Interactions of IGF-1 with the blood-brain barrier in vivo and in situ.
Insulin-like growth factor-1 (IGF-1) given peripherally has been found effective in clinical trials to slow down neuronal degeneration in some nervous system diseases. This raises the question of whether and how IGF-1 crosses the blood-brain barrier (BBB). In this report, we found that IGF-1 had a half-life of 4.5 min in blood, could remain intact for 20 min, and entered brain and spinal cord linearly. In the brain, IGF-1 had an influx rate of 0.4 microl/g x min after intravenous (iv) bolus injection as determined by multiple-time regression analysis. Intact radiolabeled IGF-1 was present in brain at 20 min after iv injection. Most of the injected IGF-1 entered the brain parenchyma instead of being entrapped in the cerebral vasculature. Addition of nonradiolabeled IGF-1 enhanced the influx of radiolabeled IGF-1 after iv injection, but inhibited the influx of radiolabeled IGF-1 by in-situ brain perfusion, suggesting that protein binding can explain the difference between the iv and perfusion experiments. In the spinal cord, the cervical region had the fastest uptake, followed by lumbar spinal cord. The thoracic spinal cord had the slowest uptake, comparable to that of brain. By contrast, des(1-3)IGF-1, an IGF-1 analogue with little protein binding but similar biological activity, had a shorter half-life in blood, slower influx rate into brain, and no alteration in pharmacokinetics after addition of nonradiolabeled peptide. We conclude that IGF-1 enters the CNS by a saturable transport system at the BBB, which functions in synchrony with IGF binding proteins in the periphery to regulate the availability of IGF-1 to the CNS.
Pan
W
W
VA Medical Center and Department of Medicine and Neuroscience Program, Tulane University School of Medicine, New Orleans, LA, USA. wpan@mailhost.tcs.tulane.edu
Kastin
A J
AJ
D000818:Animals; D001692:Biological Transport / Q000187:drug effects* / Q000502:physiology; D001774:Blood Chemical Analysis; D001776:Blood Circulation Time; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000503:physiopathology; D010446:Peptide Fragments / Q000378:metabolism / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D012044:Regression Analysis; D013116:Spinal Cord / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism
D002352:Carrier Proteins; D007457:Iodine Radioisotopes; D010446:Peptide Fragments; C058957:insulin-like growth factor 1, des-(1-3)-; D007334:Insulin-Like Growth Factor I