Effects of anti-VEGF antibody on blood-brain barrier disruption in focal cerebral ischemia.
Since cerebral ischemia increases expression of vascular endothelial growth factor (VEGF) and exogenous VEGF can aggravate BBB disruption in cerebral ischemia, we hypothesized that inhibition of endogenous VEGF would attenuate BBB disruption. To test this hypothesis, rats were mechanically ventilated with isoflurane and a craniotomy (5 mm in diameter) was performed to expose the cerebral cortex. Anti-VEGF antibody was applied topically (75 mug) 1 h before middle cerebral artery (MCA) occlusion and additional anti-VEGF antibody was applied (25 mug) immediately after MCA occlusion (anti-VEGF group). For the control animals, normal saline was applied instead of anti-VEGF antibody on the surface of the cortex (control group). One hour after MCA occlusion, the transfer coefficient (K(i)) of (14)C-alpha-aminoisobutyric acid and volume of (3)H-dextran (70,000 Da) distribution were determined to measure the degree of BBB disruption. There was no significant difference in vital signs, blood gases, and pericranial temperature between the control and the anti-VEGF group. In both of the groups, the K(i) of the ischemic cortex (IC) was higher than that of the corresponding contralateral cortex (CC) (p<0.05). The K(i) of the IC of the anti-VEGF group was significantly lower than that of the IC of the control group (-34%, p<0.05). The K(i) of the CC and pons were similar between these two groups. The data of volume of dextran distribution followed the same pattern as that of K(i) but without a statistical significance. Our data demonstrated that inhibition of endogenous VEGF by topical application of anti-VEGF antibody in the ischemic cortex decreased the K(i) of (14)C-AIB and suggest that endogenous VEGF is in part responsible for the BBB disruption during the early stage of focal cerebral ischemia.
Chi
Oak Z
OZ
Department of Anesthesia, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08901-1977, USA. chi@umdnj.edu
Hunter
Christine
C
Liu
Xia
X
Weiss
Harvey R
HR
D000287:Administration, Topical; D000621:Aminoisobutyric Acids / Q000493:pharmacokinetics; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology*; D002545:Brain Ischemia / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000378:metabolism; D003911:Dextrans / Q000493:pharmacokinetics; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism
D000621:Aminoisobutyric Acids; D000906:Antibodies; D003911:Dextrans; D042461:Vascular Endothelial Growth Factor A; C100049:2-aminoisobutyric acid