{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T11:31:02Z","timestamp":1761823862583},"reference-count":28,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2017,2]]},"abstract":"<jats:sec>\n            <jats:title>Background and Purpose\u2014<\/jats:title>\n            <jats:p>Spreading depolarizations (SDs) may contribute to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). We tested whether SD-inhibitor valproate reduces brain injury in an SAH rat model with and without experimental SD induction.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods\u2014<\/jats:title>\n            <jats:p>\n              Rats were randomized in a 2\u00d72 design and pretreated with valproate (200 mg\/kg) or vehicle for 4 weeks. SAH was induced by endovascular puncture of the right internal carotid bifurcation. One day post-SAH, brain tissue damage was measured with T\n              <jats:sub>2<\/jats:sub>\n              -weighted magnetic resonance imaging, followed by cortical application of 1 mol\/L KCl (to induce SDs) or NaCl (no SDs). Magnetic resonance imaging was repeated on day 3 followed by histology to confirm neuronal death. Neurological function was measured with an inclined slope test.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results\u2014<\/jats:title>\n            <jats:p>\n              In the groups with KCl application, lesion growth between days 1 and 3 was 57\u00b173 mm3 in the valproate-treated versus 237\u00b1232 mm3 in the vehicle-treated group. In the groups without SD induction, lesion growth in the valproate- and vehicle-treated groups was 8\u00b120 mm3 versus 27\u00b152 mm3. On fitting a 2-way analysis of variance model, we found a significant interaction effect between treatment and KCl\/NaCl application of 161 mm3 (\n              <jats:italic>P<\/jats:italic>\n              =0.04). Number and duration of SDs, mortality, and neurological function were not statistically significantly different between groups. Lesion growth on magnetic resonance imaging correlated to histological infarct volume (Spearman\u2019s rho =0.83;\n              <jats:italic>P<\/jats:italic>\n              =0.0004), with areas of lesion growth exhibiting reduced neuronal death compared with primary lesions.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>In our rat SAH model, valproate treatment significantly reduced brain lesion growth after KCl application. Future studies are needed to confirm that this protective effect is based on SD inhibition.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.116.014738","type":"journal-article","created":{"date-parts":[[2016,12,28]],"date-time":"2016-12-28T02:00:44Z","timestamp":1482890444000},"page":"452-458","update-policy":"http:\/\/dx.doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage"],"prefix":"10.1161","volume":"48","author":[{"given":"Arend M.","family":"Hamming","sequence":"first","affiliation":[{"name":"From the Departments of Neurology (A.M.H., H.J.A.v.O., M.D.F., A.M.J.M.v.d.M., M.J.H.W.), Human Genetics (A.M.J.M.v.d.M.), Medical Statistics (E.v.Z.), Leiden University Medical Center, Leiden, The Netherlands; Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands (A.M.H., A.v.d.T., U.S.R., R.M.D.); and Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Centre, Dallas (L.M., K.P., A.M..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annette","family":"van der Toorn","sequence":"additional","affiliation":[{"name":"From the Departments of Neurology (A.M.H., H.J.A.v.O., M.D.F., A.M.J.M.v.d.M., M.J.H.W.), Human Genetics (A.M.J.M.v.d.M.), Medical Statistics (E.v.Z.), Leiden University Medical Center, Leiden, The Netherlands; Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands (A.M.H., A.v.d.T., U.S.R., R.M.D.); and Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Centre, Dallas (L.M., K.P., A.M..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Umesh S.","family":"Rudrapatna","sequence":"additional","affiliation":[{"name":"From the Departments of Neurology (A.M.H., H.J.A.v.O., M.D.F., A.M.J.M.v.d.M., M.J.H.W.), Human Genetics (A.M.J.M.v.d.M.), Medical Statistics (E.v.Z.), Leiden University Medical Center, Leiden, The Netherlands; Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands (A.M.H., A.v.d.T., U.S.R., R.M.D.); and Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Centre, Dallas (L.M., K.P., A.M..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisha","family":"Ma","sequence":"additional","affiliation":[{"name":"From the Departments of Neurology (A.M.H., H.J.A.v.O., M.D.F., A.M.J.M.v.d.M., M.J.H.W.), Human Genetics (A.M.J.M.v.d.M.), Medical Statistics (E.v.Z.), Leiden University Medical Center, Leiden, The Netherlands; Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands (A.M.H., A.v.d.T., U.S.R., R.M.D.); and Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Centre, Dallas (L.M., K.P., A.M..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hine J.A.","family":"van Os","sequence":"additional","affiliation":[{"name":"From the Departments of Neurology (A.M.H., H.J.A.v.O., M.D.F., A.M.J.M.v.d.M., M.J.H.W.), Human Genetics (A.M.J.M.v.d.M.), Medical Statistics (E.v.Z.), Leiden University Medical Center, Leiden, The Netherlands; Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands (A.M.H., A.v.d.T., U.S.R., R.M.D.); and Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Centre, Dallas (L.M., K.P., A.M..