Progressive white matter atrophy with altered lipid profiles is partially reversed by short-term abstinence in an experimental model of alcohol-related neurodegeneration

Abstract

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.

Function and Mechanism of Myelin Regulation in Alcohol Abuse and Alcoholism

“…In contrast, prenatal exposure of EtOH had no effect on myelination in the developing caudal pyramidal tract (i.e., corticospinal axons) in rats . Progressive white matter atrophy in the corpus callosum with altered lipid profiles is partially reversed by short‐term abstinence in a chronic binge model with adult male rats …”

Altered Oligodendroglial and Neuroglial Gene Expression in Adult Rat Cerebral White Matter Following Short- and Long-Term Ethanol Exposures and Abbreviated Abstinence

“…This design allowed us to study ethanol's detrimental effects on the brain in its late developmental and adult stages and whether these adverse effects could be reversed by short-term abstinence. Histopathological studies revealed that ethanol caused progressive time coursedependent reductions in white matter myelin resembling human alcohol related brain disease [3,28,38]. Shortterm abstinence resulted in partial recovery of myelin suggesting similarities with alcohol abstinence effects in alcoholics [10,28,39].…”

“…Upon sacrifice, the temporal lobes were harvested, frozen on dry ice, and stored at -80°C. Although the neurotoxic and degenerative effects of alcohol occur prominently in the prefrontal cortex, temporal lobe, hippocampus, and cerebral white matter [2], our studies focused on its adverse effects in temporal white matter as an extension of previous work using this model in which we demonstrated alcohol-induced temporal lobe white matter atrophy with myelin loss, aberrant expression of mature glial and neuronal proteins, and sphingolipid and phospholipid profiles [23,28].…”

“…Previous reports demonstrating the potential for at least partial recovery of white matter atrophy and degeneration in humans and experimental models [5,9,28], along with improvements in cognitive-executive functions in humans following periods of abstinence [11], justifies further investigation to determine the mechanisms of those therapeutic responses. To begin addressing this question, the present work utilized an adult rat chronic+binge ethanol exposure model to examine time course-dependent shifts in myelin-associated gene expression and assess therapeutic responses to short-term abstinence.…”

Subventricular zone lipidomic architecture loss in Huntington's disease

“…; Yalcin et al . , ). Moreover, the small raster widths achieved by the modern commercial MALDI−IMS instruments provide high spatial resolution and thus unique opportunities to investigate the macromolecular composition of the SVZ.…”