Martins J M, Kastin A J, Banks W A
Veterans Affairs Medical Center, New Orleans, La 70146, USA.
Neuroendocrinology. 1996 Apr;63(4):338-48. doi: 10.1159/000126974.
Corticotropin-releasing hormone (CRH) is produced and acts both within the central nervous system and at several peripheral sites. However, it is not known whether CRH is able to cross the blood-brain barrier (BBB) in either direction, or whether the central and peripheral compartments are independent. We studied the transport across the BBB of both human/rat CRH (hCRH) and ovine CRH (oCRH) using the native peptides labeled with 125I at the histidine residue, thereby avoiding the use of other synthetic modifications. No apparent transport of either hCRH or oCRH into the brain from blood was found, as measured by multiple-time regression analysis after intravenous injection of the labeled peptides. There were no significant differences between the two forms of the CRH peptide. However, both hCRH and oCRH were rapidly transported out of the brain after intracerebroventricular injection, with half-time (t1/2) disappearances of 11.1 (hCRH) and 15.1 min (oCRH); the transport rate was significantly different for the human and ovine forms. The transport of hCRH could be specifically inhibited by 5 nmol of unlabeled hCRH (t1/2 = 17.7 min) but not by the same dose of the synthetic analog alpha CRH12-41. The process could also be inhibited by pretreatment with aluminum chloride (t1/2 = 18.8 min). An indirect influence of the endogenous opiate modulating peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2, 5 nmol) was apparent by a change in the initial distribution within the brain. In conclusion, there is a specific unidirectional brain to blood transport system for CRH. This transport system in the mouse has a greater affinity for the human/rat than for the ovine form of the peptide, is inhibited by hCRH itself, and can be disrupted by pretreatment with aluminum. By facilitating the rapid clearance of central CRH, this transport system could be involved in the regulation of central CRH levels and could allow central CRH to reach the general circulation and act at peripheral sites.
促肾上腺皮质激素释放激素（CRH）在中枢神经系统内以及几个外周部位产生并发挥作用。然而，尚不清楚CRH是否能够双向穿过血脑屏障（BBB），或者中枢和外周部分是否相互独立。我们使用在组氨酸残基处用125I标记的天然肽研究了人/大鼠CRH（hCRH）和羊CRH（oCRH）穿过血脑屏障的转运情况，从而避免使用其他合成修饰。静脉注射标记肽后通过多次回归分析测量，未发现hCRH或oCRH从血液向脑内有明显转运。两种形式的CRH肽之间没有显著差异。然而，脑室内注射后，hCRH和oCRH均迅速从脑内转运出来，半衰期（t1/2）分别为11.1（hCRH）和15.1分钟（oCRH）；人源和羊源形式的转运速率有显著差异。5 nmol未标记的hCRH可特异性抑制hCRH的转运（t1/2 = 17.7分钟），但相同剂量的合成类似物α CRH12 - 41则无此作用。用氯化铝预处理也可抑制该过程（t1/2 = 18.8分钟）。内源性阿片调节肽Tyr - MIF - 1（Tyr - Pro - Leu - Gly - NH2，5 nmol）通过改变脑内的初始分布产生明显的间接影响。总之，存在一种针对CRH的特定单向脑至血转运系统。小鼠中的这种转运系统对人/大鼠形式的肽的亲和力比对羊形式的肽更高，受hCRH自身抑制，并可被氯化铝预处理破坏。通过促进中枢CRH的快速清除，该转运系统可能参与中枢CRH水平的调节，并可使中枢CRH进入体循环并在外周部位发挥作用。
