Interactions of IGF-1 with the blood-brain barrier in vivo and in situ
Interactions of IGF-1 with the blood-brain barrier in vivo and in situ
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DOI：
10.1159/000054584
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发表时间：
2000-09-01
影响因子：
4.1
通讯作者：
Kastin, AJ
中科院分区：
文献类型：
--
作者：
Pan, WH;Kastin, AJ
胰岛素样生长因子-1（IGF-1）在外周给药已被发现在临床试验中有效地减缓神经系统疾病中的神经元变性。这就提出了IGF-1是否以及如何穿过血脑屏障（BBB）的问题。在本报告中，我们发现IGF-1在血液中的半衰期为4.5分钟，可以保持完整20分钟，并线性进入大脑和脊髓。在大脑中，通过多次回归分析确定，静脉（iv）推注后IGF-1的流入率为0.4 μ l/g min。完整的放射性标记的IGF-1在静脉注射后20分钟出现在脑中。大部分注射的IGF-1进入脑实质，而不是被截留在脑血管系统中。此外，非放射性标记的IGF-1增强流入的放射性标记的IGF-1静脉注射后，但抑制流入的放射性标记的IGF-1的原位脑灌注，这表明蛋白结合可以解释静脉和灌注实验之间的差异。在脊髓中，颈段摄取最快，其次是腰段。胸髓的摄取最慢，与脑的摄取相当。相比之下，des（1-3）IGF-1，一种几乎没有蛋白结合但具有相似生物活性的IGF-1类似物，在血液中具有较短的半衰期，较慢的流入脑中的速率，并且在加入非放射性标记的肽后没有药代动力学改变。我们的结论是，IGF-1进入中枢神经系统的饱和运输系统在血脑屏障，其功能与IGF结合蛋白在外周同步调节IGF-1的可用性的CNS。版权所有（C）2000 S. Karger AG，巴塞尔。
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 mu l/g min after intravenous (iv) bolus injection as determined by multiple-time regression analysis. Intact radio-labeled 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-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 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. Copyright (C) 2000 S. Karger AG, Basel.