title: Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage.
abstract: 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.
  
  
  
  Rats were randomized in a 2×2 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 T2-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.
  
  
  
  In the groups with KCl application, lesion growth between days 1 and 3 was 57±73 mm3 in the valproate-treated versus 237±232 mm3 in the vehicle-treated group. In the groups without SD induction, lesion growth in the valproate- and vehicle-treated groups was 8±20 mm3 versus 27±52 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 (P=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's rho =0.83; P=0.0004), with areas of lesion growth exhibiting reduced neuronal death compared with primary lesions.
  
  
  
  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.
authors.affiliation: 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.S.).
authors.forename: Arend M
authors.initials: AM
authors.lastname: Hamming
authors.affiliation: 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.S.).
authors.forename: Annette
authors.initials: A
authors.lastname: van der Toorn
authors.affiliation: 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.S.).
authors.forename: Umesh S
authors.initials: US
authors.lastname: Rudrapatna
authors.affiliation: 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.S.).
authors.forename: Lisha
authors.initials: L
authors.lastname: Ma
authors.affiliation: 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.S.).
authors.forename: Hine J A
authors.initials: HJ
authors.lastname: van Os
authors.affiliation: 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.S.).
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.affiliation: 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.S.).
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.affiliation: 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.S.).
authors.forename: Erik
authors.initials: E
authors.lastname: van Zwet
authors.affiliation: 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.S.).
authors.forename: Katherine
authors.initials: K
authors.lastname: Poinsatte
authors.affiliation: 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.S.).
authors.forename: Ann M
authors.initials: AM
authors.lastname: Stowe
authors.affiliation: 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.S.).
authors.forename: Rick M
authors.initials: RM
authors.lastname: Dijkhuizen
authors.affiliation: 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.S.). m.j.h.wermer@lumc.nl.
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Wermer
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000000981:diagnostic imaging* / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D014635:Valproic Acid
keywords: MRI; cortical spreading depression; experimental models; subarachnoid hemorrhage; valproic acid