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- Title
Demonstration of an anti-oxidative stress mechanism of quetiapine.
- Authors
Haiyun Xu; Haitao Wang; Lixia Zhuang; Bin Yan; Yingxin Yu; Zelan Wei; Yanbo Zhang; Dyck, Lillian E.; Richardson, Steven J.; Jue He; Xiaokun Li; Jiming Kong; Xin-Min Li
- Abstract
We have shown that quetiapine, a new antipsychotic drug, protects cultured cells against oxidative stress-related cytotoxicities induced by amyloid β (Aβ)25-35, and that quetiapine prevents memory impairment and decreases Aβ 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 Aβ(25-35) and Aβ(1-40) requires fibril formation, our first experiments determined the effect of quetiapine on Aβ(25-35) aggregation. Quetiapine inhibited Aβ(25-35) aggregation in cell-free aqueous solutions and blocked the fibrillar aggregation of Aβ(25-35), as observed under an electron microscope. We then investigated why quetiapine inhibits Aβ(25-35) aggregation. During the aggregation of Aβ(25-35), a hydroxyl radical (OH•) was released, which in turn amplified Aβ(25-35) aggregation. Quetiapine blocked OH•-induced Aβ(25-35) aggregation and scavenged the OH• produced in the Fenton system and in the Aβ(25-35) solution, as analyzed using electron paramagnetic resonance spectroscopy. Furthermore, new compounds formed by quetiapine and OH• were observed in MS analysis. Finally, we applied Aβ(25-35) to PC12 cells to observe the effect of quetiapine on living cells. Aβ(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.
- Subjects
ALZHEIMER'S disease; ANTIOXIDANTS; OXIDATIVE stress; OXIDATION-reduction reaction; ELECTRON microscopes
- Publication
FEBS Journal, 2008, Vol 275, Issue 14, p3718
- ISSN
1742-464X
- Publication type
Article
- DOI
10.1111/j.1742-4658.2008.06519.x