University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology and Experimental Therapeutics, Toledo, Ohio (H.A., W.W., Y.S.); Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania (M.A-G., W.C., E.M.); and Department of Psychiatry and Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana (R.L.B.).
University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology and Experimental Therapeutics, Toledo, Ohio (H.A., W.W., Y.S.); Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania (M.A-G., W.C., E.M.); and Department of Psychiatry and Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana (R.L.B.)
J Pharmacol Exp Ther. 2022 Dec;383(3):208-216. doi: 10.1124/jpet.122.001147. Epub 2022 Sep 24.
Chronic ethanol exposure affects the glutamatergic system in several brain reward regions including the nucleus accumbens (NAc). Our laboratory has shown that chronic exposure to ethanol reduced the expression of glutamate transporter 1 (GLT-1) and cystine/glutamate exchanger (xCT) and, as a result, increased extracellular glutamate concentrations in the NAc of alcohol-preferring (P) rats. Moreover, previous studies from our laboratory reported that chronic ethanol intake altered the expression of certain metabotropic glutamate receptors in the brain. In addition to central effects, chronic ethanol consumption induced liver injury, which is associated with steatohepatitis. In the present study, we investigated the effects of chronic ethanol consumption in the brain and liver. Male P rats had access to a free choice of ethanol and water bottles for five weeks. Chronic ethanol consumption reduced GLT-1 and xCT expression in the NAc shell but not in the NAc core. Furthermore, chronic ethanol consumption increased fat droplet content as well as peroxisome proliferator-activated receptor alpha (PPAR-) and GLT-1 expression in the liver. Importantly, treatment with the novel beta-lactam compound, MC-100093, reduced ethanol drinking behavior and normalized the levels of GLT-1 and xCT expression in the NAc shell as well as normalized GLT-1 and PPAR- expression in the liver. In addition, MC-100093 attenuated ethanol-induced increases in fat droplet content in the liver. These findings suggest that MC-100093 may be a potential lead compound to attenuate ethanol-induced dysfunction in the glutamatergic system and liver injury. SIGNIFICANCE STATEMENT: This study identified a novel beta-lactam, MC-100093, that has demonstrated upregulatory effects on GLT-1. MC-100093 reduced ethanol drinking behavior and normalized levels of GLT-1 and xCT expression in the NAc shell as well as normalized GLT-1 and PPAR- expression in the liver. In addition, MC-100093 attenuated ethanol-induced increases in fat droplet content in the liver.
慢性乙醇暴露会影响包括伏隔核（NAc）在内的多个大脑奖赏区域的谷氨酸能系统。我们的实验室已经表明，慢性暴露于乙醇会降低谷氨酸转运体 1（GLT-1）和胱氨酸/谷氨酸交换体（xCT）的表达，从而导致酒精偏好（P）大鼠 NAc 中细胞外谷氨酸浓度增加。此外，我们实验室的先前研究报告称，慢性乙醇摄入会改变大脑中某些代谢型谷氨酸受体的表达。除了中枢作用外，慢性乙醇消耗还会引起肝损伤，这与 steatohepatitis 有关。在本研究中，我们研究了慢性乙醇消耗对大脑和肝脏的影响。雄性 P 大鼠可以自由选择乙醇和水瓶，为期五周。慢性乙醇消耗会降低 NAc 壳中的 GLT-1 和 xCT 表达，但不会降低 NAc 核中的 GLT-1 和 xCT 表达。此外，慢性乙醇消耗会增加肝脏中的脂肪滴含量以及过氧化物酶体增殖物激活受体-α（PPAR-α）和 GLT-1 的表达。重要的是，新型β-内酰胺化合物 MC-100093 的治疗可减少乙醇饮用量，并使 NAc 壳中的 GLT-1 和 xCT 表达水平正常化，同时使肝脏中的 GLT-1 和 PPAR-α表达水平正常化。此外，MC-100093 可减轻乙醇诱导的肝脏脂肪滴含量增加。这些发现表明，MC-100093 可能是一种潜在的先导化合物，可减轻乙醇诱导的谷氨酸能系统功能障碍和肝损伤。意义声明：本研究鉴定了一种新型β-内酰胺化合物 MC-100093，它具有上调 GLT-1 的作用。MC-100093 可减少乙醇饮用量，并使 NAc 壳中的 GLT-1 和 xCT 表达水平正常化，同时使肝脏中的 GLT-1 和 PPAR-α表达水平正常化。此外，MC-100093 可减轻乙醇诱导的肝脏脂肪滴含量增加。
