Laboratory of Neurovascular Oxidative Injury, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Psychopharmacology (Berl). 2011 Apr;214(3):707-18. doi: 10.1007/s00213-010-2076-4. Epub 2010 Nov 16.
Evidence shows that alcohol intake causes oxidative neuronal injury and neurocognitive deficits that are distinct from the classical Wernicke-Korsakoff neuropathy. Our previous findings indicated that alcohol-elicited blood-brain barrier (BBB) damage leads to neuroinflammation and neuronal loss. The dynamic function of the BBB requires a constant supply and utilization of glucose. Here we examined whether interference of glucose uptake and transport at the endothelium by alcohol leads to BBB dysfunction and neuronal degeneration.
We tested the hypothesis in cell culture of human brain endothelial cells, neurons and alcohol intake in animal by immunofluorescence, Western blotting and glucose uptake assay methods.
We found that decrease in glucose uptake correlates the reduction of glucose transporter protein 1 (GLUT1) in cell culture after 50 mM ethanol exposure. Decrease in GLUT1 protein levels was regulated at the translation process. In animal, chronic alcohol intake suppresses the transport of glucose into the frontal and occipital regions of the brain. This finding is validated by a marked decrease in GLUT1 protein expression in brain microvessel (the BBB). In parallel, alcohol intake impairs the BBB tight junction proteins occludin, zonula occludens-1, and claudin-5 in the brain microvessel. Permeability of sodium fluorescein and Evans Blue confirms the leakiness of the BBB. Further, depletion of trans-endothelial electrical resistance of the cell monolayer supports the disruption of BBB integrity. Administration of acetyl-L: -carnitine (a neuroprotective agent) significantly prevents the adverse effects of alcohol on glucose uptake, BBB damage and neuronal degeneration.
These findings suggest that alcohol-elicited inhibition of glucose transport at the blood-brain interface leads to BBB malfunction and neurological complications.
有证据表明，饮酒会导致氧化神经元损伤和神经认知功能障碍，这与典型的韦尼克-科尔萨科夫神经病变不同。我们之前的研究结果表明，酒精引起的血脑屏障（BBB）损伤会导致神经炎症和神经元死亡。BBB 的动态功能需要葡萄糖的持续供应和利用。在这里，我们研究了酒精是否通过干扰内皮细胞的葡萄糖摄取和转运导致 BBB 功能障碍和神经元变性。
我们通过免疫荧光、Western blot 和葡萄糖摄取测定方法，在人脑血管内皮细胞、神经元和动物饮酒的细胞培养中检验了这一假说。
我们发现，在 50mM 乙醇暴露后，细胞培养中葡萄糖摄取的减少与葡萄糖转运蛋白 1（GLUT1）的减少相关。GLUT1 蛋白水平的降低是在翻译过程中调节的。在动物中，慢性饮酒抑制了葡萄糖向大脑额区和枕区的转运。这一发现通过大脑微血管（BBB）中 GLUT1 蛋白表达的明显减少得到了验证。同时，饮酒会损害大脑微血管中的紧密连接蛋白紧密连接蛋白、闭锁蛋白-1 和闭合蛋白-5，导致 BBB 通透性增加。钠荧光素和 Evans Blue 的通透性证实了 BBB 的渗漏。此外，细胞单层跨内皮电阻的耗竭支持 BBB 完整性的破坏。乙酰-L：-肉碱（一种神经保护剂）的给药可显著防止酒精对葡萄糖摄取、BBB 损伤和神经元变性的不良影响。
这些发现表明，酒精在血脑界面抑制葡萄糖转运会导致 BBB 功能障碍和神经并发症。
