| Summary: | Thioredoxin-interacting protein (<i>TXNIP</i>) is involved in multiple disease-associated functions related to oxidative stress, especially by inhibiting the anti-oxidant- and thiol-reducing activity of thioredoxin (<i>TXN</i>). 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 <i>TXNIP</i>-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 <i>TXNIP</i> mRNA (<i>p</i> = 0.0072) and protein expression (<i>p</i> = 0.0143) induced in the brain of APP/PS1 mice. In contrast, the levels of <i>TXN</i> mRNA (<i>p</i> = 0.0285) and protein (<i>p</i> = 0.0039) in the brain of APP/PS1 mice were increased after the injection of SY5. The ratio of <i>TXN</i> to <i>TXNIP</i>, which was decreased (<i>p</i> = 0.0131) in the brain of APP/PS1 mice, was significantly increased (<i>p</i> = 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.
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