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 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.
Andreassen
O A
OA
Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Jenkins
B G
BG
Dedeoglu
A
A
Ferrante
K L
KL
Bogdanov
M B
MB
Kaddurah-Daouk
R
R
Beal
M F
MF
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D027322:Amino Acid Transport System X-AG; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D003401:Creatine / Q000494:pharmacology / Q000627:therapeutic use*; D003998:Dicarboxylic Acids / Q000494:pharmacology / Q000633:toxicity; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology / Q000633:toxicity; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D016472:Motor Neuron Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology / Q000633:toxicity; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology / Q000633:toxicity; D018384:Oxidative Stress; D011597:Psychomotor Performance / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology / Q000633:toxicity; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D003998:Dicarboxylic Acids; D018690:Excitatory Amino Acid Agonists; D014179:Neurotransmitter Uptake Inhibitors; D011759:Pyrrolidines; D005973:Glutamine; D018698:Glutamic Acid; D016202:N-Methylaspartate; C083486:pyrrolidine-2,4-dicarboxylic acid; D013482:Superoxide Dismutase; D003401:Creatine