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. 2010 Mar;151(3):1221-7.
doi: 10.1210/en.2009-1039. Epub 2009 Dec 23.

Corticotropin-releasing hormone receptor-1 in cerebral microvessels changes during development and influences urocortin transport across the blood-brain barrier

Hung Hsuchou  1 , Abba J Kastin, Xiaojun Wu, Hong Tu, Weihong Pan
Affiliations

Corticotropin-releasing hormone receptor-1 in cerebral microvessels changes during development and influences urocortin transport across the blood-brain barrier

Hung Hsuchou et al. Endocrinology. 2010 Mar.

Abstract

In this study we tested the hypothesis that receptor-mediated transport of urocortin across the blood-brain barrier (BBB) undergoes developmental changes. Urocortin is a peptide produced by both selective brain regions and peripheral organs, and it is involved in feeding, memory, mood, cardiovascular functions, and immune regulation. In BBB studies with multiple-time regression analysis, we found that neonatal mice had a significant influx of (125)I-urocortin. By contrast, adult mice did not transport urocortin across the BBB. Quantitative RT-PCR showed that corticotropin-releasing hormone receptor (CRHR)-1 was developmentally regulated in enriched cerebral microvessels as well as hypothalamus, being significantly higher in neonatal than adult mice. This change was less dramatic in agouti viable yellow mice, a strain that develops adult-onset obesity. The level of expression of CRHR1 mRNA was 33-fold higher in the microvessels than in hypothalamic homogenates. The mRNA for CRHR2 was less abundant in both regions and less prone to changes with development or the agouti viable yellow mutation. Supported by previous findings of receptor-mediated endocytosis of urocortin, these results suggest that permeation of urocortin across the BBB is dependent on the level of CRHR1 expression in cerebral microvessels. These novel findings of differential regulation of CRH receptor subtypes help elucidate developmental processes in the brain, particularly for the urocortin system.

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Figures

Figure 1
Figure 1
Permeation of urocortin across the neonatal and adult BBB in the CD1 mice (n = 7/group). A, The Ki for urocortin was significantly higher in the neonate than in the adult group (P < 0.05). The Vi for urocortin was also significantly higher than that for albumin in the neonatal mice (P < 0.0001). In adults, neither urocortin nor albumin showed meaningful influx (nonsignificant Ki), and their Vi did not differ from each other. B, After correction of the vascular space by subtraction of the 131I-albumin brain to serum ratio, the permeation of 125I-urocortin remained higher in the neonates than the adults (P < 0.05). C, The half-life of 125I-urocortin was 4.4 times higher in the neonates (6.33 min) than adults (1.43 min).
Figure 2
Figure 2
Developmental changes and strain difference of CRHR1 and CRHR2 mRNA at the BBB level in C57 and Avy mice (n = 3/group). *, P < 0.05, **, P < 0.01 when the neonates and adults from the same strain are compared. A, There were significant effects of age and Avy mutation on CRHR1. In both B6 and Avy mice, neonates had higher levels of CRHR1 than adults. The Avy neonates had a lower level of CRHR1 than B6 neonates. B, There was a strain effect (P < 0.05) and only a trend toward an effect of age (P = 0.067) for CRHR2.
Figure 3
Figure 3
Developmental changes and strain difference of CRHR1 and CRHR2 mRNA in the hypothalamus (n = 3 /group). A, CRHR1 showed an age-related decrease in B6 (*, P < 0.05) and Avy (+, P = 0.06) mice. B, CRHR2 did not show significant changes, although age had an overall effect (P < 0.05) by two-way ANOVA.
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