TY - JOUR
T1 - Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage
AU - Hamming, Arend M.
AU - Van Der Toorn, Annette
AU - Rudrapatna, Umesh S.
AU - Ma, Lisha
AU - Van Os, Hine J.A.
AU - Ferrari, Michel D.
AU - Van Den Maagdenberg, Arn M.J.M.
AU - Van Zwet, Erik
AU - Poinsatte, Katherine
AU - Stowe, Ann M.
AU - Dijkhuizen, Rick M.
AU - Wermer, Marieke J.H.
N1 - Publisher Copyright:
© 2016 American Heart Association, Inc.
PY - 2017/2
Y1 - 2017/2
N2 - 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 T 2 -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.
AB - 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 T 2 -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.
KW - cortical spreading depression
KW - experimental models
KW - MRI
KW - subarachnoid hemorrhage
KW - valproic acid
UR - http://www.scopus.com/inward/record.url?scp=85007492981&partnerID=8YFLogxK
U2 - 10.1161/STROKEAHA.116.014738
DO - 10.1161/STROKEAHA.116.014738
M3 - Article
C2 - 28028144
AN - SCOPUS:85007492981
SN - 0039-2499
VL - 48
SP - 452
EP - 458
JO - Stroke
JF - Stroke
IS - 2
ER -