Cohen Ariel C, Tong Ming, Wands Jack R, de la Monte Suzanne M
Department of Medicine, Rhode Island Hospital, Warren Alpert School of Medicine at Brown University, Providence, Rhode Island, USA.
Alcohol Clin Exp Res. 2007 Sep;31(9):1558-73. doi: 10.1111/j.1530-0277.2007.00450.x. Epub 2007 Jul 11.
Previous studies linked cerebellar hypoplasia, neuronal loss, and impaired acetylcholine homeostasis to ethanol inhibition of insulin and insulin-like growth factor signaling mechanisms in experimental models of fetal alcohol syndrome (FAS).
To determine the extent to which similar abnormalities occur in mature brains, gene expression, ligand binding, and histopathological studies were performed with temporal lobe, hypothalamus, and cerebellar cortex from adult male Long Evans rats that were pair-fed for 6 weeks with liquid diets containing 0% or 37% ethanol by caloric content.
Real time quantitative RT-PCR analysis demonstrated that the chronic ethanol-fed rats had significantly reduced insulin-like growth factors (IGF)-II receptor expression in all 3 regions and reduced insulin receptor expression in the temporal lobe. However, equilibrium binding assays revealed ethanol-associated impairments in insulin and IGF-I receptor binding in all 3 regions and reduced IGF-II receptor binding in the cerebellum. These abnormalities were associated with decreased expression of Hu (neuronal loss) in the temporal lobe and cerebellum, and choline acetyltransferase (ChAT) in the hypothalamus and cerebellum, and increased expression of NADPH oxidase 3 in all 3 regions examined. Ethanol-associated neuronal loss with increased indices of lipid peroxidation and DNA damage were demonstrated by histopathological, immunohistochemical, and enzyme linked immunosorbant assay studies.
These results suggest that ethanol-induced neurodegeneration in adults is mediated by insulin/IGF resistance, persistent oxidative stress, and impaired acetylcholine biosynthesis, similar to the findings in FAS. The reductions in ChAT gene expression most likely contribute to the cognitive and motor deficits that occur with chronic alcohol abuse.
先前的研究表明，在胎儿酒精综合征（FAS）实验模型中，小脑发育不全、神经元丢失以及乙酰胆碱稳态受损与乙醇对胰岛素和胰岛素样生长因子信号传导机制的抑制作用有关。
为了确定在成熟大脑中类似异常情况出现的程度，对成年雄性Long Evans大鼠的颞叶、下丘脑和小脑皮质进行了基因表达、配体结合和组织病理学研究，这些大鼠成对喂养6周，食用热量含量分别为0%或37%乙醇的液体饮食。
实时定量逆转录聚合酶链反应（RT-PCR）分析表明，长期摄入乙醇的大鼠在所有3个区域中胰岛素样生长因子（IGF）-II受体表达显著降低，在颞叶中胰岛素受体表达降低。然而，平衡结合试验显示，所有3个区域中胰岛素和IGF-I受体结合存在与乙醇相关的损伤，小脑中IGF-II受体结合减少。这些异常与颞叶和小脑中Hu（神经元丢失）表达降低、下丘脑和小脑中胆碱乙酰转移酶（ChAT）表达降低以及所有3个检测区域中NADPH氧化酶3表达增加有关。组织病理学、免疫组织化学和酶联免疫吸附试验研究证明了与乙醇相关的神经元丢失以及脂质过氧化和DNA损伤指标增加。
这些结果表明，成年人中乙醇诱导的神经变性是由胰岛素/IGF抵抗、持续的氧化应激和乙酰胆碱生物合成受损介导的，这与FAS中的发现相似。ChAT基因表达的降低很可能导致慢性酒精滥用所出现的认知和运动缺陷。
