Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Szigony u. 43, Hungary.
Neuropharmacology. 2010 Mar-Apr;58(4-5):816-25. doi: 10.1016/j.neuropharm.2009.11.017. Epub 2009 Dec 6.
An in vitro model of mitochondrial dysfunction with subsequent oxidative stress was elaborated and utilized to study the effect of drugs, currently used for the treatment of Parkinson's disease, on pathological H(2)O(2)-evoked [(3)H]dopamine efflux and the formation of toxic dopamine metabolites in rat striatal slices. 60 min rotenone (0.1-10 muM) pretreatment decreased dopamine content and [(3)H]dopamine uptake, as well as ATP level and energy charge of the slices. In addition, a robust potentiation of H(2)O(2)-evoked [(3)H]dopamine efflux and the formation of dopamine quinone in the effluent was detected. l-DOPA (200 muM) markedly elevated resting but not 100 muM H(2)O(2)-evoked and electrically-induced [(3)H]dopamine efflux. Furthermore, l-DOPA promoted the formation of dopamine quinone. Ropinirole (100 nM) did not affect resting and H(2)O(2)-evoked [(3)H]dopamine efflux and inhibited the electrically evoked release only in untreated slices. l-deprenyl, at concentration of 0.01 muM potentiated, whilst between 1 and 50 muM diminished H(2)O(2)-evoked [(3)H]dopamine efflux. Rasagiline (0.01-50 muM) slightly inhibited H(2)O(2)-evoked [(3)H]dopamine efflux, and it was able to prevent the generation of dopamine quinone. Neither of the drugs was able to suppress both the pathological H(2)O(2)-evoked [(3)H]dopamine efflux and the formation of dopamine quinone with simultaneous augmentation of electrically evoked [(3)H]dopamine release what should be a future concept of antiparkinsonian drug-design.
建立并利用体外模型研究线粒体功能障碍伴随后续氧化应激，以研究目前用于治疗帕金森病的药物对病理 H 2 O 2 诱发的 [(3)H]多巴胺外排和有毒多巴胺代谢物在大鼠纹状体切片中的形成的影响。60 分钟鱼藤酮（0.1-10 μM）预处理降低了多巴胺含量和 [(3)H]多巴胺摄取，以及切片中的 ATP 水平和能量电荷。此外，还检测到 H 2 O 2 诱发的 [(3)H]多巴胺外排和流出物中多巴胺醌的形成明显增强。l-DOPA（200 μM）显著增加静息但不增加 100 μM H 2 O 2 诱发和电诱导的 [(3)H]多巴胺外排。此外，l-DOPA 促进了多巴胺醌的形成。罗匹尼罗（100 nM）不影响静息和 H 2 O 2 诱发的 [(3)H]多巴胺外排，仅在未处理的切片中抑制电诱发的释放。l-普萘洛尔（0.01 μM）增强了浓度为 0.01 μM 的多巴胺外排，而 1-50 μM 则减弱了 H 2 O 2 诱发的 [(3)H]多巴胺外排。rasagiline（0.01-50 μM）轻度抑制 H 2 O 2 诱发的 [(3)H]多巴胺外排，能够阻止多巴胺醌的生成。这两种药物都无法同时抑制病理性 H 2 O 2 诱发的 [(3)H]多巴胺外排和多巴胺醌的形成，同时增强电诱发的 [(3)H]多巴胺释放，这应该是未来抗帕金森病药物设计的概念。
