He Xiaohua, Sullivan Edith V, Stankovic Roger K, Harper Clive G, Pfefferbaum Adolf
Department of Pathology (D06), University of Sydney, Sydney, NSW 2006, Australia.
Neuropsychopharmacology. 2007 Oct;32(10):2207-16. doi: 10.1038/sj.npp.1301332. Epub 2007 Feb 14.
The relative roles of alcohol and thiamine deficiency in causing brain damage remain controversial in alcoholics without the Wernicke-Korsakoff syndrome. Experimental control over alcohol consumption and diet are impossible in humans but can be accomplished in animal models. This experiment was designed to differentiate the separate and combined effects on the macro- and ultrastructure of the corpus callosum of thiamine deficiency and voluntary alcohol consumption. Adult male alcohol-preferring (P) rats (9 chronically alcohol-exposed and 9 water controls) received a thiamine-deficient diet for 2 weeks. There were four groups: five rats previously exposed to alcohol were treated with pyrithiamine (a thiamine phosphorylation inhibitor); five rats never exposed to alcohol were treated with pyrithiamine; four alcohol-exposed rats were treated with thiamine; and four rats never exposed to alcohol were treated with thiamine. On day 14, thiamine was restored in all 18 rats; 2 weeks later the 10 pyrithiamine-treated rats received intraperitoneal thiamine. The rats were perfused 61 days post-pyrithiamine treatment at age 598 days. Brains were dissected and weight and volumes were calculated. Sagittal sections were stained to measure white matter structures. The corpus callosum was examined using transmission electron microscopy to determine density of myelinated fibers, fiber diameter, and myelin thickness. The corpus callosum in the alcohol/pyrithiamine group was significantly thinner, had greater fiber density, higher percentage of small fibers, and myelin thinning than in the alcohol/thiamine and water/thiamine groups. Several measures showed a graded effect, where the alcohol/pyrithiamine group had greater pathology than the water/pyrithiamine group, which had greater pathology than the two thiamine-replete groups. Across all 16 rats, thinner myelin sheaths correlated with higher percentage of small fibers. Myelin thickness and axon diameter together accounted for 71% of the variance associated with percentage of small fibers. Significant abnormalities in the alcohol/pyrithiamine group and lack of abnormality in the alcohol-exposed/thiamine-replete group indicate that thiamine deficiency caused white matter damage. The graded abnormalities across the dually to singly treated animals support a compounding effect of alcohol exposure and thiamine depletion, and indicate the potential for interaction between alcohol and thiamine deficiency in human alcohol-related brain damage.
在没有韦尼克 - 科萨科夫综合征的酗酒者中，酒精和硫胺素缺乏在导致脑损伤方面的相对作用仍存在争议。对人类的酒精摄入量和饮食进行实验控制是不可能的，但在动物模型中可以实现。本实验旨在区分硫胺素缺乏和自愿饮酒对胼胝体宏观和超微结构的单独及联合影响。成年雄性嗜酒（P）大鼠（9只长期接触酒精和9只作为水对照）接受为期2周的硫胺素缺乏饮食。实验分为四组：五只先前接触过酒精的大鼠用吡硫胺（一种硫胺素磷酸化抑制剂）处理；五只从未接触过酒精的大鼠用吡硫胺处理；四只接触过酒精的大鼠用硫胺素处理；四只从未接触过酒精的大鼠用硫胺素处理。在第14天，所有18只大鼠恢复硫胺素供应；2周后，10只用吡硫胺处理的大鼠接受腹腔注射硫胺素。在吡硫胺处理后61天、大鼠598日龄时进行灌注。解剖大脑并计算其重量和体积。矢状切片染色以测量白质结构。使用透射电子显微镜检查胼胝体，以确定有髓纤维密度、纤维直径和髓鞘厚度。与酒精/硫胺素组和水/硫胺素组相比，酒精/吡硫胺组的胼胝体明显更薄，纤维密度更高，小纤维百分比更高，且髓鞘变薄。多项测量显示出分级效应，酒精/吡硫胺组的病理变化大于水/吡硫胺组，水/吡硫胺组的病理变化大于两个硫胺素充足组。在所有16只大鼠中，较薄的髓鞘与较高的小纤维百分比相关。髓鞘厚度和轴突直径共同解释了与小纤维百分比相关的71%的变异。酒精/吡硫胺组的显著异常以及接触酒精/硫胺素充足组的无异常表明硫胺素缺乏导致了白质损伤。在双重处理到单一处理的动物中出现的分级异常支持了酒精暴露和硫胺素缺乏的复合效应，并表明在人类酒精相关脑损伤中酒精和硫胺素缺乏之间存在相互作用的可能性。
