Department of Neurology, Zhongshan Hospital & Shanghai Medical College, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
Brain. 2010 May;133(Pt 5):1342-51. doi: 10.1093/brain/awq069. Epub 2010 Apr 12.
Reduction of glucose metabolism in brain is one of the main features of Alzheimer's disease. Thiamine (vitamin B1)-dependent processes are critical in glucose metabolism and have been found to be impaired in brains from patients with Alzheimer's disease. However, thiamine treatment exerts little beneficial effect in these patients. Here, we tested the effect of benfotiamine, a thiamine derivative with better bioavailability than thiamine, on cognitive impairment and pathology alterations in a mouse model of Alzheimer's disease, the amyloid precursor protein/presenilin-1 transgenic mouse. We show that after a chronic 8 week treatment, benfotiamine dose-dependently enhanced the spatial memory of amyloid precursor protein/presenilin-1 mice in the Morris water maze test. Furthermore, benfotiamine effectively reduced both amyloid plaque numbers and phosphorylated tau levels in cortical areas of the transgenic mice brains. Unexpectedly, these effects were not mimicked by another lipophilic thiamine derivative, fursultiamine, although both benfotiamine and fursultiamine were effective in increasing the levels of free thiamine in the brain. Most notably, benfotiamine, but not fursultiamine, significantly elevated the phosphorylation level of glycogen synthase kinase-3alpha and -3beta, and reduced their enzymatic activities in the amyloid precursor protein/presenilin-1 transgenic brain. Therefore, in the animal Alzheimer's disease model, benfotiamine appears to improve the cognitive function and reduce amyloid deposition via thiamine-independent mechanisms, which are likely to include the suppression of glycogen synthase kinase-3 activities. These results suggest that, unlike many other thiamine-related drugs, benfotiamine may be beneficial for clinical Alzheimer's disease treatment.
脑内葡萄糖代谢降低是阿尔茨海默病的主要特征之一。依赖硫胺素（维生素 B1）的过程对葡萄糖代谢至关重要，并且已经发现阿尔茨海默病患者的大脑中的这些过程受损。然而，硫胺素治疗对这些患者几乎没有有益的效果。在这里，我们测试了苯磷硫胺，一种生物利用度优于硫胺素的硫胺素衍生物，对阿尔茨海默病小鼠模型，即淀粉样前体蛋白/早老素-1 转基因小鼠的认知障碍和病理改变的影响。我们发现，经过 8 周的慢性治疗后，苯磷硫胺可剂量依赖性地增强淀粉样前体蛋白/早老素-1 小鼠在 Morris 水迷宫测试中的空间记忆。此外，苯磷硫胺还可有效降低转基因小鼠大脑皮质区域的淀粉样斑块数量和磷酸化 tau 水平。出乎意料的是，另一种亲脂性硫胺素衍生物呋喃硫胺并没有模拟这些作用，尽管苯磷硫胺和呋喃硫胺都能有效地增加大脑中游离硫胺素的水平。最值得注意的是，苯磷硫胺而非呋喃硫胺可显著提高淀粉样前体蛋白/早老素-1 转基因脑中糖原合酶激酶-3α和-3β的磷酸化水平，并降低其酶活性。因此，在动物阿尔茨海默病模型中，苯磷硫胺似乎通过非硫胺素依赖的机制改善认知功能并减少淀粉样沉积，这可能包括抑制糖原合酶激酶-3 的活性。这些结果表明，与许多其他与硫胺素相关的药物不同，苯磷硫胺可能对临床阿尔茨海默病的治疗有益。
