Pong K, Doctrow S R, Baudry M
Neuroscience Program, University of Southern California, 90089-2520, Los Angeles, CA, USA.
Brain Res. 2000 Oct 27;881(2):182-9. doi: 10.1016/s0006-8993(00)02841-9.
Oxidative stress has been implicated in the selective degeneration of dopaminergic (DAergic) neurons in Parkinson's disease (PD). In this study, we tested the efficacy of EUK-134, a superoxide dismutase (SOD) and catalase mimetic, on the nitration of tyrosine hydroxylase (TH), a marker of oxidative stress, and neurotoxicity produced by 1-methyl-4-phenylpyridinium (MPP(+)) and 6-hydroxydopamine (6-OHDA) in primary DAergic neuron cultures. Exposure of cultures to 10 microM MPP(+) reduced dopamine (DA) uptake and the number of tyrosine hydroxylase immunoreactive (THir) neurons to 56 and 52% of control, while exposure to 30 microM 6-OHDA reduced DA uptake and the number of THir neurons to 58 and 59% of control, respectively. Pretreatment of cultures with 0.5 microM EUK-134 completely protected DAergic neurons against MPP(+)- and 6-OHDA-induced neurotoxicity. Exposure of primary neuron cultures to either MPP(+) or 6-OHDA produced nitration of tyrosine residues in TH. Pretreatment of cultures with 0.5 microM EUK-134 completely prevented MPP(+)- or 6-OHDA-induced nitration of tyrosine residues in TH. Taken together, these results support the idea that reactive oxygen species (ROS) are critically involved in MPP(+)- and 6-OHDA-induced neurotoxicity and suggest a potential therapeutic role for synthetic catalytic scavengers of ROS, such as EUK-134, in the treatment of PD.
氧化应激与帕金森病（PD）中多巴胺能（DAergic）神经元的选择性退化有关。在本研究中，我们测试了超氧化物歧化酶（SOD）和过氧化氢酶模拟物EUK - 134对酪氨酸羟化酶（TH）硝化作用的效果，TH是氧化应激的标志物，以及其对原代多巴胺能神经元培养物中由1 - 甲基 - 4 - 苯基吡啶鎓（MPP(+)）和6 - 羟基多巴胺（6 - OHDA）产生的神经毒性的作用。将培养物暴露于10 microM MPP(+)会使多巴胺（DA）摄取以及酪氨酸羟化酶免疫反应性（THir）神经元数量分别降至对照的56%和52%，而暴露于30 microM 6 - OHDA会使DA摄取以及THir神经元数量分别降至对照的58%和59%。用0.5 microM EUK - 134预处理培养物可完全保护多巴胺能神经元免受MPP(+)和6 - OHDA诱导的神经毒性。将原代神经元培养物暴露于MPP(+)或6 - OHDA会导致TH中酪氨酸残基的硝化。用0.5 microM EUK - 134预处理培养物可完全防止MPP(+)或6 - OHDA诱导的TH中酪氨酸残基的硝化。综上所述，这些结果支持活性氧（ROS）严重参与MPP(+)和6 - OHDA诱导的神经毒性这一观点，并表明合成的ROS催化清除剂，如EUK - 134，在PD治疗中具有潜在的治疗作用。
