Martinez Joseph M, Groot Jessica A, Curtis David C, Allison Clayton L, Marquardt Patrick C, Holmes Ashley N, Edwards David S, Trotter David R M, Syapin Peter J, Finn Deborah A, Bergeson Susan E
Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, Texas.
Department of Family and Community Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas.
Alcohol Clin Exp Res. 2016 Dec;40(12):2499-2505. doi: 10.1111/acer.13259. Epub 2016 Nov 14.
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 (New Engl J Med, 2003, 348, 1786). 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 (EtOH) consumption in both the 2-bottle choice and drinking-in-the-dark paradigms. Here, we test the hypothesis that tigecycline, a tetracycline derivative, will reduce the severity of EtOH withdrawal symptoms in a common acute model of alcohol withdrawal (AWD) using a single anesthetic dose of EtOH in seizure sensitive DBA/2J (DBA) mice.
Naïve adult female and male DBA mice were given separate injections of 4 g/kg i.p. EtOH with vehicle or tigecycline (0, 20, 40, or 80 mg/kg i.p.). The 80 mg/kg dose was tested at 3 time points (0, 4, and 7 hours) post EtOH treatment. Handling-induced convulsions (HICs) were measured before and then over 12 hours following EtOH injection. HIC scores and areas under the curve were tabulated. In separate mice, blood EtOH concentrations (BECs) were measured at 2, 4, and 7 hours postinjection of 4 g/kg i.p. EtOH 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 AWD convulsions, with no sex differences in efficacy. Importantly, tigecycline did not affect BECs over a time course of elimination.
Tigecycline effectively reduced AWD symptoms in DBA 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.
酒精使用障碍（AUD）是一种谱系障碍，其特征为症状从轻度到重度，包括在停止饮酒后可能出现的戒断症状。每年约有50万AUD患者经历具有临床相关性的戒断发作（《新英格兰医学杂志》，2003年，第348卷，第1786页）。最近的证据表明，改变神经免疫途径的药物有潜力成为新的AUD治疗方法。我们之前已经表明，免疫调节药物米诺环素和替加环素在双瓶选择和黑暗中饮酒范式中均能有效减少乙醇（EtOH）消耗。在此，我们测试以下假设：在对癫痫敏感的DBA/2J（DBA）小鼠中，使用单次麻醉剂量的EtOH建立常见的急性酒精戒断（AWD）模型，四环素衍生物替加环素将减轻EtOH戒断症状的严重程度。
将成年未处理的雌性和雄性DBA小鼠分别腹腔注射4 g/kg EtOH，同时注射赋形剂或替加环素（0、20、40或80 mg/kg腹腔注射）。在EtOH处理后3个时间点（0、4和7小时）测试80 mg/kg剂量。在EtOH注射前及注射后12小时内测量处理诱导惊厥（HICs）。记录HIC评分和曲线下面积。在另一组小鼠中，测量腹腔注射4 g/kg EtOH后2、4和7小时的血液EtOH浓度（BECs），这些小鼠分别接受0和80 mg/kg腹腔注射替加环素处理。
与对照组相比，替加环素药物治疗可减轻AWD症状的发作、峰值幅度和总体HIC严重程度。在整个AWD过程中，无论治疗时间如何，替加环素治疗均有效，早期治疗显示出更大的疗效。替加环素在急性AWD惊厥中呈现剂量依赖性降低，且疗效无性别差异。重要的是，在消除过程中，替加环素不影响BECs。
在所有测试的时间点和剂量下，替加环素均能有效减轻DBA小鼠的AWD症状，使其成为开发新型AWD药物疗法的有前景的先导化合物。需要进一步研究以确定替加环素的作用机制。
