Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier
Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier
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DOI：
10.1385/jmn:18:1-2:07
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发表时间：
2002-02-01
影响因子：
3.1
通讯作者：
Pan, WH
中科院分区：
文献类型：
--
作者：
Kastin, AJ;Akerstrom, V;Pan, WH
胰升糖素样肽-1(GLP-1)可减少糖尿病患者的胰岛素需求，促进饱腹感。外周(中枢神经系统外)的GLP-1已被证明对大脑起作用，以减少食物的摄取。由于GLP-1在血液中很容易降解，我们重点研究了[Ser(8)]GLP-1的相互作用，这是一种具有类似生物学效应且与血脑屏障(BBB)更稳定的类似物。[Ser8]GLP-1的脑内流有几个明显的特征：1.小鼠静脉注射后，经多元回归分析测得快速脑内流速率为8.867+/-0.798×10(4)m L/g·min。静脉或原位脑灌流过量的未标记的[Ser8]GLP-1缺乏自我抑制，表明BBB.3缺乏可饱和的转运系统。短期禁食和其他可能与GLP-1相互作用的消化肽缺乏调节作用，包括瘦素、胰高血糖素、胰岛素、神经肽Y和黑色素浓缩激素。选择性GLP-1受体拮抗剂exendin(9-39)不抑制内流，提示GLP-1受体不参与GLP-1快速进入脑内。同样，除了脑脊液的重吸收外，[Ser(8)]GLP-1也不存在外流系统。快速内流与高脂类溶解度无关。当到达脑室时，大量的[Ser(8)]GLP-1进入脑实质，但很大一部分与血脑屏障的血管系统松散相关。最后，比较了[Ser(8)]GLP-1和GLP-1在无血脑灌流系统中的内流速度；放射性标记的GLP-1的内流速度比其类似物更快，两种多肽都没有表现出饱和转运系统的自我抑制。因此，我们认为[Ser(8)]GLP-1和内源性多肽GLP-1可以通过简单的扩散从外周进入大脑，从而参与摄食调节。
Glucagon-like peptide-1 (GLP-1) reduces insulin requirement in diabetes mellitus and promotes satiety. GLP-1 in the periphery (outside the CNS) has been shown to act on the brain to reduce food ingestion. As GLP-1 is readily degraded in blood, we focused on the interactions of [Ser(8)]GLP-1, an analog with similar biological effects and greater stability with the blood-brain barrier (BBB). The influx of radiolabeled [Ser8]GLP-1 into brain has several distinctive characteristics:I. A rapid influx rate of 8.867 +/- 0.798 x 10(4) mL/g-min as measured by multiple-time regression analysis after iv injection in mice.2. Lack of self-inhibition by excess doses of the unlabeled [Ser8]GLP-1 either iv or by in situ brain perfusion, indicating the absence of a saturable transport system at the BBB.3. Lack of modulation by short-term fasting and some other ingestive peptides that may interact with GLP-1, including leptin, glucagon, insulin, neuropeptide Y, and melanin-concentrating hormone.4. No inhibition of influx by the selective GLP-1 receptor antagonist exendin(9-39), suggesting that the GLP-1 receptor is not involved in the rapid entry into brain.Similarly, there was no efflux system for [Ser(8)]GLP-1 to exit the brain other than following the reabsorption of cerebrospinal fluid (CSF). The fast influx was not associated with high lipid solubility. Upon reaching the brain compartment, substantial amounts of [Ser(8)]GLP-1 entered the brain parenchyma, but a large proportion was loosely associated with the vasculature at the BBB. Finally, the influx rate of [Ser(8)]GLP-1 was compared with that of GLP-1 in a blood-free brain perfusion system; radiolabeled GLP-1 had a more rapid influx than its analog and neither peptide showed the self-inhibition indicative of a saturable transport system. Therefore, we conclude that [Ser(8)]GLP-1 and the endogenous peptide GLP-1 can gain access to the brain from the periphery by simple diffusion and thus contribute to the regulation of feeding.