In vivo neuroprotective adaptation of the glutamate/glutamine cycle to neuronal death.
Synaptic increase of glutamate level, when not coupled to a heightened energy production, renders neurons susceptible to death. Astrocyte uptake and recycling of synaptic glutamate as glutamine is a major metabolic pathway dependent on energy metabolism, which inter-relationships are not fully understood and remain controversial. We examine how the glutamate-glutamine cycle and glucose metabolism are modified in two in vivo models of severe and mild brain injury. Graded reductions of glutaminase, the glutamate synthetic enzyme, were evidenced combined with increases in glutamine synthetase, the inactivating glutamate enzyme. Increased lactate dhydrogenase (LDH) activity was only present after a more severe injury. These results indicate an in vivo adaptation of the glutamate-glutamine cycle in order to increase the net glutamine output, reduce glutamate excitotoxicity, and avoid neuronal death. We conclude that the graded modification of the glutamate-glutamine correlation and neuronal lactate availability may be key factors in the apoptotic and necrotic neuronal demise, whose control may prove highly useful to potentiate neuronal survival.
Unitat de Bioquímica, Institut d'lnvestigacions Biomèdiques August Pi i Sunyer, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
D
D
Ramonet
M J
MJ
Rodríguez
K
K
Fredriksson
F
F
Bernal
N
N
Mahy
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D001930:Brain Injuries / Q000378:metabolism / Q000503:physiopathology; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D003714:Denervation; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000502:physiology; D020712:Fornix, Brain / Q000201:enzymology / Q000293:injuries / Q000503:physiopathology; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D005972:Glutaminase / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology / Q000293:injuries / Q000503:physiopathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D009336:Necrosis; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D009498:Neurotoxins; D051381:Rats; D017207:Rats, Sprague-Dawley
D009498:Neurotoxins; D005973:Glutamine; D019344:Lactic Acid; D018698:Glutamic Acid; D007770:L-Lactate Dehydrogenase; D005972:Glutaminase; D005974:Glutamate-Ammonia Ligase