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 journalArticlepeer-review

14 Scopus citations


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
Pages (from-to)452-458
Number of pages7
Issue number2
StatePublished - Feb 1 2017

Bibliographical note

Publisher Copyright:
© 2016 American Heart Association, Inc.


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

ASJC Scopus subject areas

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


Dive into the research topics of 'Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage'. Together they form a unique fingerprint.

Cite this