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). DISCUSSION: 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.[1]References
- Effects of deferoxamine on blood-brain barrier disruption and VEGF in focal cerebral ischemia. Chi, O.Z., Hunter, C., Liu, X., Weiss, H.R. Neurol. Res. (2008) [Pubmed]
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