Anti-VEGF receptor antagonist (VGA1155) reduces infarction in rat permanent focal brain ischemia.
OBJECTIVE
Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis and a strong vascular permeability factor. VEGF is known to open the blood-brain barrier (BBB) and induce cerebral edema. Experimental studies of VEGF antagonism have shown it reduces cerebral edema after ischemia, indicating its potential for prevention of secondary brain damage. We examined the therapeutic effect of VGA1155 (5- [N-Methyl-N- (4-octadecyloxyphenyl) acetyl] amino-2-methyl-thiobenzoic acid), a novel small molecule antagonist of VEGF, on rat permanent focal cerebral ischemia.


METHODS
Permanent middle cerebral artery occlusion (MCAO) was induced with the suture occlusion method. A single dose of VGA1155 (10mg/kg, i.p.) was administered 30 minutes before the induction of MCAO after which brain water content, Evans blue extravasation, neurological score, infarct volumes and VEGF expression determined by means of ELISA were compared with corresponding values for vehicle injected control rats.


RESULTS
Brain water content and Evans Blue extravasation 24 hours after ischemia were not significantly reduced, but, compared with control group, VGA1155 significantly reduced infarct volume (32.0% for VGA1155 vs. 46.7% for control; % volume of hemisphere volume) and improved neurological function 7 days after ischemia, when tissue content of the VEGF group markedly increased to nine times that of the vehicle-treated animals.


CONCLUSIONS
VGA1155 was found to protect against secondary ischemic brain damage after permanent focal cerebral ischemia, although it did not reduce vasogenic edema at 24 hours. Changes in endogenous VEGF may be related to the therapeutic effect of VGA1155.
Chiba
Yoshiyuki
Y
Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. ychiba@med.kobe-u.ac.jp
Sasayama
Takashi
T
Miyake
Shigeru
S
Koyama
Junji
J
Kondoh
Takeshi
T
Hosoda
Kohkichi
K
Kohmura
Eiji
E
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D001565:Benzoates / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000150:complications / Q000503:physiopathology*; D002544:Cerebral Infarction / Q000209:etiology* / Q000517:prevention & control*; D004553:Electric Conductivity; D004562:Electrocardiography; D004569:Electroencephalography; D051381:Rats; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D012008:Recurrence
D001565:Benzoates; C487956:VGA1155; D040262:Receptors, Vascular Endothelial Growth Factor