Inhibition of vascular endothelial growth factor receptor (VEGFR) signaling by BSF476921 attenuates regional cerebral edema following traumatic brain injury in rats.
OBJECTIVE
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.
Head Injury Center, Department of Neurosurgery, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104-6316, USA.
Philipp M
PM
Lenzlinger
Kathryn E
KE
Saatman
Rachel C
RC
Hoover
Jessica A
JA
Cheney
Florence M
FM
Bareyre
Ramesh
R
Raghupathi
Lee D
LD
Arnold
Tracy K
TK
McIntosh
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001929:Brain Edema / Q000188:drug therapy* / Q000401:mortality; D001930:Brain Injuries / Q000188:drug therapy* / Q000401:mortality; D004195:Disease Models, Animal; D008297:Male; D009930:Organic Chemicals / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
C489338:BSF 476921; D009930:Organic Chemicals; D040301:Vascular Endothelial Growth Factor Receptor-2