丁酸钠减少酒精消费潜力的临床前评估:在抗生素增强的狂饮模型中对 C57bl/6j 小鼠进行的剂量递增研究。

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pharmacology Pub Date : 2024-08-12 DOI:10.1159/000540882
Gregory C Havton, Alex T C Tai, Surabhi Vasisht, Daryl L Davies, Liana Asatryan
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引用次数: 0

摘要

导言:在早期建立酒精使用障碍(AUD)过程中肠道-大脑轴的研究中,我们已经证明在C57BL/6J雄性小鼠的饮用水中补充8 mg/ml的丁酸钠(一种主要的短链脂肪酸)可以减少乙醇摄入量,并降低抗生素(ABX)增强的自愿狂饮型酒精消费模型--黑暗中饮酒(DID)的神经炎症反应:为了进一步评估SB的临床前潜力,我们在C57BL/6J雄性小鼠中进行了一项剂量递增研究,以测试在DID程序中自由摄入20毫克/毫升SB(SB20)和50毫克/毫升SB(SB50)及其与ABX的组合对小鼠的影响,为期4周。在治疗期间,测定这些浓度的 SB 对乙醇消耗量和身体参数的影响。研究结束时,收集血液、肝脏和肠道组织,以研究任何潜在的不良影响,并测量血液中的乙醇浓度:结果:饮用水中 SB 浓度的增加会导致对乙醇摄入量的保护作用减弱,并对体重和肝脏重量产生不利影响,同时会减少总体液体摄入量。关于这些影响是由于对高浓度 SB 气味/味道的厌恶造成的这一假设,在后续的概念验证研究中通过胃内灌胃给药 SB 得到了进一步验证。较高的灌胃剂量(320 毫克/千克)导致乙醇消耗量减少,但没有任何不良影响:总之,这些研究结果进一步证实了在适当的给药方式下,SB 在治疗 AUD 方面的治疗潜力。
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Preclinical Evaluation of Sodium Butyrate's Potential to Reduce Alcohol Consumption: A Dose-Escalation Study in C57BL/6J Mice in Antibiotic-Enhanced Binge-Like Drinking Model.

Introduction: In our earlier efforts to establish gut-brain axis during alcohol use disorder (AUD), we have demonstrated that supplementation of C57BL/6J male mice with 8 mg/mL sodium butyrate, a major short-chain fatty acid, in drinking water reduced ethanol intake and neuroinflammatory response in antibiotic (ABX)-enhanced voluntary binge-like alcohol consumption model, drinking in the dark (DID).

Methods: To further evaluate the preclinical potential of SB, we have set a dose-escalation study in C57BL/6J male mice to test effects of ad libitum 20 mg/mL SB and 50 mg/mL SB and their combinations with ABX in the DID procedure for 4 weeks. Effects of these SB concentrations on ethanol consumption and bodily parameters were determined for the duration of the treatments. At the end of study, blood, liver, and intestinal tissues were collected to study any potential adverse effects ad to measure blood ethanol concentrations.

Results: Increasing SB concentrations in the drinking water caused a loss in the protective effect against ethanol consumption and produced adverse effects on body and liver weights, reduced overall liquid intake. The hypothesis that these effects were due to aversion to SB smell/taste at these high concentrations were further tested in a follow up proof-of-concept study with intragastric gavage administration of SB. The higher gavage dose (320 mg/kg) caused reduction in ethanol consumption without any adverse effects.

Conclusion: Overall, these findings added more support for the therapeutic potential of SB in management of AUD, given a proper form of administration.

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来源期刊
Pharmacology
Pharmacology 医学-药学
CiteScore
5.60
自引率
0.00%
发文量
52
审稿时长
6-12 weeks
期刊介绍: ''Pharmacology'' is an international forum to present and discuss current perspectives in drug research. The journal communicates research in basic and clinical pharmacology and related fields. It covers biochemical pharmacology, molecular pharmacology, immunopharmacology, drug metabolism, pharmacogenetics, analytical toxicology, neuropsychopharmacology, pharmacokinetics and clinical pharmacology. In addition to original papers and short communications of investigative findings and pharmacological profiles the journal contains reviews, comments and perspective notes; research communications of novel therapeutic agents are encouraged.
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