Brain imaging in methamphetamine-treated mice using a nitroxide contrast agent for EPR imaging of the redox status and a gadolinium contrast agent for MRI observation of blood-brain barrier function
Brain imaging in methamphetamine-treated mice using a nitroxide contrast agent for EPR imaging of the redox status and a gadolinium contrast agent for MRI observation of blood-brain barrier function
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DOI：
10.3109/10715762.2015.1040787
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发表时间：
2015-01-01
影响因子：
3.3
通讯作者：
Fujii, H. G.
中科院分区：
文献类型：
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作者：
Emoto, M. C.;Yamato, M.;Fujii, H. G.
甲基苯丙胺 (METH) 诱导的神经毒性与线粒体功能障碍和氧化应激增强有关。本研究在重复使用 METH 处理的小鼠大脑中进行的本研究的目的是（1）使用氧化还原敏感成像探针 3-methoxycarbonyl-2,2,5,5-tetramethylpiperidine-1-oxyl (MCP) 检查氧化还原状态，以及 (2) 通过电子顺磁共振 (EPR) 成像非侵入性地可视化大脑氧化还原状态。 MCP 的减少速率是通过小鼠头部的一系列时间 EPR 图像来测量的，并且该速率用于构建速率常数的二维图，称为“氧化还原图”。获得的氧化还原图清楚地表明了经过冰毒治疗的小鼠大脑中氧化还原平衡的变化，这是氧化损伤的已知结果。生化检测还表明，甲基苯丙胺会增加小鼠大脑中硫代巴比妥酸反应物质（脂质过氧化指数）的水平。在小鼠大脑中观察到的 MCP 减少增强被多巴胺合成酶抑制剂 α-甲基-p-酪氨酸治疗显着抑制，这表明 MCP 还原反应的增强是由线粒体呼吸链中的酶促减少引起的。此外，使用血脑屏障（BBB）不可渗透的顺磁造影剂对接受 METH 治疗的小鼠进行磁共振成像（MRI）显示，在 METH 治疗 7 天后，BBB 功能障碍。 MRI 还表明，停药后受损的 BBB 已恢复。 EPR 成像和 MRI 不仅可以用于跟踪重复施用 METH 的小鼠大脑中氧化还原状态和 BBB 功能的变化，而且可以用于追踪 METH 停药后的药物作用。
Methamphetamine (METH)-induced neurotoxicity is associated with mitochondrial dysfunction and enhanced oxidative stress. The aims of the present study conducted in the mouse brain repetitively treated with METH were to (1) examine the redox status using the redox-sensitive imaging probe 3-methoxycarbonyl-2,2,5,5-tetramethylpiperidine-1-oxyl (MCP) and (2) non-invasively visualize the brain redox status with electron paramagnetic resonance (EPR) imaging. The rate of reduction of MCP was measured from a series of temporal EPR images of mouse heads, and this rate was used to construct a two-dimensional map of rate constants called a "redox map." The obtained redox map clearly illustrated the change in redox balance in the METH-treated mouse brain that is a known result of oxidative damage. Biochemical assays also showed that the level of thiobarbituric acid-reactive substance, an index of lipid peroxidation, was increased in mouse brains by METH. The enhanced reduction in MCP observed in mouse brains was remarkably suppressed by treatment with the dopamine synthase inhibitor, alpha-methyl-p-tyrosine, suggesting that enhancement of the reduction reaction of MCP resulted from enzymatic reduction in the mitochondrial respiratory chain. Furthermore, magnetic resonance imaging (MRI) of METH-treated mice using a blood-brain barrier (BBB)-impermeable paramagnetic contrast agent revealed BBB dysfunction after treatment with METH for 7 days. MRI also indicated that the impaired BBB recovered after withdrawal of METH. EPR imaging and MRI are useful tools not only for following changes in the redox status and BBB dysfunction in mouse brains repeatedly administered METH, but also for tracing the drug effect after withdrawal of METH.