title: Endogenous dopamine enhances the neurotoxicity of 3-nitropropionic acid in the striatum through the increase of mitochondrial respiratory inhibition and free radicals production.
abstract: 3-Nitropropionic acid (3-NP), an inhibitor of the mitochondrial enzyme succinate dehydrogenase, induces neuronal degeneration in the striatum. It is known that dopamine (DA) enhances this toxic effect. In this work, we study how the increase of DA influences the toxic effect of 3-NP on DAergic terminals, GABAergic neurons, astroglia and microglia in the striatum. We increased the content of DA through the inhibition of its uptake by nomifensine or the inhibition of its catabolism by deprenyl. We found that although nomifensine and deprenyl enhanced the DA overflow produced by 3-NP perfusion, they protected against the damage induced by 3-NP in the DAergic terminals and the GABAergic neurons in the striatum. Moreover, there was a decrease of apoptotic cells, astrogliosis and activation of microglia as index of damage. We also found that depletion of DA by reserpine and alpha-methyl-p-tyrosine produced a significant reduction of the inhibition of the respiratory rate and of the production of superoxide radical induced by 3-NP in synaptosomes from the striatum. All these results suggest that endogenous dopamine within the dopaminergic terminals of the striatum enhances the mitochondrial production of radical oxygen species along with the respiratory inhibition produced by 3-NP and thus increases the toxicity produced by 3-NP in the striatum.
authors: Departamento de Bioquímica, Bromatología, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, C/Profesor García González, 2, 41012-Sevilla, Spain.
authors: Ruth F
authors: RF
authors: Villarán
authors: M
authors: M
authors: Tomás-Camardiel
authors: Rocío M
authors: RM
authors: de Pablos
authors: Marti
authors: M
authors: Santiago
authors: Antonio J
authors: AJ
authors: Herrera
authors: Ana
authors: A
authors: Navarro
authors: Alberto
authors: A
authors: Machado
authors: Josefina
authors: J
authors: Cano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000633:toxicity*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009574:Nitro Compounds / Q000633:toxicity*; D009627:Nomifensine / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012110:Reserpine / Q000494:pharmacology; D012642:Selegiline / Q000494:pharmacology; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation; D019805:alpha-Methyltyrosine / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D008996:Monoamine Oxidase Inhibitors; D009574:Nitro Compounds; D011422:Propionates; D017382:Reactive Oxygen Species; D013481:Superoxides; D009627:Nomifensine; D012642:Selegiline; D005680:gamma-Aminobutyric Acid; D019805:alpha-Methyltyrosine; D012110:Reserpine; D014446:Tyrosine 3-Monooxygenase; D013385:Succinate Dehydrogenase; C015392:3-nitropropionic acid; D004298:Dopamine