Effective Reduction of Acute Ethanol Withdrawal by the Tetracycline Derivative, Tigecycline, in Female and Male DBA/2J Mice.
Effective Reduction of Acute Ethanol Withdrawal by the Tetracycline Derivative, Tigecycline, in Female and Male DBA/2J Mice.
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在雌性和雄性DBA/2J小鼠中，四环素衍生物Tigecycline有效减少了急性乙醇的提取。
DOI：
10.1111/acer.13259
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发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
Bergeson SE
中科院分区：
文献类型：
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作者：
Martinez JM;Groot JA;Curtis DC;Allison CL;Marquardt PC;Holmes AN;Edwards DS;Trotter DR;Syapin PJ;Finn DA;Bergeson SE
酒精使用障碍（AUD）是一种以轻度至重度症状为特征的谱系障碍，包括停止饮酒后潜在的戒断症状。每年大约有50万AUD患者经历临床相关的戒断发作。最近的证据表明，改变神经免疫通路的药物有可能成为新的AUD治疗方法。我们之前已经证明免疫调节药物，米诺环素和替加环素，在两瓶选择和在黑暗中饮用的范式中都有效地减少了乙醇消耗。在这里，我们验证了一个假设，即替加环素，四环素的衍生物，将在癫痫发作敏感的DBA/2J （DBA）小鼠中使用单次麻醉剂量的乙醇，降低普通急性酒精戒断（AWD）模型中乙醇戒断症状的严重程度。分别注射4 g/kg / p乙醇和替加环素（0、20、40、80 mg/kg / p）。在乙醇处理后的3个时间点（0、4、7小时）检测80 mg/kg剂量。在注射乙醇前和注射后12小时测量处理性惊厥（HIC）。HIC分数和曲线下面积被制成表格。替加环素剂量分别为0和80 mg/kg，分别在小鼠注射4 g/kg乙醇后2、4和7小时测定其血乙醇浓度（BEC）。与对照组相比，替加环素药物治疗降低了AWD症状发作、峰值幅度和总体HIC严重程度。在整个AWD中，替加环素治疗无论何时都是有效的，越早治疗效果越好。替加环素在急性酒精戒断惊厥中显示出剂量反应性降低，在疗效上没有性别差异。重要的是，替加环素在消除过程中不会影响BECs。替加环素在所有时间和剂量测试中都有效地减轻了DBA/2J小鼠的酒精戒断症状，使其成为开发一种新型药物治疗AWD的有希望的先导化合物。需要进一步的研究来确定替加环素的作用机制。
Alcohol Use Disorder (AUD) is a spectrum disorder characterized by mild to severe symptoms, including potential withdrawal signs upon cessation of consumption. Approximately five hundred thousand patients with AUD undergo clinically relevant episodes of withdrawal annually. Recent evidence indicates potential for drugs that alter neuroimmune pathways as new AUD therapies. We have previously shown the immunomodulatory drugs, minocycline and tigecycline, were effective in reducing ethanol consumption in both the two-bottle choice and drinking-in-the-dark paradigms. Here, we test the hypothesis that tigecycline, a tetracycline derivative, will reduce the severity of ethanol withdrawal symptoms in a common acute model of alcohol withdrawal (AWD) using a single anesthetic dose of ethanol in seizure sensitive DBA/2J (DBA) mice. Naive adult female and male DBA mice were given separate injections of 4 g/kg i.p. ethanol with vehicle or tigecycline (0, 20, 40 or 80 mg/kg i.p.). The 80 mg/kg dose was tested at three time-points (0, 4, 7 hrs) post-ethanol treatment. Handling-induced convulsions (HIC) were measured before, and then over 12 hours following ethanol injection. HIC scores and areas under the curve were tabulated. In separate mice, blood ethanol concentrations (BEC) were measured at 2, 4, and 7 hours post injection of 4 g/kg i.p. ethanol in mice treated with 0 and 80 mg/kg i.p. tigecycline. AWD symptom onset, peak magnitude, and overall HIC severity were reduced by tigecycline drug treatment compared to controls. Tigecycline treatment was effective regardless of timing throughout AWD, with earlier treatment showing greater efficacy. Tigecycline showed a dose responsive reduction in acute alcohol withdrawal convulsions, with no sex-differences in efficacy. Importantly, tigecycline did not affect BECs over a time course of elimination. Tigecycline effectively reduced alcohol withdrawal symptoms in DBA/2J mice at all times and dosages tested, making it a promising lead compound for development of a novel pharmacotherapy for AWD. Further studies are needed to determine the mechanism of tigecycline action.