脱髓鞘的铜螯合剂小鼠模型中的异常氧化代谢：一项体内近红外光谱-磁共振成像研究。
Abnormal oxidative metabolism in the cuprizone mouse model of demyelination: An in vivo NIRS-MRI study.
作者信息
Hashem Mada, Shafqat Qandeel, Wu Ying, Rho Jong M, Dunn Jeff F
机构信息
Biomedical Engineering Graduate Program, University of Calgary, Calgary, Alberta T2N 4N1, Canada; Department of Radiology, Faculty of Medicine, University of Calgary, 3330 Hospital Drive, N.W., Calgary, Alberta T2N 4N1, Canada; Hotchkiss Brain Institute, University of Calgary, Alberta T2N 4N1, Canada; Experimental Imaging Centre, Cumming School of Medicine, University of Calgary, Alberta T2N 4N1, Canada.
Department of Radiology, Faculty of Medicine, University of Calgary, 3330 Hospital Drive, N.W., Calgary, Alberta T2N 4N1, Canada; Hotchkiss Brain Institute, University of Calgary, Alberta T2N 4N1, Canada; Experimental Imaging Centre, Cumming School of Medicine, University of Calgary, Alberta T2N 4N1, Canada.
出版信息
Neuroimage. 2022 Apr 15;250:118935. doi: 10.1016/j.neuroimage.2022.118935. Epub 2022 Jan 25.
Disruptions in oxidative metabolism may occur in multiple sclerosis and other demyelinating neurological diseases. The impact of demyelination on metabolic rate is also not understood. It is possible that mitochondrial damage may be associated with many such neurological disorders. To study oxidative metabolism with one model of demyelination, we implemented a novel multimodal imaging technique combining Near-Infrared Spectroscopy (NIRS) and MRI to cuprizone mouse model. The cuprizone model is used to study demyelination and may be associated with inhibition of mitochondrial function. Cuprizone mice showed reduced oxygen extraction fraction (-39.1%, p ≤ 0.001), increased tissue oxygenation (6.4%, p ≤ 0.001), and reduced cerebral metabolic rate of oxygen in cortical gray matter (-62.1%, p ≤ 0.001). These changes resolved after the cessation of cuprizone exposure and partial remyelination. A decrease in hemoglobin concentration (-34.4%, p ≤ 0.001), but no change in cerebral blood flow were also observed during demyelination. The oxidized state of the mitochondrial enzyme, Cytochrome C Oxidase (CCO) increased (46.3%, p ≤ 0.001) while the reduced state decreased (-34.4%, p ≤ 0.05) significantly in cuprizone mice. The total amount of CCO did not change significantly during cuprizone exposure. Total CCO did decline after recovery both in control (-23.1%, p ≤ 0.01) and cuprizone (-28.8%, p ≤ 0.001) groups which may relate to age. A reduction in the magnetization transfer ratio, indicating demyelination, was found in the cuprizone group in the cerebral cortex (-3.2%, p ≤ 0.01) and corpus callosum (-5.5%, p ≤ 0.001). In summary, we were able to detect evidence of altered CCO metabolism during cuprizone exposure, consistent with a mitochondrial defect. We observed increased oxygenation and reduced metabolic rate associated with reduced myelination in the gray and white matter. The novel multimodal imaging technique applied here shows promise for noninvasively assessing parameters associated with oxidative metabolism in both mouse models of neurological disease and for translation to study oxidative metabolism in the human brain.
氧化代谢紊乱可能发生在多发性硬化症和其他脱髓鞘性神经疾病中。脱髓鞘对代谢率的影响也尚不清楚。线粒体损伤可能与许多此类神经疾病有关。为了用一种脱髓鞘模型研究氧化代谢，我们采用了一种结合近红外光谱（NIRS）和MRI的新型多模态成像技术应用于铜螯合剂小鼠模型。铜螯合剂模型用于研究脱髓鞘，可能与线粒体功能抑制有关。铜螯合剂处理的小鼠显示氧摄取分数降低（-39.1%，p≤0.001），组织氧合增加（6.4%，p≤0.001），皮质灰质的脑氧代谢率降低（-62.1%，p≤0.001）。在停止铜螯合剂暴露和部分髓鞘再生后，这些变化得到缓解。在脱髓鞘过程中还观察到血红蛋白浓度降低（-34.4%，p≤0.001），但脑血流量没有变化。在铜螯合剂处理的小鼠中，线粒体酶细胞色素C氧化酶（CCO）的氧化状态增加（46.3%，p≤0.001），而还原状态显著降低（-34.4%，p≤0.05）。在铜螯合剂暴露期间，CCO的总量没有显著变化。在恢复后，对照组（-23.1%，p≤0.01）和铜螯合剂处理组（-28.8%，p≤0.001）的总CCO均下降，这可能与年龄有关。在铜螯合剂处理组的大脑皮质（-3.2%，p≤0.01）和胼胝体（-5.5%，p≤0.001）中发现磁化传递率降低，表明存在脱髓鞘。总之，我们能够检测到铜螯合剂暴露期间CCO代谢改变的证据，这与线粒体缺陷一致。我们观察到与灰质和白质髓鞘减少相关的氧合增加和代谢率降低。这里应用的新型多模态成像技术有望在神经疾病小鼠模型中无创评估与氧化代谢相关的参数，并转化用于研究人类大脑的氧化代谢。
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