Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation

Several lines of evidence implicate excitotoxic mechanisms in the pathogene sis of amyotrophic lateral sclerosis (ALS). Transgenic mice with a superoxi de dismutase mutation (G93A) have been utilized as an animal model of famil ial ALS (FALS). We examined the cortical concentrations of glutamate using in vivo microdialysis and in vivo nuclear magnetic resonance (NMR) spectros copy, and the effect of long-term creatine supplementation. NMDA-stimulated and L-trans-pyrrolidine-2,4-dicarboxylate (LTPD)-induced increases in glut amate were significantly higher in G93A mice compared with littermate wild- type mice at 115 days of age. At this age, the tissue concentrations of glu tamate were also significantly increased as measured with NMR spectroscopy. Creatine significantly increased longevity and motor performance of the G9 3A mice, and significantly attenuated the increases in glutamate measured w ith spectroscopy at 75 days of age, but had no effect at 115 days of age. T hese results are consistent with impaired glutamate transport in G93A trans genic 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.