| 5α-Reduced Glucocorticoids Exhibit Dissociated Anti-Inflammatory and Metabolic Effects. | |
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MedLine Citation:
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PMID: 21542833 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Background and purpose. Dissociating anti-inflammatory efficacy from the metabolic side-effects of glucocorticoids is an attractive therapeutic goal. 5α-Tetrahydro-corticosterone (5αTHB), produced from corticosterone by 5α-reductases, activates glucocorticoid receptors. This study compares the effects of 5αTHB on inflammation and metabolism in vitro and in vivo. Method. Suppression of cytokine release by 5αTHB and corticosterone were studied following lipopolysaccharide (LPS) activation of mouse bone marrow derived macrophages. In vivo the efficacy of these steroids to dysregulate metabolic homeostasis and modulate immune suppression and the responses to thioglycollate-induced peritonitis in C57BL/6 mice were studied following acute injection (1.5-15mg/20µl i.p.) and chronic infusion (50 µg/day, 14 days). Data are % vehicle, treated with 5αTHB and corticosterone, respectively; *P < 0.05 versus vehicle. Results. In macrophages, 5αTHB increased secretion of IL-10 similarly to corticosterone (180%*, 340%*) and suppressed LPS-induced secretion of TNFα (21.9%*, 74.2%*) and IL-6 (16.4%*, 69.4%*). In mice with thioglycollate-induced peritonitis, both 5αTHB and corticosterone reduced the numbers of neutrophils (58.6%*, 49.9%*) and inflammatory monocytes (69.5%*, 96.4%*), and also suppressed MCP-1 (48.7%*, 80.9%*) and IL-6 (53.5%*, 86.7%*) in peritoneal exudate. In mice chronically infused with 5αTHB and corticosterone LPS-induced production of TNFα from whole blood was suppressed to the same degree (63.2%*, 37.2%*). However, 5αTHB did not induce body weight loss, increase blood pressure and induce hyperinsulinaemia in contrast to corticosterone. Conclusions. 5αTHB has anti-inflammatory effects in vitro and vivo. At doses with equivalent anti-inflammatory efficacy to corticosterone, 5αTHB did not induce metabolic toxicity and thus may be a prototype for a safer anti-inflammatory drug. |
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Authors:
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C Yang; M Nixon; Cj Kenyon; Dew Livingstone; R Duffin; Ag Rossi; Br Walker; R Andrew |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-4 |
Journal Detail:
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Title: British journal of pharmacology Volume: - ISSN: 1476-5381 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-5 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. |
Affiliation:
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Centre for Cardiovascular Science,Centre for Inflammation Research Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, United Kingdom Telephone: 0044 131 242 6763, Fax: 0044 131 242 6779. |
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