2008 JASN IMPACT FACTOR 7.505	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text Full Text (PDF) All Versions of this Article: ASN.2006091024v1 18/9/2517    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cheung, W. W. Articles by Mak, R. H. Search for Related Content PubMed PubMed Citation Articles by Cheung, W. W. Articles by Mak, R. H.

Peripheral Administration of the Melanocortin-4 Receptor Antagonist NBI-12i Ameliorates Uremia-Associated Cachexia in Mice

Wai W. Cheung^*,, Huey-Ju Kuo, Stacy Markison, Chen Chen, Alan C. Foster, Daniel L. Marks and Robert H. Mak^*,

^* Department of Pediatrics, University of California at San Diego, La Jolla, California; Department of Pediatrics, Oregon Health & Sciences University, Portland, Oregon; and Neurocrine Biosciences, San Diego, California

Correspondence: Dr. Robert H. Mak, Division of Pediatric Nephrology, University of California at San Diego, 9500 Gilman Drive, MC 0634, La Jolla, CA 92093-0634. Phone: 858-822-6717; Fax: 858-822-6776; romak{at}ucsd.edu

Received for publication September 19, 2006. Accepted for publication May 31, 2007.

We have recently shown that genetic or pharmacological blockade of the melanocortin-4 receptor (MC4-R) attenuates uremia-associated cachexia. However, the potential clinical utility of this approach has been limited by the need to deliver a peptide MC4-R antagonist into the ventricles of the brain. NBI-12i is a recently developed small molecule MC4-R antagonist, with high affinity and selectivity that penetrates the central nervous system after peripheral administration. We tested whether NBI-12i would also be effective in attenuating uremia-associated cachexia in a mouse model. Intraperitoneal administration of NBI-12i stimulated food intake and weight gain in uremic mice. Furthermore, NBI-12i–treated uremic mice gained lean body mass, fat mass, and had a lower basal metabolic rate compared to vehicle-treated and diet-supplemented uremic mice, which lost both lean body mass and fat mass and had an increase in basal metabolic rate. We found that NBI-12i normalizes the expression of uncoupling protein, which is normally upregulated in uremic mice, and we speculate that this may contribute to the drug’s protective effect. These data underscore the importance of melanocortin signaling in the pathogenesis of uremia-associated cachexia and demonstrate the potential of peripheral administration of MC4-R antagonists as a novel therapeutic approach.

This article has been cited by other articles:

				A. Laviano, A. Inui, D. L. Marks, M. M. Meguid, C. Pichard, F. Rossi Fanelli, and M. Seelaender Neural control of the anorexia-cachexia syndrome Am J Physiol Endocrinol Metab, November 1, 2008; 295(5): E1000 - E1008. [Abstract] [Full Text] [PDF]

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673