Acute modulation of active carrier-mediated brain-to-blood transport of corticotropin-releasing hormone

Abstract

The unidirectional brain-to-blood transport system for corticotropin-releasing hormone (CRH) across the blood-brain barrier could be instrumental in the homeostasis of central CRH. To characterize this system, the intracerebroventricular injection of 125I-CRH was used in mice. CRH was rapidly transported out of the brain with a half-time disappearance (t1/2) of 15 min, much faster than albumin (t1/2 = 50 min). Kinetic analysis revealed a saturable component with a low maximum velocity (apaproximately 0.020 nmol x min(-1) x brain(-1)) and low capacity (Michaelis constant approximately 1.4 nmol/brain). Transport was inhibited by verapamil, ouabain, and colchicine but not by cyclosporin. Transport was increased by corticosterone and inhibited by tumor necrosis factor-alpha and beta-endorphin. These results suggest that the specific unidirectional brain-to-blood transport system for CRH is dependent on energy and calcium channels, involves microtubules, is independent of the P-glycoprotein transporter, and is acutely modulated by adrenal steroids, cytokines, and endogenous opiates. This suggests its participation in the control of the stress response.

Elevated Plasma Corticotrophin Release Factor Levels and In Utero Meconium Passage

“…Studies in adult mice report the existence of specific unidirectional brain-to-blood transport system for CRF (34). Furthermore, this transport system is acutely modulated by adrenal steroids suggesting the participation in the control of stress response (35). In the present investigation, we have observed marked increases in plasma corticosterone levels both in pregnant rats and fetuses under hypoxic stress condition suggesting the possibility that plasma glucocorticoids may have stimulated transport of brain CRF to plasma in hypoxic groups.…”

Human urocortin II, a new CRF-related peptide, displays selective CRF2-mediated action on gastric transit in rats

“…The possible leakage of CRF from the brain to the periphery during stress is supported by the demonstration of active CRF transport from the brain to the periphery (22). However, CRF and Ucn are expressed in the GI tract (9,12,16,25) and immune cells (2).…”

Differential Interactions of Urocortin/Corticotropin-Releasing Hormone Peptides with the Blood-Brain Barrier

“…CRH has such an efflux system, but results obtained after administration of aluminum suggest that the efflux system is unrelated to the influx system [2]. By contrast, UCN I and UCN II exited the brain at the same rate as the normal reabsorption of cerebrospinal fluid, indicating another way in which their interactions with the BBB differ from those of CRH.…”

“…Among peptides that can affect food ingestion, corticotropin-releasing hormone (CRH) is unusual in that it has a saturable transport system out of the brain sufficient to affect the periphery [1, 2, 3]. Urocortin (UCN) I, a member of the CRH family that binds better to CRH-2 receptors than does CRH [4], also has an unusual but very different relationship with the blood-brain barrier (BBB).…”