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Gevaert, Bert; Wynendaele, Evelien; Stalmans, Sofie; Bracke, Nathalie; D'Hondt, Matthias; Smolders, Ilse; van Eeckhaut, Ann; De Spiegeleer, Bart
Neuropharmacology, August 2016, 2016-08-00, 20160801, Letnik: 107Journal Article
The neuromedin peptides are peripherally and centrally produced, but until now, it is generally believed that they only function as locally acting compounds without any quantitative knowledge about their blood-brain barrier (BBB) passage. Here, we characterize the transport kinetics of four neuromedins (NMU, NMN, NMB and NT) across the BBB, as well as their metabolization profile, and evaluate if they can act as endocrine hormones. Using the in vivo mouse model, multiple time regression (MTR), capillary depletion (CD) and brain efflux studies were performed. Data was fitted using linear (NMU, NT and NMB) or biphasic modeling (NMU and NMN). Three of the four investigated peptides, i.e. NMU, NT and NMN, showed a significant influx into the brain with unidirectional influx rate constants of 1.31 and 0.75 μL/(g × min) for NMU and NT respectively and initial influx constants (K1) of 72.14 and 7.55 μL/(g × min) and net influx constants (K) of 1.28 and 1.36 × 10−16 μL/(g×min) for NMU and NMN respectively. The influx of NMB was negligible. Only NMN and NT showed a significant efflux out of the brain with an efflux constant (kout) of 0.042 min−1 and 0.053 min−1 respectively. Our results indicate that locally produced neuromedin peptides and/or fragments can be transported through the whole body, including passing the BBB, and taken up by different organs/tissues, supporting the idea that the neuromedins could have a much bigger role in the regulation of biological processes than currently assumed. Display omitted •The peptides NMU, NT and NMN show a clear influx from the blood to the brain.•The peptides that enter the brain capillaries continue to the brain parenchyma.•NMN and NT show an efflux from the brain to the blood.•The stability of all peptides was evaluated and the metabolites identified.
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