| Autor: |
Yang, C, Nixon, M, Kenyon, CJ, Livingstone, DEW, Duffin, R, Rossi, AG, Walker, BR, Andrew, R, Kenyon, C J, Livingstone, D E W, Rossi, A G, Walker, B R |
| Předmět: |
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| Zdroj: |
British Journal of Pharmacology; Nov2011, Vol. 164 Issue 6, p1661-1671, 11p |
| Abstrakt: |
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.Methods: Suppression of cytokine release by 5αTHB and corticosterone were studied following 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 (1.5-15 mg) and chronic infusion (50 µg·day(-1) , 14 days).Results: In macrophages, 5αTHB increased secretion of IL-10 similarly to corticosterone (180%, 340%; data are % vehicle, treated with 5αTHB and corticosterone, respectively) and suppressed LPS-induced secretion of TNF-α (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 TNF-α from whole blood was suppressed to the same degree (63.2%, 37.2%). However, in contrast to corticosterone, 5αTHB did not induce body weight loss, increase blood pressure or induce hyperinsulinaemia.Conclusions: 5αTHB has anti-inflammatory effects in vitro and in 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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