Related Experiment Video
Updated: Mar 9, 2026
A Low Mortality Rat Model to Assess Delayed Cerebral Vasospasm After Experimental Subarachnoid Hemorrhage
Published on: January 17, 2013
Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage
Arend M Hamming1, Annette van der Toorn1, Umesh S Rudrapatna1
1From 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.).
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.
