Arend M Hamming1, Annette van der Toorn1, Umesh S Rudrapatna1, Lisha Ma1, Hine J A van Os1, Michel D Ferrari1, Arn M J M van den Maagdenberg1, Erik van Zwet1, Katherine Poinsatte1, Ann M Stowe1, Rick M Dijkhuizen1, Marieke J H Wermer2. 1. 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.). 2. 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.
Abstract
BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND AND PURPOSE: Spreading depolarizations (SDs) may contribute to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). We tested whether SD-inhibitor valproate reduces brain injury in an SAHrat model with and without experimental SD induction. METHODS: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. RESULTS: 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. CONCLUSIONS: In our ratSAH 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: William S Dodd; Dimitri Laurent; Aaron S Dumont; David M Hasan; Pascal M Jabbour; Robert M Starke; Koji Hosaka; Adam J Polifka; Brian L Hoh; Nohra Chalouhi Journal: J Am Heart Assoc Date: 2021-07-30 Impact factor: 5.501