Titus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90033, USA.
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033, USA.
Int J Neuropsychopharmacol. 2014 Jun;17(6):907-16. doi: 10.1017/S1461145713001703. Epub 2014 Jan 22.
Our laboratory is investigating ivermectin (IVM) and other members of the avermectin family as new pharmaco-therapeutics to prevent and/or treat alcohol use disorders (AUDs). Earlier work found that IVM significantly reduced ethanol intake in mice and that this effect likely reflects IVM's ability to modulate ligand-gated ion channels. We hypothesized that structural modifications that enhance IVM's effects on key receptors and/or increase its brain concentration should improve its anti-alcohol efficacy. We tested this hypothesis by comparing the abilities of IVM and two other avermectins, abamectin (ABM) and selamectin (SEL), to reduce ethanol intake in mice, to alter modulation of GABAARs and P2X4Rs expressed in Xenopus oocytes and to increase their ability to penetrate the brain. IVM and ABM significantly reduced ethanol intake and antagonized the inhibitory effects of ethanol on P2X4R function. In contrast, SEL did not affect either measure, despite achieving higher brain concentrations than IVM and ABM. All three potentiated GABAAR function. These findings suggest that chemical structure and effects on receptor function play key roles in the ability of avermectins to reduce ethanol intake and that these factors are more important than brain penetration alone. The direct relationship between the effect of these avermectins on P2X4R function and ethanol intake suggest that the ability to antagonize ethanol-mediated inhibition of P2X4R function may be a good predictor of the potential of an avermectin to reduce ethanol intake and support the use of avermectins as a platform for developing novel drugs to prevent and/or treat AUDs.
我们的实验室正在研究伊维菌素（IVM）和其他阿维菌素类药物作为预防和/或治疗酒精使用障碍（AUDs）的新药物。早期的研究发现，IVM 可显著减少小鼠的乙醇摄入量，而这种效果可能反映了 IVM 调节配体门控离子通道的能力。我们假设，增强 IVM 对关键受体的作用和/或增加其脑浓度的结构修饰应该可以提高其抗酒精功效。我们通过比较 IVM 和另外两种阿维菌素，阿维菌素（ABM）和塞拉菌素（SEL），来检验这一假设，比较它们减少小鼠乙醇摄入量的能力，改变它们在非洲爪蟾卵母细胞中表达的 GABAAR 和 P2X4R 的调制作用，以及增加它们穿透大脑的能力。IVM 和 ABM 显著减少了乙醇摄入量，并拮抗了乙醇对 P2X4R 功能的抑制作用。相比之下，SEL 既没有影响这两种措施，尽管它在大脑中的浓度比 IVM 和 ABM 都高。这三种药物都增强了 GABAAR 的功能。这些发现表明，化学结构和对受体功能的影响在阿维菌素减少乙醇摄入量的能力中起着关键作用，这些因素比脑渗透本身更为重要。这些阿维菌素对 P2X4R 功能的作用与乙醇摄入量之间的直接关系表明，拮抗乙醇介导的 P2X4R 功能抑制的能力可能是阿维菌素减少乙醇摄入量的潜在能力的良好预测指标，并支持使用阿维菌素作为开发预防和/或治疗 AUDs 的新型药物的平台。
