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 effe ctive 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 h alf-life of 4.5 min in blood, could remain intact for 20 min, and entered b rain and spinal cord linearly. In the brain, IGF-1 had an influx rate of 0. 4 mu l/g min after intravenous (iv) bolus injection as determined by multip le-time regression analysis. Intact radio-labeled IGF-1 was present in brai n at 20 min after iv injection. Most of the injected IGF-1 entered the brai n parenchyma instead of being entrapped in the cerebral vasculature. Additi on 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 br ain perfusion, suggesting that protein binding can explain the difference b etween the iv and perfusion experiments. In the spinal cord, the cervical r egion had the fastest uptake, followed by lumbar spinal cord. The thoracic spinal cord had the slowest uptake, comparable to that of brain. By contras t, des(1-3)IGF-l, 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 nonradi olabeled peptide. We conclude that IGF-1 enters the CNS by a saturable tran sport system at the BBB, which functions in synchrony with IGF binding prot eins in the periphery to regulate the availability of IGF-1 to the CNS. Cop yright (C) 2000 S. Karger AG, Basel.