Mahogany (1377-1428) enters brain by a saturable transport system.
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 (125)I-mahogany (1377-1428) from blood-to-brain was 5.5 x 10(-4) ml/g. min. 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 (99m)Tcalbumin, 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 (125)I-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.
Kastin
A J
AJ
Veterans Affairs Medical Center and Tulane University School of Medicine, New Orleans, LA 70112-1262, USA.
Akerstrom
V
V
D054369:Agouti-Related Protein; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D002021:Buffers; D002196:Capillaries / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006207:Half-Life; D036341:Intercellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D007700:Kinetics; D020738:Leptin / Q000494:pharmacology; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D008565:Membrane Proteins / Q000097:blood / Q000493:pharmacokinetics*; D051379:Mice; D008813:Mice, Inbred ICR; D000442:Octanols / Q000737:chemistry; D010446:Peptide Fragments / Q000097:blood / Q000493:pharmacokinetics*; D011506:Proteins / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D000521:alpha-MSH / Q000494:pharmacology
C515197:AGRP protein, rat; D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; C117928:Atrn protein, mouse; C492191:Atrn protein, rat; D002021:Buffers; D036341:Intercellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D020738:Leptin; D008565:Membrane Proteins; D000442:Octanols; D010446:Peptide Fragments; D011506:Proteins; D000521:alpha-MSH; D004815:Epidermal Growth Factor; D009074:Melanocyte-Stimulating Hormones