Kastin Abba J, Akerstrom Victoria, Pan Weihong
VA Medical Center, New Orleans, LA, USA.
J Mol Neurosci. 2002 Feb-Apr;18(1-2):7-14. doi: 10.1385/JMN:18:1-2:07.
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 [Ser8]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: 1. 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 [Ser8]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 [Ser8]GLP-1 entered the brain parenchyma, but a large proportion was loosely associated with the vasculature at the BBB. Finally, the influx rate of [Ser8]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 [Ser8]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.
胰高血糖素样肽-1（GLP-1）可降低糖尿病患者的胰岛素需求量并促进饱腹感。外周（中枢神经系统之外）的GLP-1已被证明可作用于大脑以减少食物摄入。由于GLP-1在血液中易降解，我们重点研究了具有相似生物学效应且稳定性更高的类似物[Ser8]GLP-1与血脑屏障（BBB）的相互作用。放射性标记的[Ser8]GLP-1进入大脑具有几个显著特征：1. 通过对小鼠静脉注射后进行多次回归分析测量，其快速流入速率为8.867 +/- 0.798 x 10(4) mL/g - min。2. 静脉注射或原位脑灌注过量未标记的[Ser8]GLP-1均无自我抑制现象，表明血脑屏障不存在可饱和转运系统。3. 短期禁食以及一些可能与GLP-1相互作用的其他摄食肽（包括瘦素、胰高血糖素、胰岛素、神经肽Y和黑色素浓缩激素）对其无调节作用。4. 选择性GLP-1受体拮抗剂艾塞那肽（9 - 39）对其流入无抑制作用，表明GLP-1受体不参与其快速进入大脑的过程。同样，除了随脑脊液（CSF）重吸收外，[Ser8]GLP-1没有从大脑流出的系统。快速流入与高脂溶性无关。到达脑区后，大量的[Ser8]GLP-1进入脑实质，但很大一部分与血脑屏障处的血管系统松散结合。最后，在无血脑灌注系统中比较了[Ser8]GLP-1和GLP-1的流入速率；放射性标记的GLP-1比其类似物流入更快，且两种肽均未表现出可饱和转运系统的自我抑制现象。因此，我们得出结论，[Ser8]GLP-1和内源性肽GLP-1可通过简单扩散从外周进入大脑，从而有助于调节进食。
