Yalcin Emine B, McLean Tory, Tong Ming, de la Monte Suzanne M
Liver Research Center, Division of Gastroenterology, Department of Medicine, Brown University, Providence, RI, USA; Rhode Island Hospital, The Alpert Medical School of Brown University, Providence, RI, USA.
Neuroscience Graduate Program, Brown University, Providence, RI, USA.
Alcohol. 2017 Dec;65:51-62. doi: 10.1016/j.alcohol.2017.05.008. Epub 2017 Sep 15.
Chronic ethanol exposure causes white matter (WM) atrophy and degeneration with major impairments in the structural integrity of myelin. Since myelin is composed of oligodendrocyte lipid-rich membranes, understanding the consequences and reversibility of alcohol-related oligodendrocyte dysfunction in relation to myelin structure could provide new insights into the pathogenesis of WM degeneration and potential strategies for treatment. Adult male Long Evans rats were pair-fed with isocaloric liquid diets containing 0% or 26% ethanol (caloric) for 3 or 8 weeks. During the last 2 weeks of feeding, the ethanol groups were binged with 2 g/kg of ethanol by intraperitoneal (i.p.) injection on Mondays, Wednesdays, and Fridays; controls were treated with i.p. saline. For recovery effects, at the 6-week time point, ethanol exposures were tapered over 2 days, and then discontinued, rendering the rats ethanol-free for 12 days. Anterior corpus callosum WM lipid ion profiles were analyzed using matrix-assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) and correlated with histopathology. Ethanol exposures caused progressive atrophy and reductions in myelin staining intensity within the corpus callosum, whereas short-term recovery partially reversed those effects. MALDI-IMS demonstrated striking ethanol-associated alterations in WM lipid profiles characterized by reduced levels of phosphatidylinositols, phosphatidylserines, phosphatidylethanolamines, and sulfatides, and partial "normalization" of lipid expression with recovery. Ethanol exposure duration and recovery responses were further distinguished by heatmap hierarchical dendrogram and PCA plots. In conclusion, chronic+binge ethanol exposures caused progressive, partially reversible WM atrophy with myelin loss associated with reduced expression of WM phospholipids and sulfatides. The extent of WM lipid abnormalities suggests that ethanol broadly impairs molecular and biochemical functions regulating myelin synthesis, degradation, and maintenance in oligodendrocytes.
长期暴露于乙醇会导致白质（WM）萎缩和变性，髓鞘的结构完整性受到严重损害。由于髓鞘由富含脂质的少突胶质细胞膜组成，了解与酒精相关的少突胶质细胞功能障碍对髓鞘结构的影响及其可逆性，可为WM变性的发病机制和潜在治疗策略提供新的见解。成年雄性Long Evans大鼠分别用含0%或26%乙醇（热量）的等热量液体饲料配对喂养3周或8周。在喂养的最后2周，乙醇组在周一、周三和周五通过腹腔内（i.p.）注射2 g/kg乙醇进行暴饮；对照组接受腹腔内注射生理盐水治疗。为了观察恢复效果，在6周时间点，乙醇暴露在2天内逐渐减少，然后停止，使大鼠在12天内无乙醇。使用基质辅助激光解吸电离成像质谱（MALDI-IMS）分析胼胝体前WM脂质离子谱，并与组织病理学相关联。乙醇暴露导致胼胝体内髓鞘染色强度逐渐萎缩和降低，而短期恢复部分逆转了这些影响。MALDI-IMS显示，WM脂质谱与乙醇相关的显著变化，其特征是磷脂酰肌醇、磷脂酰丝氨酸、磷脂酰乙醇胺和硫脂水平降低，脂质表达在恢复时部分“正常化”。通过热图层次树状图和主成分分析（PCA）图进一步区分了乙醇暴露持续时间和恢复反应。总之，慢性暴饮乙醇暴露导致进行性、部分可逆的WM萎缩，并伴有髓鞘丢失，同时WM磷脂和硫脂表达降低。WM脂质异常的程度表明，乙醇广泛损害调节少突胶质细胞中髓鞘合成、降解和维持的分子和生化功能。
