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 (Abeta)25-35, and that quetiapine prevents memory impairment and decreases Abeta 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 Abeta(25-35) and Abeta(1-40) requires fibril formation, our first experiments determined the effect of quetiapine on Abeta(25-35) aggregation. Quetiapine inhibited Abeta(25-35) aggregation in cell-free aqueous solutions and blocked the fibrillar aggregation of Abeta(25-35), as observed under an electron microscope. We then investigated why quetiapine inhibits Abeta(25-35) aggregation. During the aggregation of Abeta(25-35), a hydroxyl radical (OH*) was released, which in turn amplified Abeta(25-35) aggregation. Quetiapine blocked OH*-induced Abeta(25-35) aggregation and scavenged the OH* produced in the Fenton system and in the Abeta(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 Abeta(25-35) to PC12 cells to observe the effect of quetiapine on living cells. Abeta(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.
Xu
Haiyun
H
Department of Anatomy, Southern Illinois University at Carbondale, IL, USA.
Wang
Haitao
H
Zhuang
Lixia
L
Yan
Bin
B
Yu
Yingxin
Y
Wei
Zelan
Z
Zhang
Yanbo
Y
Dyck
Lillian E
LE
Richardson
Steven J
SJ
He
Jue
J
Li
Xiaokun
X
Kong
Jiming
J
Li
Xin-Min
XM
D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000648:ultrastructure; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D003987:Dibenzothiazepines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016166:Free Radical Scavengers / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000648:ultrastructure; D000069348:Quetiapine Fumarate; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D016166:Free Radical Scavengers; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C074636:amyloid beta-protein (25-35); D000069348:Quetiapine Fumarate; D017665:Hydroxyl Radical