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

Abstract

The two newest members of the urocortin (UCN)/corticotropin-releasing hormone (CRH) family of peptides – UCN II and UCN III – bind to the CRH-2 receptor, suppress feeding, and are expressed in the periphery as well as the brain. We used several sensitive techniques to examine their interactions with the blood-brain barrier (BBB). Of the four known peptides in this family, each interacts with the BBB differently. UCN I barely enters the brain from blood unless its latent saturable influx system is activated by leptin or pretreatment with glucose. However, neither leptin nor glucose affected the entry of intact UCN II. UCN II reached brain paranchyma at a moderate rate that was not self-inhibited or cross-inhibited by UCN/CRH peptides. The apparent, but misleading, rapid influx of UCN III (stresscopin) could be explained by degradation at the BBB itself. Influx of CRH into brain was slower than UCN II but faster than UCN I; it was inhibited by excess CRH but not by excess UCN I, II, III, or leptin. CRH is the only member of this family to have a saturable efflux system out of the brain. Determination of hydrogen bonding, newly applied here to ingestive peptides, was not helpful in explaining these differential interactions of the UCN peptides with the BBB.

Prolonged Urocortin 2 Administration in Experimental Heart Failure

“…In agreement with this hypothesis, repeated administration of Ucn1 in mice results in a reduced effect to inhibit food consumption, while the hypotensive action of the peptide persists, 28 and transgenic mice lacking the CRF-R2 receptor exhibit normal basal feeding and weight gain. 27 Previous work in rats has demonstrated the appetite-suppressive effects of Ucn2 after intracerebroventricular injection, 29 and, although a direct effect of peripheral Ucn2 at the feeding centers of the brain (especially the hypothalamic ventromedial nucleus, which is suggested to be a key site that transduces CRF receptor-mediated anorexigenic effects), 30 is possible given the report of passive movement of the peptide across the blood-brain barrier, 31 other possible contributory influences may include reduced gastric emptying, 2 as well as interaction with other factors known to regulate appetite, such as leptin, neuropeptide Y, and orexin A. 32 …”

Cardiovascular responses to microinjections of urocortin 3 into the nucleus tractus solitarius of the rat

“…Moreover, the fenestrated capillaries and perivascular spaces present in the NTS may permit a brisk influx of solutes into the neuropil of the mNTS (12). Hypotension caused by systemically infused Ucn2 and other CRF analogs (6,33) may also be partially mediated via the activation of CRF 2 Rs in the mNTS because they cross the blood-brain barrier by a unique transport system (19). Acute stress is often associated with increases in BP and HR.…”

Urocortin 2 induces potent long-lasting inhibition of cardiac sympathetic drive despite baroreflex activation in conscious sheep

“…The mechanism underlying UCN2-induced inhibition of CSNA cannot be defined by the present study but presumably occurs via central pathways. Of note, UCN2 has been shown to cross the blood-brain barrier in intact form by passive diffusion, entering brain parenchyma at a moderate rate (Kastin & Akerstrom 2002). The neuroanatomy of sympathetic outflow is well known, in that the hypothalamus sends both direct and indirect projections, via the brainstem, to sympathetic preganglionic neurons in the spinal cord (Saper et al 1976).…”