Mefloquine induces oxidative stress and neurodegeneration in primary rat cortical neurons
Mefloquine induces oxidative stress and neurodegeneration in primary rat cortical neurons
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DOI：
10.1016/j.neuro.2010.05.005
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发表时间：
2010-09-01
期刊：
影响因子：
3.4
通讯作者：
Aschner, Michael
中科院分区：
文献类型：
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作者：
Hood, Jonathan E.;Jenkins, Jerry W.;Aschner, Michael
甲氟喹是一种有效的抗疟药，可引起不良神经系统事件，包括头痛、恶心、疲劳、失眠、焦虑和抑郁。在这项研究中，我们研究了氧化应激反应，在原代大鼠皮质神经元与甲氟喹处理，通过定量氧化应激标志物谷胱甘肽（GSH）和F-2-异前列腺素（F-2-isoPs）。此外，我们研究了甲氟喹是否诱导原代大鼠皮层神经元突触树突变性。谷胱甘肽定量皮质神经元后24小时治疗甲氟喹（0，1，5，10 μ M）使用monochlorobimane。用甲氟喹（0，1，5，10 μ M）处理24小时后，皮质神经元中的F-2-isoPs进行定量，采用稳定同位素稀释法，通过气相色谱/质谱和选择性离子监测进行检测。GSH的浓度依赖性降低和伴随的F2-isoPs的增加表明在用甲氟喹处理的原代大鼠皮层神经元中存在氧化应激。用甲氟喹处理24小时后，用4%多聚甲醛固定原代大鼠皮层神经元（0，5，10 μ M）。使用共焦激光扫描单元从覆盖z轴上的2.88 μ m的距离的8个光学部分获取图像。用NeuroExplorer（一种神经生理学数据分析软件包）分析跟踪图像。甲氟喹诱导浓度依赖性减少的棘数每个神经元和棘密度，表明甲氟喹诱导的氧化应激可能与突触树突状细胞变性。与以前的工作一起，有强有力的证据表明钙稳态破坏，ER应激反应，氧化应激反应和神经退行性变之间存在关系。了解氧化应激如何改变用甲氟喹治疗的皮质神经元的形态将提供对与临床观察到的不良神经事件相关的机制的进一步了解。(C)2010年爱思唯尔公司All rights reserved.
Mefloquine is an effective antimalarial that can cause adverse neurological events including headache, nausea, fatigue, insomnia, anxiety and depression. In this study, we examined the oxidative stress response in primary rat cortical neurons treated with mefloquine by quantifying oxidative stress markers glutathione (GSH) and F-2-isoprostanes (F-2-isoPs). Furthermore, we examined whether mefloquine induces synaptodendritic degeneration of primary rat cortical neurons. GSH was quantified in cortical neurons after 24-h treatment with mefloquine (0, 1, 5, 10 mu M) using monochlorobimane. F-2-isoPs were quantified in cortical neurons after 24-h treatment with mefloquine (0, 1, 5, 10 mu M) using a stable isotope dilution method with detection by gas chromatography/mass spectrometry and selective ion monitoring. The concentration dependent decrease in GSH and the concomitant increase of F2-isoPs indicates the presence of oxidative stress in primary rat cortical neurons treated with mefloquine. Following a 24-h treatment with mefloquine, primary rat cortical neurons (0, 5, 10 mu M) were fixed with 4% paraformaldehyde. Images from eight optical sections covering a distance of 2.88 mu m on the z-axis were acquired using a confocal laser scanning unit. Traced images were analyzed with NeuroExplorer, a neurophysiological data analysis package. Mefloquine induces a concentration dependent decrease in the number of spines per neuron and the spine density, suggesting that mefloquine induced oxidative stress may be associated with the synaptodendritic degeneration. Together with previous work, there is strong evidence that a relationship exists between calcium homeostasis disruption, ER stress response, the oxidative stress response, and neurodegeneration. Understanding how oxidative stress alters the morphology of cortical neurons treated with mefloquine will provide further insight into the mechanism(s) related to clinically observed adverse neurological events. (C) 2010 Elsevier Inc. All rights reserved.