Abstract
Canine hypercortisolism is most often caused by an ACTH-secreting pituitary adenoma (pituitary-dependent hypercortisolism; PDH). An interesting target for a selective medical treatment of PDH would be the receptor for ACTH: the melanocortin 2 receptor (MC2R). In this study we investigated whether two peptide compounds, BIM-22776 (#776) and BIM-22A299 (#299), are effective MC2R antagonists in vitro. Their effects on cortisol production and mRNA expression of steroidogenic enzymes, MC2R and melanocortin 2 receptor accessory protein (MRAP) were evaluated in primary adrenocortical cell cultures (n = 8) of normal canine adrenal glands. Cortisol production stimulated by 50 nM ACTH was dose-dependently inhibited by #299 (inhibition 90.7 ± 2.3% at 5 μM) and by #776 (inhibition 38.0 ± 5.2% at 5 μM). The ACTH-stimulated mRNA expression of steroidogenic enzymes, MC2R and MRAP was significantly inhibited by both compounds, but most potently by #299. These results indicate that canine primary cell culture is a valuable in vitro system to test MC2R antagonists, and that these compounds, but especially #299, are effective MC2R antagonists in vitro. To determine its efficacy in vivo, further studies are warranted. Antagonism of the MC2R is a promising potential treatment approach in canine PDH.
Highlights
Hypercortisolism (Cushing’s syndrome) is one of the most frequently diagnosed endocrinopathies in dogs (Galac et al 2010c)
The aim of this study was to evaluate whether the two peptide compounds BIM-22776 (#776) and BIM-22A299 (#299) are potent melanocortin 2 receptor (MC2R) antagonists in vitro, and to determine whether MC2R antagonists have potential as a future treatment option for canine PDH
The results of this study show that canine primary adrenocortical cell culture stimulated with synthetic ACTH(1–24) is a functional in vitro model to test the efficacy of MC2R antagonists
Summary
Hypercortisolism (Cushing’s syndrome) is one of the most frequently diagnosed endocrinopathies in dogs (Galac et al 2010c). This serious endocrine disorder is characterized by chronic exposure to excessive amounts of glucocorticoids, which can be caused by either glucocorticoid administration or endogenous cortisol overproduction. The current drug of choice for the medical treatment of canine PDH is trilostane, which competitively inhibits the steroidogenic enzyme 3β-hydroxysteroid dehydrogenase type. A more selective treatment option where the negative effects of increased ACTH secretion are countered could improve the current medical treatment of canine PDH
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