Mahogany (1377-1428) enters brain by a saturable transport system

作     者：Kastin, AJ Akerstrom, V 

作者机构：Vet Affairs Med Ctr New Orleans LA 70112 USA Tulane Univ Sch Med New Orleans LA 70112 USA 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：2000年第294卷第2期

页      面：633-636页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：NIDDK NIH HHS [DK54880] Funding Source: Medline 

主　　题：刺鼠相关蛋白质 生物转运 主动/药物作用 血脑屏障/药物作用 血脑屏障/生理学 脑/血液供给 脑/代谢 缓冲剂 毛细血管/代谢 色谱法 高压液相 表皮生长因子/药理学 半衰期 胞间信号肽类和蛋白质类 碘放射性同位素/诊断应用 动力学 瘦素/药理学 黑素细胞刺激激素类/药理学 膜蛋白质类/血液 膜蛋白质类/药代动力学 小鼠 近交ICR 辛醇类/化学 肽碎片/血液 肽碎片/药代动力学 蛋白质类/药理学 溶解度 α促黑素/药理学 动物 男(雄)性 小鼠 大鼠 

摘      要：The mouse mahogany gene encodes a protein that is involved in the suppression of diet-induced obesity. We studied the ability of its widely conserved C-terminal fragment to cross the blood-brain barrier (BBB) in mice. Multiple-time regression analysis showed that the entry rate (K-i) of I-125-mahogany (1377-1428) from blood-to-brain was 5.5 X 10(-4) ml/***. After coinjection of unlabeled mahogany (1377-1428), the K-i was significantly decreased, showing the self-inhibition characteristic of a saturable transport mechanism. The excess mahogany (1377-1428) did not change the influx rate of Tc-99m-albumin, the vascular control, indicating a lack of disruption of the BBB. Statistically significant cross-inhibition was not seen with agouti-related protein (83-132), melanin-concentrating hormone, epidermal growth factor, leptin, a melanocortin-4 receptor antagonist, or alpha-melanocyte-stimulating hormone. HPLC showed that most of the injected I-125-mahogany (1377-1428) reached the brain intact, and capillary depletion with washout showed that most of it reached the parenchyma. There was no brain-to-blood efflux system for mahogany (1377-1428) but rather retention after i.c.v. administration, and the octanol/buffer partition coefficient showed low lipophilicity. Thus, the results show that the C-terminal peptide product encoded by the mahogany gene crosses the BBB by a transport mechanism that is saturable. The ability of this system to be regulated indicates the therapeutic potential of mahogany (1377-1428) in the treatment of obesity.