Glycogen synthase kinase-3β (GSK-3β) is a key enzyme in hyperphosphorylation of tau proteins and is a promising therapeutic target in Alzheimer's disease (AD). Here, we reported, for the first time, that the stereoisomers of Schisandrin B (Sch B), (+)-1, (-)-1, (+)-2, and (-)-2, were potent GSK-3β inhibitors. They were demonstrated to selectively target GSK-3β in an orthosteric binding mode, with IC50 values of 340, 290, 80, and 70 nM, respectively. Further study showed that these stereoisomers can significantly increase the expression of p-GSK-3β (Ser9) and decrease the expressions of p-GSK-3β (Tyr216) and p-GSK-3β (Tyr279). Finally, these compounds can alleviate the cell injury induced by Aβ, and the cognitive disorders in AD mice, especially (+)-2 and (-)-2. Collectively, the stereoisomers of Sch B, especially (+)-2 and (-)-2, were found to be potential selective ATP-competitive GSK-3β inhibitors, which further affected their anti-AD effects. These promising findings explained the biological target of Sch B in AD, and bring a new understanding in the stereochemistry and bioactivities of Sch B.
Keywords: Alzheimer’s disease; GSK-3β inhibitors; SH-SY5Y cells; Schisandrin B; stereoisomers.