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Toxicologic Pathology, Vol. 34, No. 6, 738-743 (2006)
DOI: 10.1080/01926230600932505
© 2006 Society of Toxicologic Pathology

Articles

Gastric Mucosal Damage Following Repeat Administration of Melanocortin Subtype-4 Receptor Ligands to Fischer 344 Rats

Tracy M. Williams and Kevin B. Donnelly

Lilly Research Laboratories, Eli Lilly and Company, Greenfield, Indiana 46140, USA

Correspondence: Address correspondence to: Tracy M. Williams, Lilly Research Laboratories, Eli Lilly and Company, P.O. Box 708, Greenfield, IN 46140, USA; e-mail:tracy.williams{at}lilly.com

Since the melanocortin system plays a role in the central control of feeding, melanocortin receptor ligands may be efficacious in treating human obesity. Ten structurally similar melanocortin subtype-4 receptor (MC4R) ligands from an aryl piperazine chemical platform were evaluated in female Fischer 344 rats to assess the toxicity of this class of compounds. Rats were orally gavaged with 100, 250, or 500 mg/kg of each compound in 10% acacia and purified water daily for 4 days. In treated rats, notable clinical observations included a dose-dependent decrease in mean body weight and food consumption. A morphologically unique compound-related histologic lesion occurred in the nonglandular gastric mucosa. The lesions consisted of multiple, raised, sometimes ulcerated, white foci which, microscopically, were discrete, intraepithelial vesicles containing dense accumulations of neutrophils continuous with inflammation in the submucosa. Ruptured vesicles resulted in ulcers and occasionally gastric perforation. The morphologic characteristics of this acute lesion were described and concluded to be a direct toxicity of the compounds unrelated to melanocortin-mediated pharmacology.

Key Words: Melanocortin subtype-4 agonist • nonglandular stomach • gastric • mucosal • rat • ulceration

Abbreviations: MC4R, Melanocortin 4 receptor


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