Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier.
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.
Kastin
Abba J
AJ
VA Medical Center, New Orleans, LA, USA.
Akerstrom
Victoria
V
Pan
Weihong
W
D000818:Animals; D001069:Appetite Regulation / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005508:Food Deprivation / Q000502:physiology; D005934:Glucagon / Q000378:metabolism* / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1; D007028:Hypothalamic Hormones / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D020738:Leptin / Q000494:pharmacology; D008297:Male; D008543:Melanins / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009478:Neuropeptide Y / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D010907:Pituitary Hormones / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism*
D007028:Hypothalamic Hormones; D007328:Insulin; D020738:Leptin; D008543:Melanins; D009478:Neuropeptide Y; D010446:Peptide Fragments; D010907:Pituitary Hormones; D011498:Protein Precursors; C083773:exendin (9-39); C019463:melanin-concentrating hormone; D052216:Glucagon-Like Peptide 1; D005934:Glucagon