Permeation of hepatocyte growth factor across the blood-brain barrier.
Hepatocyte growth factor (HGF), mainly produced and acting in the periphery, attenuates cerebral ischemia-induced cell death and thus shows therapeutic potential in CNS regeneration. Accordingly, we tested its ability to permeate the blood-brain barrier (BBB). HGF was stable in the circulating blood of adult mice for up to 20 min, as HPLC showed intact (125)I-HGF in both serum and brain homogenate. Multiple time regression analysis revealed a rapid blood-to-brain influx rate of 0.38 +/- 0.07 microl/g min, faster than might be expected for a protein of this size. Although excess unlabeled HGF failed to inhibit of the influx of (125)I-HGF in mice, the use of a higher dose of unlabeled HGF in cellular uptake studies showed the presence of saturable endocytosis. Furthermore, capillary depletion studies showed that about 32% of the HGF present in brain entered the parenchymal compartment in contrast to the 11% entrapped in endothelial cells 10 min after intravenous bolus injection. The amount of HGF that crossed the BBB in intact form was substantial and could be physiologically important in the CNS.
Pan
Weihong
W
Pennington Biomedical Research Center, LSU System, 6400 Perkins Road, Baton Rouge, LA 70808, USA. weihong.pan@pbrc.edu
Yu
Yongmei
Y
Yemane
Ruth
R
Cain
Courtney
C
Yu
Chuanhui
C
Kastin
Abba J
AJ
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D002460:Cell Line; D004705:Endocytosis; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D019859:Proto-Oncogene Proteins c-met / Q000276:immunology / Q000502:physiology; D013997:Time Factors
D000906:Antibodies; D007457:Iodine Radioisotopes; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met