Alexander Jessy J, Zwingmann Claudia, Quigg Richard
Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC5100 Chicago, IL 60637, USA.
Neurochem Int. 2005 Jul;47(1-2):143-51. doi: 10.1016/j.neuint.2005.04.016.
Cerebral glucose metabolism and cerebral blood flow are altered in patients with lupus who have neuropsychiatric manifestations. However, the dynamics of changes in glucose metabolism remain unclear. The present study was undertaken using 1H and 13C nuclear magnetic resonance (NMR) spectroscopy to determine the rates of incorporation of glucose into amino acids and lactate via cell-specific pathways in mice with lupus. In the well-established MRL/lpr lupus mouse model, 24-week-old mice had a significant increase of 30-80% (P<0.001) in total brain glutamine, glutamate and lactate concentrations, while alanine, aspartate, N-acetyl aspartate (NAA) and gamma-aminobutyric acid (GABA) remained unchanged as compared to the congenic MRL+/+control mice. Although succinate concentration was increased in lupus brain, it did not reach statistical significance. Furthermore, 13C isotopomer analysis showed a selective increase of de novo synthesis of lactate from [1-(13)C] glucose through glycolysis resulting in 1.5-fold increased fractional 13C enrichments in lactate in MRL/lpr mice. [4-(13)C] Glutamate, which is synthesized mainly by the neuronal pyruvate dehydogenase, was selectively increased, while [2-(13)C] and [3-(13)C] GABA synthesis were decreased by 25% compared to controls. In accordance with the total concentrations, aspartate synthesis remained unaltered in brains of lupus mice, while alanine synthesis was elevated, indicating increased utilization of alanine. Creatine was unchanged in MRL/lpr mice as compared to controls. An interesting finding was a significant increase (158%, P<0.005) in choline concentration in MRL/lpr mice while the myo-inositol concentration remained the same in both groups. Furthermore a significant increase in total brain water content was observed, indicative of possible edema. In conclusion, the cumulative effect of increased brain lactate synthesis, altered glucose metabolism and intracellular glutamine accumulation could be an important mechanism causing brain pathology in SLE. The alteration in metabolites could alter downstream pathways and cause neurological dysfunction. Future NMR spectroscopic studies using stable isotopes and real-time measurements of metabolic rates, along with levels of metabolites in plasma and cerebrospinal fluid, could be valuable in the elucidation of the cerebral metabolic consequences of systemic lupus erythematosis (SLE) in humans.
患有神经精神症状的狼疮患者的脑葡萄糖代谢和脑血流量会发生改变。然而，葡萄糖代谢变化的动态过程仍不清楚。本研究采用1H和13C核磁共振波谱法，以确定狼疮小鼠体内葡萄糖通过细胞特异性途径掺入氨基酸和乳酸的速率。在成熟的MRL/lpr狼疮小鼠模型中，与同基因MRL+/+对照小鼠相比，24周龄小鼠的全脑谷氨酰胺、谷氨酸和乳酸浓度显著增加30 - 80%（P<0.001），而丙氨酸、天冬氨酸、N - 乙酰天门冬氨酸（NAA）和γ - 氨基丁酸（GABA）保持不变。虽然狼疮小鼠脑内琥珀酸浓度有所增加，但未达到统计学意义。此外，13C同位素异构体分析显示，通过糖酵解由[1 - (13)C]葡萄糖从头合成乳酸有选择性增加，导致MRL/lpr小鼠乳酸中13C富集分数增加1.5倍。主要由神经元丙酮酸脱氢酶合成的[4 - (13)C]谷氨酸有选择性增加，而[2 - (13)C]和[3 - (13)C]GABA合成与对照相比减少25%。与总浓度一致，狼疮小鼠脑内天冬氨酸合成保持不变，而丙氨酸合成增加，表明丙氨酸利用增加。与对照相比，MRL/lpr小鼠体内肌酸无变化。一个有趣的发现是，MRL/lpr小鼠脑内胆碱浓度显著增加（158%，P<0.005），而两组的肌醇浓度保持相同。此外，观察到全脑含水量显著增加，提示可能存在水肿。总之，脑乳酸合成增加、葡萄糖代谢改变和细胞内谷氨酰胺积累的累积效应可能是导致系统性红斑狼疮（SLE）脑病变的重要机制。代谢物的改变可能会改变下游途径并导致神经功能障碍。未来使用稳定同位素和代谢率实时测量以及血浆和脑脊液中代谢物水平的核磁共振波谱研究，对于阐明人类系统性红斑狼疮（SLE）的脑代谢后果可能具有重要价值。
