Lack of involvement of glutamate-induced excitotoxicity in MPP+ toxicity in striatal dopaminergic terminals: possible involvement of ascorbate.
1. The present study concerns the possible relationship between glutamate excitotoxicity and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP+) neurotoxicity on striatal dopaminergic terminals. 2. MPP+ neurotoxicity has been studied by means of two MPP+ perfusions separated by 24 h. After the second MPP+ 1 mM perfusion, dopamine extracellular output, measured by microdialysis, was considered to be an index of the dopaminergic neurone damage produced by the first MPP+ 1 mM perfusion. 3. High concentration (10 mM) of glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) stimulated basal release of dopamine and protected against the neurotoxic effect of MPP+. 4. PDC 10 mM perfusion produced an increase in the extracellular output of glutamate and aspartate, and a decrease in that of ascorbate. 5. The protective effect against MPP+ toxicity observed with PDC 10 mM was completely abolished when this glutamate uptake inhibitor was co-perfused with ascorbate 0.5 mM. 6. These results suggest that glutamate-induced neurotoxicity is not involved in MPP+ toxicity. The protective effect found with the glutamate uptake inhibitor could be due to a decrease in extracellular ascorbate levels.
Matarredona
E R
ER
Departamento de Bioquímica, Bromatología y Toxicología, Facultad de Farmacía, Sevilla, Spain.
Santiago
M
M
Machado
A
A
Cano
J
J
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000601:Amino Acids, Essential / Q000633:toxicity*; D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism / Q000502:physiology*; D001224:Aspartic Acid / Q000378:metabolism; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D015259:Dopamine Agents / Q000633:toxicity*; D005110:Extracellular Space / Q000201:enzymology / Q000378:metabolism; D018698:Glutamic Acid / Q000502:physiology*; D007150:Immunohistochemistry; D020267:MPTP Poisoning; D008297:Male; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D009411:Nerve Endings / Q000187:drug effects*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000601:Amino Acids, Essential; D003998:Dicarboxylic Acids; D015259:Dopamine Agents; D014179:Neurotransmitter Uptake Inhibitors; D011759:Pyrrolidines; D001224:Aspartic Acid; D018698:Glutamic Acid; C083486:pyrrolidine-2,4-dicarboxylic acid; D014446:Tyrosine 3-Monooxygenase; D001205:Ascorbic Acid; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine