Villarán Ruth F, Tomás-Camardiel M, de Pablos Rocío M, Santiago Marti, Herrera Antonio J, Navarro Ana, Machado Alberto, Cano Josefina
Departamento de Bioquímica, Bromatología, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, C/Profesor García González, 2, 41012-Sevilla, Spain.
Neurotoxicology. 2008 Mar;29(2):244-58. doi: 10.1016/j.neuro.2007.11.001. Epub 2007 Nov 17.
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.
3-硝基丙酸（3-NP）是线粒体酶琥珀酸脱氢酶的抑制剂，可诱导纹状体中的神经元变性。已知多巴胺（DA）会增强这种毒性作用。在这项研究中，我们研究了多巴胺的增加如何影响3-NP对纹状体中多巴胺能终末、γ-氨基丁酸能神经元、星形胶质细胞和小胶质细胞的毒性作用。我们通过诺米芬辛抑制多巴胺摄取或通过司来吉兰抑制其分解代谢来增加多巴胺含量。我们发现，尽管诺米芬辛和司来吉兰增强了3-NP灌注产生的多巴胺溢出，但它们可保护纹状体中的多巴胺能终末和γ-氨基丁酸能神经元免受3-NP诱导的损伤。此外，作为损伤指标的凋亡细胞减少、星形胶质细胞增生和小胶质细胞活化也有所减轻。我们还发现，利血平和α-甲基对酪氨酸耗竭多巴胺可显著降低3-NP对纹状体突触体呼吸速率的抑制以及超氧自由基的产生。所有这些结果表明，纹状体多巴胺能终末内的内源性多巴胺会增强3-NP产生的线粒体活性氧生成以及呼吸抑制，从而增加3-NP在纹状体中的毒性。
