The novel VEGF receptor antagonist, VGA1155, reduces edema, decreases infarct and improves neurological function after stroke in rats.
Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis and also a strong vascular permeability factor. Blockade of VEGF may have a potential to treat cerebral edema after brain injury. We evaluated the effect of VGA1155 (5- [N-Methyl-N-(4-octadecyloxyphenyl)acetyl]amino-2- methylthiobenzoic acid), a novel binding antagonist of VEGF, on cerebral edema after transient focal cerebral ischemia. Focal cerebral ischemia was induced with the suture occlusion method for 2 h. In the treatment group, a single dose of VGA1155 (1 ~ 50 mg/kg i.p.) was administrated 30 min before the induction of focal ischemia, and the vehicle group received phosphate buffer only. The brain water content, Evans blue extravasation, infarct volumes and neurological score were determined. Physiological parameters were not influenced by the administration of VGA1155. The brain water content at 24 h after cerebral ischemia was significantly reduced by intraperitoneal administration of VGA1155 and the dose of 10 mg/kg showed the maximum effect on brain water content (81.8 ± 0.5% in non treated group vs. 80.2 ± 0.6% in treated group). With this dose, VGA1155 also reduced vascular permeability from 2.2 ± 0.8 µg/g to 1.2 ± 0.5 µg/g studied at 6 h after the ischemia by intravenous injection of Evans blue. VGA1155 administration significantly reduced infarct volume and improved neurological scores at 1 week after ischemic injury. The data suggested that VGA1155 has antiedematous effect in acute phase after transient focal cerebral ischemia and improves neurological and histological outcomes 1 week after ischemic injury.
Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. jkoyama@hp.pref.hyogo.jp
Junji
J
Koyama
Shigeru
S
Miyake
Takashi
T
Sasayama
Yoshiyuki
Y
Chiba
Takeshi
T
Kondoh
Eiji
E
Kohmura
D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects; D001834:Body Water / Q000378:metabolism; D001929:Brain Edema / Q000188:drug therapy; D002545:Brain Ischemia / Q000188:drug therapy; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
D001565:Benzoates; C487956:VGA1155; D040262:Receptors, Vascular Endothelial Growth Factor