Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
Neurochem Int. 2010 Dec;57(7):830-7. doi: 10.1016/j.neuint.2010.08.022. Epub 2010 Sep 21.
Wernicke's encephalopathy is a cerebral metabolic disorder caused by thiamine (vitamin B1) deficiency (TD). Neuropathologic consequences of TD include region-selective neuronal cell loss and blood-brain barrier (BBB) breakdown. Caveolin-1 is involved in the regulation of tight junction proteins and BBB permeability, and is modulated by oxidative stress, a feature of vulnerable brain regions in TD. We hypothesized that TD-related oxidative stress alters BBB integrity via induction of the caveolin-1 pathway. TD was induced in C57BL6 mice by treatment with a thiamine-deficient diet and administration of the thiamine antagonist pyrithiamine, in the absence or presence of the antioxidant N-acetylcysteine (NAC). A significant and focal increase in both caveolin-1 gene and protein expression was detected in the thalamus of thiamine-deficient mice, concomitant with IgG extravasation. Reduction of oxidative stress by NAC, as shown by normalization of reduced glutathione levels and attenuation of endothelial heme oxygenase-1 and nitric oxide synthase expression, resulted in prevention of the up-regulation of caveolin-1 in TD. Normalization of caveolin-1 levels by NAC was accompanied by a reduction in BBB breakdown, indicated by decreased IgG extravasation, normalization of occludin levels and prevention of matrix metalloproteinase-9 up-regulation. These findings demonstrate a role for caveolin-1 in TD pathogenesis, and suggest that oxidative stress contributes to BBB alterations in TD via modulation of this pathway.
威尼克脑病是一种由硫胺素（维生素 B1）缺乏症（TD）引起的脑代谢紊乱。TD 的神经病理学后果包括区域选择性神经元细胞死亡和血脑屏障（BBB）破裂。小窝蛋白-1 参与调节紧密连接蛋白和 BBB 通透性，并受氧化应激调节，这是 TD 中易损脑区的特征。我们假设 TD 相关的氧化应激通过诱导小窝蛋白-1 通路改变 BBB 完整性。在 C57BL6 小鼠中，通过用缺乏硫胺素的饮食和硫胺素拮抗剂吡哆醇胺处理，并在存在或不存在抗氧化剂 N-乙酰半胱氨酸（NAC）的情况下，诱导 TD。在缺乏硫胺素的小鼠的丘脑，小窝蛋白-1 基因和蛋白表达均显著且局灶性增加，同时 IgG 外渗。NAC 通过还原型谷胱甘肽水平的正常化和内皮血红素加氧酶-1 和一氧化氮合酶表达的减弱来减轻氧化应激，导致 TD 中小窝蛋白-1 的上调得到预防。NAC 使小窝蛋白-1 水平正常化，同时减少 BBB 破裂，表现为 IgG 外渗减少、occludin 水平正常化和基质金属蛋白酶-9 上调的预防。这些发现表明小窝蛋白-1 在 TD 发病机制中的作用，并表明氧化应激通过调节该途径导致 TD 中 BBB 改变。
