High-dose thiamine prevents brain lesions and prolongs survival of Slc19a3-deficient mice.
High-dose thiamine prevents brain lesions and prolongs survival of Slc19a3-deficient mice.
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DOI：
10.1371/journal.pone.0180279
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Wakamatsu N
中科院分区：
文献类型：
--
作者：
Suzuki K;Yamada K;Fukuhara Y;Tsuji A;Shibata K;Wakamatsu N
SLC19A3 缺乏症，也称为硫胺素代谢功能障碍综合征 2 (THMD2；OMIM 607483)，是一种由编码硫胺素转运蛋白 2 的基因 SLC19A3 突变引起的常染色体隐性神经退行性疾病。旨在研究 SLC19A3 缺乏症神经退行性变的分子机制以及是否给予大剂量硫胺素 为了防止神经退行性变，我们培育了纯合 Slc19a3 E314Q 敲入 (KI) 小鼠，其含有与人类 SLC19A3 E320Q 相对应的突变，该突变与严重的 THMD2 相关。饲喂硫胺素限制饮食（硫胺素：0.60 mg/100 g 食物）的纯合 KI 小鼠和之前报道的纯合 Slc19a3 敲除（KO）小鼠分别在 30 和 12 天内死亡，血液和大脑中的硫胺素浓度显着降低，出现急性神经退行性变，丘脑和腹侧下核星形胶质细胞增生 丘脑的前外侧复合体。这些发现可能具有由吡硫胺注射和硫胺素缺乏饮食产生的硫胺素缺乏小鼠的一些特征，表明THMD2的主要原因可能是焦磷酸硫胺素（TPP）缺乏。接下来，我们分析了大剂量硫胺素治疗的治疗效果。当硫胺素限制后饮食恢复为常规饮食（硫胺素：1.71mg/100g食物）时，所有纯合KO小鼠均死亡。相比之下，当硫胺素限制后饮食改为高硫胺素饮食（硫胺素：8.50毫克/100克食物）时，超过一半的纯合KO小鼠存活下来，并且脑部病变没有进展。出乎意料的是，当康复小鼠的高硫胺素饮食恢复为常规饮食时，一些纯合KO小鼠死亡。这些结果表明，硫胺素缺乏引起的急性神经变性在大多数情况下是可以预防的，及时给予大剂量硫胺素对于治疗 THMD2 至关重要。然而，硫胺素的减少应谨慎进行，以防止疾病恢复后复发。
SLC19A3 deficiency, also called thiamine metabolism dysfunction syndrome-2 (THMD2; OMIM 607483), is an autosomal recessive neurodegenerative disorder caused by mutations in SLC19A3, the gene encoding thiamine transporter 2. To investigate the molecular mechanisms of neurodegeneration in SLC19A3 deficiency and whether administration of high-dose thiamine prevents neurodegeneration, we generated homozygous Slc19a3 E314Q knock-in (KI) mice harboring the mutation corresponding to the human SLC19A3 E320Q, which is associated with the severe form of THMD2. Homozygous KI mice and previously reported homozygous Slc19a3 knock-out (KO) mice fed a thiamine-restricted diet (thiamine: 0.60 mg/100 g food) died within 30 and 12 days, respectively, with dramatically decreased thiamine concentration in the blood and brain, acute neurodegeneration, and astrogliosis in the submedial nucleus of the thalamus and ventral anterior-lateral complex of the thalamus. These findings may bear some features of thiamine-deficient mice generated by pyrithiamine injection and a thiamine-deficient diet, suggesting that the primary cause of THMD2 could be thiamine pyrophosphate (TPP) deficiency. Next, we analyzed the therapeutic effects of high-dose thiamine treatment. When the diet was reverted to a conventional diet (thiamine: 1.71 mg/100 g food) after thiamine restriction, all homozygous KO mice died. In contrast, when the diet was changed to a high-thiamine diet (thiamine: 8.50 mg/100 g food) after thiamine restriction, more than half of homozygous KO mice survived, without progression of brain lesions. Unexpectedly, when the high-thiamine diet of recovered mice was reverted to a conventional diet, some homozygous KO mice died. These results showed that acute neurodegeneration caused by thiamine deficiency is preventable in most parts, and prompt high-dose thiamine administration is critical for the treatment of THMD2. However, reduction of thiamine should be performed carefully to prevent recurrence after recovery of the disease.