Department of Neurology, Zhongshan Hospital; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science; Institutes of Brain Science; National Clinical Research Center for Aging and Medicine, Huashan Hospital; Fudan University.
Department of Neurology, Shanghai Tenth People's Hospital, Tongji University School of Medicine.
Neuroreport. 2024 Oct 16;35(15):1000-1009. doi: 10.1097/WNR.0000000000002094. Epub 2024 Aug 23.
Thiamine deficiency is a well-known risk factor for the development of severe encephalopathy, such as Wernicke encephalopathy and Korsakoff syndrome, but the underlying mechanism is still mysterious. This study aims to investigate the expression levels of thiamine metabolism genes in different tissues and their impact on brain susceptibility to thiamine deficiency. The mRNA and protein levels of four genes known to be associated with thiamine metabolism: thiamine pyrophosphokinase-1 ( Tpk ), Solute carrier family 19 member 2 ( Slc19a2 ), Slc19a3 , and Slc25a19 , in the brain, kidney, and liver of mice were examined. Thiamine diphosphate (TDP) levels were measured in these tissues. Mice were subjected to dietary thiamine deprivation plus pyrithiamine (PTD), a specific TPK inhibitor, or pyrithiamine alone to observe the reduction in TDP and associated pathological changes. TPK mRNA and protein expression levels were lowest in the brain compared to the kidney and liver. Correspondingly, TDP levels were also lowest in the brain. Mice treated with PTD or pyrithiamine alone showed an initial reduction in brain TDP levels, followed by reductions in the liver and kidney. PTD treatment caused significant neuron loss, neuroinflammation, and blood-brain barrier disruption, whereas dietary thiamine deprivation alone did not. TPK expression level is the best indicator of thiamine metabolism status. Low TPK expression in the brain appears likely to contribute to brain susceptibility to thiamine deficiency, underscoring a critical role of TPK in maintaining cerebral thiamine metabolism and preventing thiamine deficiency-related brain lesions.
硫胺素缺乏是严重脑病（如韦尼克脑病和柯萨科夫综合征）发展的一个众所周知的危险因素，但潜在机制仍不清楚。本研究旨在研究不同组织中硫胺素代谢基因的表达水平及其对大脑对硫胺素缺乏易感性的影响。检测了与硫胺素代谢相关的四个基因（硫胺素焦磷酸激酶-1（Tpk）、溶质载体家族 19 成员 2（Slc19a2）、Slc19a3和 Slc25a19）的 mRNA 和蛋白质水平，在小鼠的大脑、肾脏和肝脏中。测定了这些组织中的硫胺素二磷酸（TDP）水平。用膳食硫胺素剥夺加吡哆醇（PTD），一种特定的 Tpk 抑制剂，或单独吡哆醇处理小鼠，观察 TDP 的减少和相关的病理变化。与肾脏和肝脏相比，TPK mRNA 和蛋白表达水平在大脑中最低。相应地，TDP 水平在大脑中也最低。用 PTD 或单独吡哆醇处理的小鼠表现出大脑 TDP 水平的初始降低，随后是肝脏和肾脏的降低。PTD 处理导致明显的神经元丢失、神经炎症和血脑屏障破坏，而单独的膳食硫胺素剥夺则没有。TPK 表达水平是硫胺素代谢状态的最佳指标。大脑中 TPK 表达水平低，可能导致大脑对硫胺素缺乏的易感性增加，这突显了 TPK 在维持大脑硫胺素代谢和预防与硫胺素缺乏相关的脑损伤方面的关键作用。
