\">LEV<\/jats:styled-content> failed to increase apoptosis in all regions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Commonly used anticonvulsants (<jats:styled-content style=\"fixed-case\">PB<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> PHT<\/jats:styled-content>) cause apoptosis in the developing <jats:styled-content style=\"fixed-case\">WM<\/jats:styled-content> in a rat model; the <jats:italic>N<\/jats:italic>\u2010methyl\u2010<jats:sc>d<\/jats:sc>\u2010aspartate (<jats:styled-content style=\"fixed-case\">NMDA<\/jats:styled-content>) receptor antagonist <jats:styled-content style=\"fixed-case\">MK<\/jats:styled-content>\u2010801 has a similar effect. These results are consistent with reports of anesthesia\u2010induced <jats:styled-content style=\"fixed-case\">WMA<\/jats:styled-content> during brain development. Consistent with the lack of neuronal apoptosis caused by <jats:styled-content style=\"fixed-case\">LTG<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> LEV<\/jats:styled-content>, and <jats:styled-content style=\"fixed-case\">CBZ<\/jats:styled-content>, these drugs did not cause <jats:styled-content style=\"fixed-case\">WMA<\/jats:styled-content>. Many infants treated with anticonvulsant drugs have underlying neurologic injury, including WM damage (e.g., following intraventricular hemorrhage [<jats:styled-content style=\"fixed-case\">IVH<\/jats:styled-content>] or hypoxic\u2010ischemic encephalopathy [<jats:styled-content style=\"fixed-case\">HIE<\/jats:styled-content>]). The degree to which anticonvulsant drug treatment will alter outcomes in the presence of underlying injury remains to be examined, but avoiding drugs (when possible) that induce <jats:styled-content style=\"fixed-case\">WMA<\/jats:styled-content> may be beneficial.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.13365","type":"journal-article","created":{"date-parts":[[2016,3,25]],"date-time":"2016-03-25T06:46:42Z","timestamp":1458888402000},"page":"727-734","source":"Crossref","is-referenced-by-count":87,"title":["Anticonvulsant drug\u2013induced cell death in the developing white matter of the rodent brain"],"prefix":"10.1111","volume":"57","author":[{"given":"Suhasini","family":"Kaushal","sequence":"first","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Georgetown University School of Medicine Washington DC U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zenab","family":"Tamer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; 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