Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu 520-2192, Japan.
Molecules. 2021 Sep 2;26(17):5342. doi: 10.3390/molecules26175342.
Thioredoxin-interacting protein () is involved in multiple disease-associated functions related to oxidative stress, especially by inhibiting the anti-oxidant- and thiol-reducing activity of thioredoxin (). Shiga-Y5 (SY5), a fluorine-19 magnetic resonance probe for detecting amyloid-β deposition in the brain, previously showed therapeutic effects in a mouse model of Alzheimer's disease; however, the mechanism of action of SY5 remains unclear. SY5 passes the blood-brain barrier and then undergoes hydrolysis to produce a derivative, Shiga-Y6 (SY6), which is a -negative regulator. Therefore, this study investigates the therapeutic role of SY5 as the prodrug of SY6 in the thioredoxin system in the brain of a mouse model of Alzheimer's disease. The intraperitoneal injection of SY5 significantly inhibited mRNA ( = 0.0072) and protein expression ( = 0.0143) induced in the brain of APP/PS1 mice. In contrast, the levels of mRNA ( = 0.0285) and protein ( = 0.0039) in the brain of APP/PS1 mice were increased after the injection of SY5. The ratio of to , which was decreased ( = 0.0131) in the brain of APP/PS1 mice, was significantly increased ( = 0.0072) after the injection of SY5. These results suggest that SY5 acts as a prodrug of SY6 in targeting the thioredoxin system and could be a potential therapeutic compound in oxidative stress-related diseases in the brain.
硫氧还蛋白相互作用蛋白 () 参与多种与氧化应激相关的疾病相关功能，特别是通过抑制硫氧还蛋白 () 的抗氧化和巯基还原活性。先前，氟-19 磁共振探针 Shiga-Y5 (SY5) 在阿尔茨海默病小鼠模型中显示出治疗效果；然而，SY5 的作用机制仍不清楚。SY5 通过血脑屏障，然后水解产生衍生物 Shiga-Y6 (SY6)，后者是一种 - 阴性调节剂。因此，本研究探讨了 SY5 作为 SY6 的前药在阿尔茨海默病小鼠模型的硫氧还蛋白系统中的治疗作用。SY5 的腹腔注射显著抑制了 APP/PS1 小鼠大脑中 mRNA（=0.0072）和蛋白表达（=0.0143）。相比之下，注射 SY5 后 APP/PS1 小鼠大脑中 mRNA（=0.0285）和蛋白（=0.0039）水平增加。APP/PS1 小鼠大脑中减少的 与 的比值（=0.0131），在注射 SY5 后显著增加（=0.0072）。这些结果表明，SY5 作为 SY6 的前药在靶向硫氧还蛋白系统中起作用，可能是大脑中氧化应激相关疾病的潜在治疗化合物。
