Immunosuppressant neurotoxicity in rat brain models: oxidative stress and cellular metabolism.
Immunosuppressant neurotoxicity in rat brain models: oxidative stress and cellular metabolism.
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DOI：
10.1021/tx900351q
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发表时间：
2010-03-15
影响因子：
4.1
通讯作者：
Serkova, Natalie J.
中科院分区：
文献类型：
--
作者：
Klawitter, Jelena;Gottschalk, Sven;Hainz, Carsten;Leibfritz, Dieter;Christians, Uwe;Serkova, Natalie J.
钙调磷酸酶抑制剂环孢素（CsA）和mTOR抑制剂西罗莫司（SRL）或依维莫司（RAD）联合使用可增加器官移植后免疫抑制的效果。CsA的神经毒性是一个重要的临床问题。我们的目的是评估CsA、SRL和RAD对脑细胞代谢的影响。研究包括比较免疫抑制剂介导的对灌注大鼠脑切片、原代大鼠星形胶质细胞和c6胶质瘤细胞的葡萄糖代谢、能量产生和活性氧（ROS）形成的影响。在脑切片和星形胶质细胞中，CsA抑制克雷布斯循环代谢，同时激活厌氧糖酵解，最有可能补偿线粒体能量产生的抑制。SRL和RAD抑制细胞质糖酵解，但不引起线粒体能量产生的变化。CsA+SRL抑制克雷布斯循环和糖酵解，从而降低细胞补偿CsA对线粒体核苷三磷酸合成的负面影响的能力。与SRL相比，在测试浓度下，RAD减少了csa诱导的ROS形成，并拮抗csa诱导的葡萄糖和能量代谢。令人惊讶的是，在C6细胞中，SRL和RAD暴露导致高浓度ROS，而细胞代谢没有明显损伤。我们的研究结果表明，SRL可以增强CsA诱导的脑细胞中ROS的形成和负代谢作用，而RAD似乎可以拮抗CsA的作用。然而，三种模型在使用研究药物时表现出不同的代谢反应。与SRL相比，RAD增强了C6胶质瘤细胞中ROS的形成，但对正常大鼠脑组织的影响很小。
Co-administration of the calcineurin inhibitor cyclosporine (CsA) and the mTOR inhibitors sirolimus (SRL) or everolimus (RAD) increases efficacy of immunosuppression after organ transplantation. Neurotoxicity of CsA is a major clinical problem. Our goal was to assess the effects of CsA, SRL and RAD on the brain cell metabolism. The studies included the comparison of immunosuppressant-mediated effects on glucose metabolism, energy production and reactive oxygen species (ROS) formation in perfused rat brain slices, primary rat astrocytes and C6-glioma cells. In brain slices and astrocytes, CsA inhibited Krebs cycle metabolism, while activating anaerobic glycolysis most likely to compensate for the inhibition of mitochondrial energy production. SRL and RAD inhibited cytosolic glycolysis, but did not cause changes in mitochondrial energy production. CsA+SRL inhibited Krebs cycle and glycolysis, thus reducing the ability of the cell to compensate for the negative effects of CsA on mitochondrial nucleoside triphosphate synthesis. In contrast to SRL at the concentrations tested, RAD reduced the CsA-induced ROS formation and antagonized CsA-induced effects on glucose and energy metabolism. Surprisingly, in C6 cells, SRL and RAD exposure resulted in high ROS concentrations without significant impairment of cell metabolism. Our results suggested that SRL enhances CsA-induced ROS formation and negative metabolic effects in brain cells, while RAD seems to antagonize the CsA effects. However, the three models showed different metabolic responses when challenged with the study drugs. In contrast to SRL, RAD enhances ROS formation in C6 glioma cells, but has only minor effects on normal rat brain tissue.
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影响因子：
8.8
作者：
Klawitter, J.;Anderson, N.;Klawitter, J.;Christians, U.;Leibfritz, D.;Eckhardt, S. G.;Serkova, N. J.
通讯作者：
Serkova, N. J.
影响因子：
7.3
作者：
Klawitter, Jelena;Kominsky, Douglas J.;Serkova, Natalie J.
通讯作者：
Serkova, Natalie J.
影响因子：
5.8
作者：
Andrés, D;Sanz, N;Cascales, M
通讯作者：
Cascales, M
影响因子：
6.7
作者：
Kahan, BD;Kramer, WG
通讯作者：
Kramer, WG
影响因子：
64.8
作者：
Gordon GR;Choi HB;Rungta RL;Ellis-Davies GC;MacVicar BA
通讯作者：
MacVicar BA