A Fluorine-19 Magnetic Resonance Probe, Shiga-Y5, Downregulates Thioredoxin-Interacting Protein Expression in the Brain of a Mouse Model of Alzheimer's Disease.

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.