11β-hydroxysteroid dehydrogenase inhibition as a new potential therapeutic target for alcohol abuse.
11β-hydroxysteroid dehydrogenase inhibition as a new potential therapeutic target for alcohol abuse.
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DOI：
10.1038/tp.2016.13
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发表时间：
2016-03-15
影响因子：
6.8
通讯作者：
Repunte-Canonigo V
中科院分区：
文献类型：
--
作者：
Sanna PP;Kawamura T;Chen J;Koob GF;Roberts AJ;Vendruscolo LF;Repunte-Canonigo V
确定新的和更有效的酗酒治疗方法仍然是一个优先事项。酒精摄入会激活糖皮质激素，而糖皮质激素在酒精的强化特性中起着关键作用。糖皮质激素的作用部分由作为前受体的11β-羟基类固醇脱氢酶（11β-HSD）的活性调节。在这里，我们测试了11β-HSD 1抑制剂甘珀酸（CBX，18β-大黄酸3β-O-半琥珀酸酯）对酒精摄入量的影响，它已被广泛用于临床治疗胃炎和消化性溃疡，对11β-HSD 1和11β-HSD 2亚型都有活性。我们观察到CBX减少了大鼠和小鼠的基线和过量饮酒。我们发现CBX非对映体18α-大黄酸3β-O-半琥珀酸酯（αCBX）对11β-HSD 2具有选择性，也可有效减少小鼠的饮酒量。因此，11β-HSD抑制剂可能是一类有前途的新的候选酒精滥用药物，现有的11β-HSD抑制剂药物可能被重新用于酒精滥用治疗。
The identification of new and more effective treatments for alcohol abuse remains a priority. Alcohol intake activates glucocorticoids, which have a key role in alcohol's reinforcing properties. Glucocorticoid effects are modulated in part by the activity of 11β-hydroxysteroid dehydrogenases (11β-HSD) acting as pre-receptors. Here, we tested the effects on alcohol intake of the 11β-HSD inhibitor carbenoxolone (CBX, 18β-glycyrrhetinic acid 3β-O-hemisuccinate), which has been extensively used in the clinic for the treatment of gastritis and peptic ulcer and is active on both 11β-HSD1 and 11β-HSD2 isoforms. We observed that CBX reduces both baseline and excessive drinking in rats and mice. The CBX diastereomer 18α-glycyrrhetinic acid 3β-O-hemisuccinate (αCBX), which we found to be selective for 11β-HSD2, was also effective in reducing alcohol drinking in mice. Thus, 11β-HSD inhibitors may be a promising new class of candidate alcohol abuse medications, and existing 11β-HSD inhibitor drugs may be potentially re-purposed for alcohol abuse treatment.