Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
Proteomics. 2018 Apr;18(7):e1700417. doi: 10.1002/pmic.201700417.
Acamprosate is an FDA-approved medication for the treatment of alcoholism that is unfortunately only effective in certain patients. Although acamprosate is known to stabilize the hyper-glutamatergic state in alcoholism, pharmacological mechanisms of action in brain tissue remains unknown. To investigate the mechanism of acamprosate efficacy, the authors employ a pharmacoproteomics approach using an animal model of alcoholism, type 1 equilibrative nucleoside transporter (ENT1) null mice. The results demonstrate that acamprosate treatment significantly decreased both ethanol drinking and preference in ENT1 null mice compared to that of wild-type mice. Then, to elucidate acamprosate efficacy mechanism in ENT1 null mice, the authors utilize label-free quantification proteomics comparing both genotype and acamprosate treatment effects in the nucleus accumbens (NAc). A total of 1040 protein expression changes are identified in the NAc among 3634 total proteins detected. The proteomics and Western blot result demonstrate that acamprosate treatment decreased EAAT expression implicating stabilization of the hyper-glutamatergic condition in ENT1 null mice. Pathway analysis suggests that acamprosate treatment in ENT1 null mice seems to rescue glutamate toxicity through restoring of RTN4 and NF-κB medicated neuroimmune signaling compared to wild-type mice. Overall, pharmacoproteomics approaches suggest that neuroimmune restoration is a potential efficacy mechanism in the acamprosate treatment of certain sub-populations of alcohol dependent subjects.
安非他酮是一种获得 FDA 批准的治疗酒精中毒的药物，但不幸的是，它仅对某些患者有效。尽管安非他酮已知可稳定酒精中毒中的谷氨酸过度兴奋状态，但脑组织中的药物作用机制仍不清楚。为了研究安非他酮疗效的机制，作者采用了一种基于动物模型的药物蛋白质组学方法，即 1 型平衡核苷转运蛋白（ENT1）缺失小鼠。结果表明，与野生型小鼠相比，安非他酮治疗可显著降低 ENT1 缺失小鼠的乙醇饮用量和偏好性。然后，为了阐明 ENT1 缺失小鼠中安非他酮的疗效机制，作者利用无标记定量蛋白质组学方法，比较了两种基因型和安非他酮治疗在伏隔核（NAc）中的作用。在检测到的 3634 种总蛋白中，有 1040 种蛋白在 NAc 中表达发生了变化。蛋白质组学和 Western blot 结果表明，安非他酮治疗降低了 EAAT 的表达，这表明在 ENT1 缺失小鼠中稳定了谷氨酸过度兴奋状态。通路分析表明，与野生型小鼠相比，ENT1 缺失小鼠中安非他酮治疗似乎通过恢复 RTN4 和 NF-κB 介导的神经免疫信号来减轻谷氨酸毒性。总体而言，药物蛋白质组学方法表明，神经免疫恢复是安非他酮治疗某些酒精依赖亚群的潜在疗效机制。
