Pramipexole protects against apoptotic cell death by non-dopaminergic mechanisms
Pramipexole protects against apoptotic cell death by non-dopaminergic mechanisms
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DOI：
10.1111/j.1471-4159.2004.02804.x
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发表时间：
2004-12-01
影响因子：
4.7
通讯作者：
Schapira, AHV
中科院分区：
文献类型：
--
作者：
Gu, M;Irvani, M;Schapira, AHV
我们研究了普拉克索（一种用于帕金森病 (PD) 对症治疗的多巴胺激动剂）在多巴胺能和非多巴胺能细胞中防止 1-甲基-4-苯基吡啶鎓 (MPP(+)) 和鱼藤酮诱导的细胞死亡的能力。在多巴胺能 SHSY-5Y 细胞和非多巴胺能 JK 细胞中，与活性 (-)- 或非活性 (+)- 对映体形式的普拉克索 (10 muM) 预孵育可减少 MPP(+) 和鱼藤酮响应的细胞死亡。使用舒必利或氯氮平阻断多巴胺受体并不能阻止保护作用。在普拉克索不表现出抗氧化活性的浓度下发生保护，如未能维持乌头酸酶活性所示。然而，普拉克索减少了 caspase-3 的激活，减少了细胞色素 c 的释放，并阻止了 MPP(+) 和鱼藤酮诱导的线粒体膜电位下降。这表明普拉克索具有抗细胞凋亡作用。结果扩展了普拉克索神经保护作用的证据，并表明这不依赖于多巴胺受体占据或抗氧化活性。需要进一步评估以确定普拉克索的神经保护作用是否转化为帕金森病患者的疾病缓解作用。
We have investigated the ability of pramipexole, a dopamine agonist used in the symptomatic treatment of Parkinson's disease (PD), to protect against cell death induced by 1-methyl-4-phenylpyridinium (MPP(+)) and rotenone in dopaminergic and non-dopaminergic cells. Pre-incubation with either the active (-)- or inactive (+)-enantiomer forms of pramipexole (10 muM) decreased cell death in response to MPP(+) and rotenone in dopaminergic SHSY-5Y cells and in non-dopaminergic JK cells. The protective effect was not prevented by dopamine receptor blockade using sulpiride or clozapine. Protection occurred at concentrations at which pramipexole did not demonstrate antioxidant activity, as shown by the failure to maintain aconitase activity. However, pramipexole reduced caspase-3 activation, decreased the release of cytochrome c and prevented the fall in the mitochondrial membrane potential induced by MPP(+) and rotenone. This suggests that pramipexole has anti-apoptotic actions. The results extend the evidence for the neuroprotective effects of pramipexole and indicate that this is not dependent on dopamine receptor occupation or antioxidant activity. Further evaluation is required to determine whether the neuroprotective action of pramipexole is translated to a disease-modifying effect in PD patients.