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Curcumin analogue as a novel 11βHSD1 modulator to treat glucocorticoid excess diseases
Author(s) -
Xiao Jian,
Zhang Hongyu,
Wang Zhouguang,
Shi Hongxue,
Wu Fenzan,
Lin Beibei,
Li Xiaokun
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.564.5
Subject(s) - curcumin , endocrinology , medicine , glucocorticoid , chemistry , in vivo , testosterone (patch) , oxidative stress , nadph oxidase , oral administration , pharmacology , biochemistry , biology , microbiology and biotechnology
Background Glucocorticoid (GC) excess is associated with metabolic syndrome and hypogonadism. 11β‐hydroxysteroid dehydrogenase 1 (11βHSD1) regulates intracellular GC concentration thus being a therapeutic target. Methods A new curcumin analogue, (1E,4E)‐1,5‐bis(2‐bromophenyl)penta‐1,4‐dien‐3‐one (GL63) was synthesized, and we compared the effect of GL63 and curcumin in 11β‐HSD1 oxidase activity and reductase activity in primary rat Leydig cells, CHOP cell lines transfected human 11βHSD1 gene in vitro , and in vivo effects in GC‐excessive model: acute stress and high fat diet (HFD) model. Results The IC 50 of inhibiting 11βHSD1 reductase activity was 3 ± 0.2 μM and 100 nM, and the EC 50 of stimulating oxidase activity was 2.04 ± 0.2 μM and 86 ± 0.2 nM by curcumin and GL63, respectively, in rat Leydig cells. Curcumin inhibited 11βHSD2 with IC 50 of 13 μM for rat kidney, while GL63 did not. Oral administration of curcumin (100 to 200 mg/kg/day) or GL63 (1–4 mg/kg/day) for 3 d completely prevented the decreases of serum testosterone levels induced by restraint stress in male rats, and oral administration of curcumin (200 mg/kg/day) and GL63 (2 and 4 mg/kg/day) for 2 months improved lipid profiles induced by HFD. Conclusion A novel 11β‐HSD1 modulator, GL63, has been developed and effectively prevented GC excess diseases such as stress‐induced hypogonadism or HFD‐induced fatty liver.