Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage

Arend M. Hamming, Annette Van Der Toorn, Umesh S. Rudrapatna, Lisha Ma, Hine J A Van Os, Michel D. Ferrari, Arn M J M Van Den Maagdenberg, Erik Van Zwet, Katherine Poinsatte, Ann M. Stowe, Rick M. Dijkhuizen, Marieke J H Wermer

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)452-458
Number of pages7
JournalStroke
Volume48
Issue number2
DOIs
StatePublished - Feb 1 2017

Fingerprint

Valproic Acid
Subarachnoid Hemorrhage
Brain Injuries
Growth
Magnetic Resonance Imaging
Brain
Brain Ischemia
Punctures
Histology
Analysis of Variance
Mortality
Therapeutics

Keywords

  • cortical spreading depression
  • experimental models
  • MRI
  • subarachnoid hemorrhage
  • valproic acid

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

Cite this

Hamming, A. M., Van Der Toorn, A., Rudrapatna, U. S., Ma, L., Van Os, H. J. A., Ferrari, M. D., ... Wermer, M. J. H. (2017). Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage. Stroke, 48(2), 452-458. https://doi.org/10.1161/STROKEAHA.116.014738

Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage. / Hamming, Arend M.; Van Der Toorn, Annette; Rudrapatna, Umesh S.; Ma, Lisha; Van Os, Hine J A; Ferrari, Michel D.; Van Den Maagdenberg, Arn M J M; Van Zwet, Erik; Poinsatte, Katherine; Stowe, Ann M.; Dijkhuizen, Rick M.; Wermer, Marieke J H.

In: Stroke, Vol. 48, No. 2, 01.02.2017, p. 452-458.

Research output: Contribution to journalArticle

Hamming, AM, Van Der Toorn, A, Rudrapatna, US, Ma, L, Van Os, HJA, Ferrari, MD, Van Den Maagdenberg, AMJM, Van Zwet, E, Poinsatte, K, Stowe, AM, Dijkhuizen, RM & Wermer, MJH 2017, 'Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage', Stroke, vol. 48, no. 2, pp. 452-458. https://doi.org/10.1161/STROKEAHA.116.014738
Hamming AM, Van Der Toorn A, Rudrapatna US, Ma L, Van Os HJA, Ferrari MD et al. Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage. Stroke. 2017 Feb 1;48(2):452-458. https://doi.org/10.1161/STROKEAHA.116.014738
Hamming, Arend M. ; Van Der Toorn, Annette ; Rudrapatna, Umesh S. ; Ma, Lisha ; Van Os, Hine J A ; Ferrari, Michel D. ; Van Den Maagdenberg, Arn M J M ; Van Zwet, Erik ; Poinsatte, Katherine ; Stowe, Ann M. ; Dijkhuizen, Rick M. ; Wermer, Marieke J H. / Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage. In: Stroke. 2017 ; Vol. 48, No. 2. pp. 452-458.
@article{2d28b3421d47439a854351aad7ef5754,
title = "Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage",
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 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.",
keywords = "cortical spreading depression, experimental models, MRI, subarachnoid hemorrhage, valproic acid",
author = "Hamming, {Arend M.} and {Van Der Toorn}, Annette and Rudrapatna, {Umesh S.} and Lisha Ma and {Van Os}, {Hine J A} and Ferrari, {Michel D.} and {Van Den Maagdenberg}, {Arn M J M} and {Van Zwet}, Erik and Katherine Poinsatte and Stowe, {Ann M.} and Dijkhuizen, {Rick M.} and Wermer, {Marieke J H}",
year = "2017",
month = "2",
day = "1",
doi = "10.1161/STROKEAHA.116.014738",
language = "English (US)",
volume = "48",
pages = "452--458",
journal = "Stroke",
issn = "0039-2499",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

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

PY - 2017/2/1

Y1 - 2017/2/1

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

UR - http://www.scopus.com/inward/citedby.url?scp=85007492981&partnerID=8YFLogxK

U2 - 10.1161/STROKEAHA.116.014738

DO - 10.1161/STROKEAHA.116.014738

M3 - Article

C2 - 28028144

AN - SCOPUS:85007492981

VL - 48

SP - 452

EP - 458

JO - Stroke

JF - Stroke

SN - 0039-2499

IS - 2

ER -