Effects of deferoxamine on blood-brain barrier disruption and VEGF in focal cerebral ischemia.
OBJECTIVE
Deferoxamine, an iron chelator, is reported to induce hypoxia-inducible factor 1 (HIF-1) that leads to transcriptional activation of numerous genes including vascular endothelial growth factor (VEGF) that is known to increase blood-brain barrier (BBB) permeability. This study was performed to test whether deferoxamine would disrupt BBB further in focal cerebral ischemia by altering the level of VEGF.


METHODS
Rats were injected intraperitoneally with normal saline (control group), 300 mg/kg deferoxamine mesylate 18 (deferoxamine 18 group) or 48 (deferoxamine 48 group) hours before middle cerebral artery (MCA) occlusion. The transfer coefficient (Ki) of 14C-alpha-aminoisobutyric acid (14C-AIB) and the volume of 3H-dextran distribution were determined to measure the degree of BBB disruption 1 hour after MCA occlusion. Immunohistochemistry using a monoclonal VEGF antibody was performed to determine the protein level of VEGF.


RESULTS
In all groups of animals, the Ki of the ischemic cortex (IC) was higher than that of the corresponding contralateral cortex (CC). In the deferoxamine 18 group, the Ki of the IC was significantly higher than that in the control group (+52%, p<0.05) or deferoxamine 48 group (+72%, p<0.05). The Ki of the CC of all experimental groups were similar. The volume of dextran distribution of the IC was significantly higher than that of the CC only in the deferoxamine 18 group. The number of areas that were stained with VEGF antibody in the deferoxamine 18 group (106 +/- 5/mm2) was significantly higher than that in the control group (54 +/- 2/mm2) or deferoxamine 48 group (58 +/- 1/mm2).


CONCLUSIONS
Our data suggest that deferoxamine induced an increase in VEGF but that its effect depends on the time of administration. The increase in VEGF by deferoxamine could aggravate the disruption of BBB in focal cerebral ischemia.
Chi
Oak Z
OZ
Department of Anesthesia, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 125 Paterson Street, Suite 3100, New Brunswick, NJ 08901-1977, USA. chi@umdnj.edu
Hunter
Christine
C
Liu
Xia
X
Weiss
Harvey R
HR
D000621:Aminoisobutyric Acids; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D003676:Deferoxamine / Q000627:therapeutic use*; D003911:Dextrans; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D007554:Isotopes; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017262:Siderophores / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D000621:Aminoisobutyric Acids; D003911:Dextrans; D007554:Isotopes; D017262:Siderophores; D042461:Vascular Endothelial Growth Factor A; C100049:2-aminoisobutyric acid; D003676:Deferoxamine