Zwingmann Claudia, Leibfritz Dieter, Hazell Alan S
Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
Glia. 2007 Nov 15;55(15):1610-7. doi: 10.1002/glia.20575.
A central question in manganese neurotoxicity concerns the focal neuronal damage in the globus pallidus. In the present study, we investigated specific pathways of [1-(13)C]glucose as well as of [2-(13)C]acetate in this brain region and the frontal cortex following 4-day manganese treatment by high-resolution NMR spectroscopy. Following administration of 50 mg/kg/day manganese, glutamine concentration in the globus pallidus was decreased to 67% of control values but increased in frontal cortex by 56%. Manganese treatment also caused pronounced changes in glutamine-glutamate-GABA interconversion in which region-selective differences were observed in the isotopomer pattern of GABA compared with that of glutamine when including the astrocyte-specific substrate [2-(13)C]acetate. In particular, decreased (13)C-labeled glutamine, synthesized from [1-(13)C]glucose, paralleled accumulation of (13)C-labeled GABA in globus pallidus but not in frontal cortex. On the other hand, increased synthesis of glutamine from [2-(13)C]acetate showed that GABA accumulation was not due to increased synthesis from astrocytic glutamine. Furthermore, treatment with manganese resulted in a selective decrease in N-acetyl-aspartate in the globus pallidus. These data illustrate the potential importance of alterations in neuronal metabolic function. In particular, neuronal metabolic derangements and regional differences in the ability of astrocytes to fulfill their contribution to the glutamine-glutamate-GABA cycle during the early phase of manganese neurotoxicity may be crucial in determining the severity of cellular injury.
锰神经毒性的一个核心问题涉及苍白球中的局灶性神经元损伤。在本研究中，我们通过高分辨率核磁共振波谱法，研究了在4天锰处理后，该脑区以及额叶皮质中[1-(13)C]葡萄糖和[2-(13)C]乙酸盐的特定代谢途径。给予50mg/kg/天的锰后，苍白球中的谷氨酰胺浓度降至对照值的67%，但额叶皮质中的谷氨酰胺浓度增加了56%。锰处理还导致谷氨酰胺-谷氨酸-γ-氨基丁酸相互转化发生显著变化，当加入星形胶质细胞特异性底物[2-(13)C]乙酸盐时，与谷氨酰胺相比，γ-氨基丁酸的同位素异构体模式存在区域选择性差异。特别是，由[1-(13)C]葡萄糖合成的(13)C标记谷氨酰胺减少，与苍白球中(13)C标记的γ-氨基丁酸积累平行，但在额叶皮质中并非如此。另一方面，由[2-(13)C]乙酸盐合成的谷氨酰胺增加表明，γ-氨基丁酸的积累并非由于星形胶质细胞谷氨酰胺合成增加。此外，锰处理导致苍白球中N-乙酰天门冬氨酸选择性减少。这些数据说明了神经元代谢功能改变的潜在重要性。特别是，在锰神经毒性早期，神经元代谢紊乱以及星形胶质细胞在谷氨酰胺-谷氨酸-γ-氨基丁酸循环中发挥作用的能力存在区域差异，可能对确定细胞损伤的严重程度至关重要。
