Exacerbation of excitotoxic neuronal death induced during mitochondrial inhibition in vivo: relation to energy imbalance or ATP depletion?
During the past two decades a close relationship between the energy state of the cell and glutamate neurotoxicity has been suggested. We have previously shown that increasing the extracellular concentration of glutamate does not cause neuronal death unless a deficit in energy metabolism occurs. The mechanisms of glutamate-induced neuronal death have been extensively studied in vitro and it has been associated with a rapid and severe decrease in ATP levels, accompanied with mitochondrial dysfunction. In this study we aimed to investigate the time course of the changes in energy metabolites during glutamate-induced neuronal death, in the presence of a moderate inhibition of mitochondrial metabolism in the rat striatum in vivo. We also aimed to study whether or not, as reported in vitro, changes in ATP levels are related to the extension of neuronal death. Results show that glutamate-induced lesions are exacerbated when rats are previously treated with a subtoxic dose of the mitochondrial toxin 3-nitropropionic acid (3-NP). However, changes in nucleotide levels were similar in rats injected with glutamate alone and in rats injected with glutamate and previously treated with 3-NP. In spite of the presence of an extensive striatal lesion, nucleotide levels were recovered in 3-NP-treated rats 24 h after glutamate injection. Results show that 3-NP pre-treatment induced an imbalance in nucleotide levels that predisposed cells to glutamate toxicity; however it did not influence the bioenergetic changes induced by glutamate alone. Enhancement of glutamate neurotoxicity in 3-NP pre-treated rats is more related to a sustained nucleotide imbalance than just to a rapid decrease in ATP levels.
Del Río
P
P
Depto. de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México, D.F. CP 04510, Mexico.
Montiel
T
T
Chagoya
V
V
Massieu
L
L
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology*; D019344:Lactic Acid; D008297:Male; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000494:pharmacology*; D009574:Nitro Compounds / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013997:Time Factors
D005904:Glial Fibrillary Acidic Protein; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D019344:Lactic Acid; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D013385:Succinate Dehydrogenase; C015392:3-nitropropionic acid