Activation of glutathione peroxidase and inhibition of p53-related apoptosis by apomorphine.
Activation of glutathione peroxidase and inhibition of p53-related apoptosis by apomorphine.
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DOI：
10.3233/jad-2011-110140
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发表时间：
2011
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影响因子：
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通讯作者：
Linqing Ma;Y. Ohyagi;Norimichi Nakamura;K. Iinuma;Katsue Miyoshi;E. Himeno;N. Soejima;Y. Yanagihara;N. Sakae;R. Yamasaki;J. Kira
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作者：
Linqing Ma;Y. Ohyagi;Norimichi Nakamura;K. Iinuma;Katsue Miyoshi;E. Himeno;N. Soejima;Y. Yanagihara;N. Sakae;R. Yamasaki;J. Kira
盐酸阿朴吗啡(APO)是一种多巴胺受体激动剂，最近被发现是治疗阿尔茨海默病(AD)的新药。我们发现，APO治疗改善了AD小鼠模型的氧化应激，并特异性地减弱了过氧化氢诱导的SH-SY5Y神经母细胞瘤细胞系中P53相关的凋亡。为了进一步了解这一作用背后的机制，我们研究了APO对细胞内氧化还原系统的作用，如谷胱甘肽循环和过氧化氢酶。我们研究了谷胱甘肽过氧化物酶(GPX)、谷胱甘肽还原酶(GR)和过氧化氢酶的特异性抑制剂(分别为BCNU、MCS和ATZ)对APO作用的影响。MCS或BCNU处理显著减弱APO的保护作用，而ATZ不处理。有趣的是，APO处理提高了GPX活性，但没有增加GPX1蛋白的表达。虽然BCNU处理减弱了APO的作用，但APO处理并没有提高GR活性。在原代神经元培养中也观察到了同样的效果。此外，多巴胺D_1、D_2、D_3和D_4受体拮抗剂的处理不能抵消APO的保护作用。因此，APO可能通过多巴胺受体非依赖性途径增强GPX活性。
Apomorphine hydrochloride (APO) is known to be a dopamine receptor agonist, and has recently been found to be a novel drug for Alzheimer's disease (AD). We found that APO treatment ameliorated oxidative stress in an AD mouse model and specifically attenuated the hydrogen peroxide-induced p53-related apoptosis in the SH-SY5Y neuroblastoma cell line. To further understand the mechanism behind this action, we investigated the actions of APO on intracellular redox systems, such as the glutathione cycle and catalase. We studied the effects of specific inhibitors for glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (BCNU, MCS, and ATZ, respectively) on the effects of APO. Treatments with MCS or BCNU, but not ATZ, significantly attenuated the protective effects of APO. Interestingly, APO treatment elevated GPx activity, but did not increase the expression of the GPx1 protein. Although BCNU treatment attenuated APO effects, GR activity was not elevated by APO treatment. The same effects were observed in primary neuronal cultures. In addition, treatment with dopamine D1, D2, D3 and D4 receptor antagonists did not counteract the protective action of APO. Thus, APO may enhance GPx activity through dopamine receptor-independent pathways.