Andreassen O A, Jenkins B G, Dedeoglu A, Ferrante K L, Bogdanov M B, Kaddurah-Daouk R, Beal M F
Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
J Neurochem. 2001 Apr;77(2):383-90. doi: 10.1046/j.1471-4159.2001.00188.x.
Several lines of evidence implicate excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis (ALS). Transgenic mice with a superoxide dismutase mutation (G93A) have been utilized as an animal model of familial ALS (FALS). We examined the cortical concentrations of glutamate using in vivo microdialysis and in vivo nuclear magnetic resonance (NMR) spectroscopy, and the effect of long-term creatine supplementation. NMDA-stimulated and Ltrans-pyrrolidine-2,4-dicarboxylate (LTPD)-induced increases in glutamate were significantly higher in G93A mice compared with littermate wild-type mice at 115 days of age. At this age, the tissue concentrations of glutamate were also significantly increased as measured with NMR spectroscopy. Creatine significantly increased longevity and motor performance of the G93A mice, and significantly attenuated the increases in glutamate measured with spectroscopy at 75 days of age, but had no effect at 115 days of age. These results are consistent with impaired glutamate transport in G93A transgenic mice. The beneficial effect of creatine may be partially mediated by improved function of the glutamate transporter, which has a high demand for energy and is susceptible to oxidative stress.
多条证据表明兴奋性毒性机制与肌萎缩侧索硬化症（ALS）的发病机制有关。携带超氧化物歧化酶突变（G93A）的转基因小鼠已被用作家族性ALS（FALS）的动物模型。我们使用体内微透析和体内核磁共振（NMR）光谱检查了皮质谷氨酸浓度，以及长期补充肌酸的效果。在115日龄时，与同窝野生型小鼠相比，G93A小鼠中NMDA刺激和L-反式-吡咯烷-2,4-二羧酸（LTPD）诱导的谷氨酸增加显著更高。在这个年龄，用NMR光谱测量的谷氨酸组织浓度也显著增加。肌酸显著延长了G93A小鼠的寿命并改善了其运动性能，并且在75日龄时显著减弱了用光谱测量的谷氨酸增加，但在115日龄时没有效果。这些结果与G93A转基因小鼠中谷氨酸转运受损一致。肌酸的有益作用可能部分由谷氨酸转运体功能的改善介导，谷氨酸转运体对能量需求高且易受氧化应激影响。
