Demonstration of an anti-oxidative stress mechanism of quetiapine - Implications for the treatment of Alzheimer's disease

We have shown that quetiapine, a new antipsychotic drug, protects cultured cells against oxidative stress-related cytotoxicities induced by amyloid beta (A beta)25-35, and that quetiapine prevents memory impairment and decreases A beta plaques in the brains of amyloid precursor protein (APP)/presenilin-1 (PS-1) double-mutant mice. The aim of this study was to understand why quetiapine has these protective effects. Because the cytotoxicity of both A beta(25-35) and A beta(1-40) requires fibril formation, our first experiments determined the effect of quetiapine on A beta(25-35) aggregation. Quetiapine inhibited A beta(25-35) aggregation in cell-free aqueous solutions and blocked the fibrillar aggregation of A beta(25-35), as observed under an electron microscope. We then investigated why quetiapine inhibits A beta(25-35) aggregation. During the aggregation of A beta(25-35), a hydroxyl radical (OH center dot) was released, which in turn amplified A beta(25-35) aggregation. Quetiapine blocked OH center dot-induced A beta(25-35) aggregation and scavenged the OH center dot produced in the Fenton system and in the A beta(25-35) solution, as analyzed using electron paramagnetic resonance spectroscopy. Furthermore, new compounds formed by quetiapine and OH center dot were observed in MS analysis. Finally, we applied A beta(25-35) to PC12 cells to observe the effect of quetiapine on living cells. A beta(25-35) increased levels of intracellular reactive oxygen species and calcium in PC12 cells and caused cell death, but these toxic effects were prevented by quetiapine. These results demonstrate an anti-oxidative stress mechanism of quetiapine, which contributes to its protective effects observed in our previous studies and explains the effectiveness of this drug for Alzheimer's disease patients with psychiatric and behavioral complications.