Comparison of the effects of cyclosporin A on the metabolism of perfused rat brain slices during normoxia and hypoxia
Comparison of the effects of cyclosporin A on the metabolism of perfused rat brain slices during normoxia and hypoxia
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DOI：
10.1097/00004647-200203000-00012
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发表时间：
2002-03-01
影响因子：
6.3
通讯作者：
Christians, U
中科院分区：
文献类型：
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作者：
Serkova, N;Donohoe, P;Christians, U
作者评估并比较了环孢素A在常氧和缺氧/再灌注大鼠脑中的代谢作用。基于灌注大鼠脑片的体外P-31磁共振波谱实验显示，在正常缺氧条件下，500杯/L环孢素A通过抑制克雷伯循环（谷氨酸，77 +/- 5%）和氧化磷酸化（NAD(+), 65 +/- 14%）显著降低线粒体能量代谢（核苷酸三磷酸，83 +/- 9%，磷酸肌酸，69 +/- 9%），并增加活性氧的产生（285 +/- 78%，对照组）。然而，相同的环孢素A浓度（500马克杯/升）被发现是抑制低氧诱导的大鼠海马细胞线粒体Ca2+释放的最有效浓度，胞质Ca2+浓度与常氧对照没有显著差异。灌注液中加入500杯/L的环孢素A可保护缺氧30 min大鼠脑切片的高能磷酸盐代谢（核苷酸三磷酸，对照组为11 +/- 15%，500杯/L环孢素A组为35 +/- 9%）和细胞内pH（对照组为6.2 +/- 0.1，环孢素A组为6.6 +/- 0.1）。结果表明，环孢素A可同时降低和保护细胞葡萄糖和能量代谢。整体效果是降低还是保护细胞能量代谢取决于缓冲溶液中氧和环孢素a的浓度。
The authors evaluated and compared the metabolic effects of cyclosporin A in the rat brain during normoxia and hypoxia/reperfusion. Ex vivo P-31 magnetic resonance spectroscopy experiments based on perfused rat brain slices showed that under normoxic conditions, 500 mug/L cyclosporin A significantly reduced mitochondrial energy metabolism (nucleotide triphosphate, 83 +/- 9% of controls; phosphocreatine, 69 +/- 9%) by inhibition of the Krebs cycle (glutamate, 77 +/- 5%) and oxidative phosphorylation (NAD(+), 65 +/- 14%) associated with an increased generation of reactive oxygen species (285 +/- 78% of control). However, the same cyclosporin A concentration (500 mug/L) was found to be the most efficient concentration to inhibit the hypoxia-induced mitochondrial release of Ca2+ in primary rat hippocampal cells with cytosolic Ca2+ concentrations not significantly different from normoxic controls. Addition of 500 mug/L cyclosporin A to the perfusion medium protected high-energy phosphate metabolism (nucleotide triphosphate, 11 +/- 15% of control vs. 35 +/- 9% with 500 mug/L cyclosporin A) and the intracellular pH (6.2 +/- 0.1 control vs. 6.6 +/- 0.1 with cyclosporin A) in rat brain slices during 30 minutes of hypoxia, Results indicate that cyclosporin A simultaneously decreases and protects cell glucose and energy metabolism. Whether the overall effect was a reduction or protection of cell energy metabolism depended on the concentrations of both oxygen and cyclosporin A in the buffer solution.