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首页> 外文期刊>The FEBS journal >Demonstration of an anti-oxidative stress mechanism of quetiapine: implications for the treatment of Alzheimer's disease.
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Demonstration of an anti-oxidative stress mechanism of quetiapine: implications for the treatment of Alzheimer's disease.

机译：喹硫平抗氧化应激机制的证明：对阿尔茨海默氏病治疗的意义。

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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.
机译：我们已经证明喹硫平是一种新的抗精神病药物，可以保护培养的细胞免受由淀粉样蛋白β（Abeta）25-35诱导的氧化应激相关的细胞毒性，喹硫平可以防止记忆障碍并减少淀粉样蛋白前体蛋白（APP）大脑中的Abeta斑块。 ）/早老素-1（PS-1）双突变小鼠。这项研究的目的是了解喹硫平为什么具有这些保护作用。因为Abeta（25-35）和Abeta（1-40）的细胞毒性都需要原纤维形成，所以我们的第一个实验确定了喹硫平对Abeta（25-35）聚集的影响。电子显微镜下观察到，喹硫平抑制无细胞水溶液中的Abeta（25-35）聚集并阻止Abeta（25-35）的纤维状聚集。然后，我们调查了喹硫平为什么会抑制Abeta（25-35）聚集。在Abeta（25-35）聚集期间，释放了一个羟基（OH *），这又放大了Abeta（25-35）聚集。喹硫平通过电子顺磁共振波谱分析阻止了OH *诱导的Abeta（25-35）聚集并清除了Fenton系统和Abeta（25-35）溶液中产生的OH *。此外，在MS分析中观察到了由喹硫平和OH *形成的新化合物。最后，我们将Abeta（25-35）应用于PC12细胞，以观察喹硫平对活细胞的作用。 Abeta（25-35）增加PC12细胞内细胞内活性氧和钙的水平，并引起细胞死亡，但喹硫平可防止这些毒性作用。这些结果证明了喹硫平的抗氧化应激机制，有助于其在我们先前的研究中观察到的保护作用，并解释了该药物对患有精神病和行为并发症的阿尔茨海默氏病患者的有效性。

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