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michel D.","family":"Ferrari","sequence":"additional","affiliation":[{"name":"From the Departments of Neurology (A.M.H., H.J.A.v.O., M.D.F., A.M.J.M.v.d.M., M.J.H.W.), Human Genetics (A.M.J.M.v.d.M.), Medical Statistics (E.v.Z.), Leiden University Medical Center, Leiden, The Netherlands; Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands (A.M.H., A.v.d.T., U.S.R., R.M.D.); and Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Centre, Dallas (L.M., K.P., A.M..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arn M.J.M.","family":"van den Maagdenberg","sequence":"additional","affiliation":[{"name":"From the Departments of Neurology (A.M.H., H.J.A.v.O., M.D.F., A.M.J.M.v.d.M., M.J.H.W.), Human Genetics (A.M.J.M.v.d.M.), Medical Statistics (E.v.Z.), Leiden University Medical Center, Leiden, The Netherlands; Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands (A.M.H., A.v.d.T., U.S.R., R.M.D.); and Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Centre, Dallas (L.M., K.P., A.M..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik","family":"van Zwet","sequence":"additional","affiliation":[{"name":"From the Departments of Neurology (A.M.H., H.J.A.v.O., M.D.F., A.M.J.M.v.d.M., M.J.H.W.), Human Genetics (A.M.J.M.v.d.M.), Medical Statistics (E.v.Z.), Leiden University Medical Center, Leiden, The Netherlands; Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands (A.M.H., A.v.d.T., U.S.R., R.M.D.); and Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Centre, Dallas (L.M., K.P., A.M..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine","family":"Poinsatte","sequence":"additional","affiliation":[{"name":"From the Departments of Neurology (A.M.H., H.J.A.v.O., M.D.F., A.M.J.M.v.d.M., M.J.H.W.), Human Genetics (A.M.J.M.v.d.M.), Medical Statistics (E.v.Z.), Leiden University Medical Center, Leiden, The Netherlands; Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands (A.M.H., A.v.d.T., U.S.R., R.M.D.); and Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Centre, Dallas (L.M., K.P., A.M..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann M.","family":"Stowe","sequence":"additional","affiliation":[{"name":"From the Departments of Neurology (A.M.H., H.J.A.v.O., M.D.F., A.M.J.M.v.d.M., M.J.H.W.), Human Genetics (A.M.J.M.v.d.M.), Medical Statistics (E.v.Z.), Leiden University Medical Center, Leiden, The Netherlands; Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands (A.M.H., A.v.d.T., U.S.R., R.M.D.); and Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Centre, Dallas (L.M., K.P., A.M..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rick M.","family":"Dijkhuizen","sequence":"additional","affiliation":[{"name":"From the Departments of Neurology (A.M.H., H.J.A.v.O., M.D.F., A.M.J.M.v.d.M., M.J.H.W.), Human Genetics (A.M.J.M.v.d.M.), Medical Statistics (E.v.Z.), Leiden University Medical Center, Leiden, The Netherlands; Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands (A.M.H., A.v.d.T., U.S.R., R.M.D.); and Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Centre, Dallas (L.M., K.P., A.M..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marieke J.H.","family":"Wermer","sequence":"additional","affiliation":[{"name":"From the Departments of Neurology (A.M.H., H.J.A.v.O., M.D.F., A.M.J.M.v.d.M., M.J.H.W.), Human Genetics (A.M.J.M.v.d.M.), Medical Statistics (E.v.Z.), Leiden University Medical Center, Leiden, The Netherlands; Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands (A.M.H., A.v.d.T., U.S.R., R.M.D.); and Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Centre, Dallas (L.M., K.P., A.M..."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)60153-6"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2333"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2001.81.3.1065"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.071582498"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl297"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-2982.2009.01982.x"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1227\/01.NEU.0000309123.22032.55"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(02)01120-5"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20778"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2010.10.014"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.117101"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.112.652545"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(99)01769-2"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awq117"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-04981-6_14"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X15619189"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1159\/000352048"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.3171\/jns.2002.97.2.0416"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1097\/00004647-199810000-00006"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.1284"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1361-8415(01)00036-6"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2007.08.004"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22367"},{"key":"e_1_3_4_25_2","first-page":"221","article-title":"The behavior of maximum likelihood estimates under nonstandard conditions.","volume":"1","author":"Huber PJ","year":"1967","unstructured":"Huber PJ. 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