Molecular mechanisms of 6-hydroxydopamine-induced cytotoxicity in PC12 cells: Involvement of hydrogen peroxide-dependent and -independent action
Molecular mechanisms of 6-hydroxydopamine-induced cytotoxicity in PC12 cells: Involvement of hydrogen peroxide-dependent and -independent action
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DOI：
10.1016/j.freeradbiomed.2006.12.004
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发表时间：
2007-03-01
影响因子：
7.4
通讯作者：
Niki, Etsuo
中科院分区：
文献类型：
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作者：
Saito, Yoshiro;Nishio, Keiko;Niki, Etsuo
神经毒素 6-羟基多巴胺 (6-OHDA) 已被广泛用于生成帕金森病的实验模型。据报道，6-OHDA 产生的活性氧 (ROS)，如超氧阴离子和过氧化氢 (H2O2) 参与其细胞毒性；然而，ROS 在 6-OHDA 诱导的细胞死亡中的贡献和作用尚未完全阐明。在目前使用PC12细胞的研究中，我们观察到在几分钟内从致死浓度的100μM 6-OHDA产生50μM H2O2，并比较了H2O2与6-OHDA的单独作用。过氧化氢酶是一种去除 H2O2 的酶，它完全消除了 H2O2 的细胞毒性作用，同时观察到对 6-OHDA 具有显着但部分的保护作用。 6-OHDA 诱导过氧化还原蛋白氧化、细胞色素 c 释放和 caspase-3 激活。过氧化氢酶对6-OHDA诱导的过氧化还原蛋白氧化和细胞色素c释放有很强的抑制作用；然而，过氧化氢酶并不能有效抑制 caspase-3 的激活。另一方面，在 caspase-8、caspase-9 和钙蛋白酶抑制剂存在的情况下，6-OHDA 诱导的 caspase-3 激活受到抑制。这些结果表明，6-OHDA 产生的 H2O2 在 6-OHDA 诱导的过氧化还原蛋白氧化和细胞色素 c 释放中起着关键作用，而 H2O2 和细胞色素 c 独立的 caspase 激活途径参与 6-OHDA 诱导的神经毒性。这些发现可能有助于解释生成的 H2O2 和次级产物作为与帕金森病相关的 6-OHDA 诱导的细胞死亡信号的第二信使的重要性。 (c) 2006 Elsevier Inc. 保留所有权利。
The neurotoxin 6-hydroxydopamine (6-OHDA) has been widely used to generate an experimental model of Parkinson's disease. It has been reported that reactive oxygen species (ROS), such as the superoxide anion and hydrogen peroxide (H2O2), generated from 6-OHDA are involved in its cytotoxicity; however, the contribution and role of ROS in 6-OHDA-induced cell death have not been fully elucidated. In the present study using PC12 cells, we observed the generation of 50 mu M H2O2 from a lethal concentration of 100 mu M 6-OHDA within a few minutes, and compared the sole effect of H2O2 with 6-OHDA. Catalase, an H2O2-removing enzyme, completely abolished the cytotoxic effect of H2O2, While a significant but partial protective effect was observed against 6-OHDA. 6-OHDA induced peroxiredoxin oxidation, cytochrome c release, and caspase-3 activation. Catalase exhibited a strong inhibitory effect against the peroxiredoxin oxidation, and cytochrome c release induced by 6-OHDA; however, caspase-3 activation was not effectively inhibited by catalase. On the other hand, 6-OHDA-induced caspase-3 activation was inhibited in the presence of caspase-8, caspase-9, and calpain inhibitors. These results suggest that the H2O2 generated from 6-OHDA plays a pivotal role in 6-OHDA-induced peroxiredoxin oxidation, and cytochrome c release, while H2O2- and cytochrome c-independent caspase activation pathways are involved in 6-OHDA-induced neurotoxicity. These findings may contribute to explain the importance of generated H2O2 and secondary products as a second messenger of 6-OHDA-induced cell death signal linked to Parkinson's disease. (c) 2006 Elsevier Inc. All rights reserved.