Affiliations: Head Injury Center, Department of Neurosurgery,
University of Pennsylvania, School of Medicine, Philadelphia, PA, USA | Veterans Administration Medical Center, Philadelphia,
PA, USA | BASF Bioresearch Corporation, Worcester, MA, USA
Note: [] Corresponding author: Tracy K. McIntosh, PhD, Head Injury
Center, Department of Neurosurgery, University of Pennsylvania, 105 Hayden
Hall, 3320 Smith Walk, Philadelphia, PA 19104-6316, USA. Tel.: +1 215 573 2871;
Fax: +1 215 573 3808; E-mail: mcintosh@seas.upenn.edu
Abstract: Purpose: In the present study we assessed the ability of BSF476921,
an inhibitor of vascular endothelial growth factor receptor (VEGFR) kinase
signal transduction, to reduce edema formation and neurologic motor dysfunction
following lateral fluid percussion (FP) brain injury in rats. Methods: Anesthetized adult male rats were subjected to either
lateral FP brain injury of moderate severity (n = 37) or sham injury (n = 22,
surgery without brain injury). Animals were randomized to receive i.p.
injections of either BSF476921 (30 mg/kg bw; injured n = 15, sham n = 11) or
sterile water (injured n = 14, sham n = 11) at 1, 11 and 22 hours post-injury.
After assessment of motor function using a standard 28-point neuroscore,
animals were sacrificed 24 hours following trauma and their brains evaluated
for regional water content using the wet-weight/dry-weight technique. Results: Although brain-injured animals showed a significant motor
deficit compared to uninjured animals, no differences were detected between
BSF476921- and vehicle-treated animals at the acute 24 hour post-injury time
point. However, BSF476921 significantly attenuated regional edema formation in
brain-injured animals in the ipsilateral hippocampus (p < 0.05) and in the
cortex adjacent to the injury (p < 0.05) when compared to vehicle treatment.
Conclusions: To our knowledge, this is the first report of a small
molecule VEGFR kinase inhibitor reducing cerebral edema in a widely accepted
model of brain injury.
Keywords: blood brain-barrier, cerebral edema, head injury, neuromotor function
