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Effects of Carbenoxolone on the Canine Pituitary-Adrenal Axis

Cushing’s disease caused by pituitary corticotroph adenoma is a common endocrine disease in dogs. A characteristic biochemical feature of corticotroph adenomas is their relative resistance to suppressive negative feedback by glucocorticoids. The abnormal expression of 11beta-hydroxysteroid dehydroge...

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Autores principales: Teshima, Takahiro, Matsumoto, Hirotaka, Okusa, Tomoko, Nakamura, Yumi, Koyama, Hidekazu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532459/
https://www.ncbi.nlm.nih.gov/pubmed/26262685
http://dx.doi.org/10.1371/journal.pone.0135516
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author Teshima, Takahiro
Matsumoto, Hirotaka
Okusa, Tomoko
Nakamura, Yumi
Koyama, Hidekazu
author_facet Teshima, Takahiro
Matsumoto, Hirotaka
Okusa, Tomoko
Nakamura, Yumi
Koyama, Hidekazu
author_sort Teshima, Takahiro
collection PubMed
description Cushing’s disease caused by pituitary corticotroph adenoma is a common endocrine disease in dogs. A characteristic biochemical feature of corticotroph adenomas is their relative resistance to suppressive negative feedback by glucocorticoids. The abnormal expression of 11beta-hydroxysteroid dehydrogenase (11HSD), which is a cortisol metabolic enzyme, is found in human and murine corticotroph adenomas. Our recent studies demonstrated that canine corticotroph adenomas also have abnormal expression of 11HSD. 11HSD has two isoforms in dogs, 11HSD type1 (HSD11B1), which converts cortisone into active cortisol, and 11HSD type2 (HSD11B2), which converts cortisol into inactive cortisone. It has been suggested that glucocorticoid resistance in corticotroph tumors is related to the overexpression of HSD11B2. Therefore it was our aim to investigate the effects of carbenoxolone (CBX), an 11HSD inhibitor, on the healthy dog’s pituitary-adrenal axis. Dogs were administered 50 mg/kg of CBX twice each day for 15 days. During CBX administration, no adverse effects were observed in any dogs. The plasma adrenocorticotropic hormone (ACTH), and serum cortisol and cortisone concentrations were significantly lower at day 7 and 15 following corticotropin releasing hormone stimulation. After completion of CBX administration, the HSD11B1 mRNA expression was higher, and HSD11B2 mRNA expression was significantly lower in the pituitaries. Moreover, proopiomelanocortin mRNA expression was lower, and the ratio of ACTH-positive cells in the anterior pituitary was also significantly lower after CBX treatment. In adrenal glands treated with CBX, HSD11B1 and HSD11B2 mRNA expression were both lower compared to normal canine adrenal glands. The results of this study suggested that CBX inhibits ACTH secretion from pituitary due to altered 11HSD expressions, and is potentially useful for the treatment of canine Cushing’s disease.
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spelling pubmed-45324592015-08-20 Effects of Carbenoxolone on the Canine Pituitary-Adrenal Axis Teshima, Takahiro Matsumoto, Hirotaka Okusa, Tomoko Nakamura, Yumi Koyama, Hidekazu PLoS One Research Article Cushing’s disease caused by pituitary corticotroph adenoma is a common endocrine disease in dogs. A characteristic biochemical feature of corticotroph adenomas is their relative resistance to suppressive negative feedback by glucocorticoids. The abnormal expression of 11beta-hydroxysteroid dehydrogenase (11HSD), which is a cortisol metabolic enzyme, is found in human and murine corticotroph adenomas. Our recent studies demonstrated that canine corticotroph adenomas also have abnormal expression of 11HSD. 11HSD has two isoforms in dogs, 11HSD type1 (HSD11B1), which converts cortisone into active cortisol, and 11HSD type2 (HSD11B2), which converts cortisol into inactive cortisone. It has been suggested that glucocorticoid resistance in corticotroph tumors is related to the overexpression of HSD11B2. Therefore it was our aim to investigate the effects of carbenoxolone (CBX), an 11HSD inhibitor, on the healthy dog’s pituitary-adrenal axis. Dogs were administered 50 mg/kg of CBX twice each day for 15 days. During CBX administration, no adverse effects were observed in any dogs. The plasma adrenocorticotropic hormone (ACTH), and serum cortisol and cortisone concentrations were significantly lower at day 7 and 15 following corticotropin releasing hormone stimulation. After completion of CBX administration, the HSD11B1 mRNA expression was higher, and HSD11B2 mRNA expression was significantly lower in the pituitaries. Moreover, proopiomelanocortin mRNA expression was lower, and the ratio of ACTH-positive cells in the anterior pituitary was also significantly lower after CBX treatment. In adrenal glands treated with CBX, HSD11B1 and HSD11B2 mRNA expression were both lower compared to normal canine adrenal glands. The results of this study suggested that CBX inhibits ACTH secretion from pituitary due to altered 11HSD expressions, and is potentially useful for the treatment of canine Cushing’s disease. Public Library of Science 2015-08-11 /pmc/articles/PMC4532459/ /pubmed/26262685 http://dx.doi.org/10.1371/journal.pone.0135516 Text en © 2015 Teshima et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Teshima, Takahiro
Matsumoto, Hirotaka
Okusa, Tomoko
Nakamura, Yumi
Koyama, Hidekazu
Effects of Carbenoxolone on the Canine Pituitary-Adrenal Axis
title Effects of Carbenoxolone on the Canine Pituitary-Adrenal Axis
title_full Effects of Carbenoxolone on the Canine Pituitary-Adrenal Axis
title_fullStr Effects of Carbenoxolone on the Canine Pituitary-Adrenal Axis
title_full_unstemmed Effects of Carbenoxolone on the Canine Pituitary-Adrenal Axis
title_short Effects of Carbenoxolone on the Canine Pituitary-Adrenal Axis
title_sort effects of carbenoxolone on the canine pituitary-adrenal axis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532459/
https://www.ncbi.nlm.nih.gov/pubmed/26262685
http://dx.doi.org/10.1371/journal.pone.0135516
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