Peptide Drug Design, Pharmacology, And Delivery In Health And Disease

Journal of Molecular Neuroscience

, Volume 18, Issue 1, pp 7-14

Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier

  • Abba J. KastinAffiliated withVA Medical Center and Tulane University School of Medicine
  • , Victoria AkerstromAffiliated withVA Medical Center and Tulane University School of Medicine
  • , Weihong PanAffiliated withVA Medical Center and Tulane University School of Medicine

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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. 1.

    A rapid influx rate of 8.867±0.798 × 104 mL/g-min as measured by multiple-time regression analysis after iv injection in mice.

  2. 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. 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. 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.

Index Entries

Feeding blood-brain barrier GLP-1 peptide