Role of the redox protein thioredoxin in cytoprotective mechanism evoked by (-)-deprenyl
Role of the redox protein thioredoxin in cytoprotective mechanism evoked by (-)-deprenyl
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DOI：
10.1124/mol.105.012302
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发表时间：
2005-11-01
影响因子：
3.6
通讯作者：
Chiueh, CC
中科院分区：
文献类型：
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作者：
Andoh, T;Chock, PB;Chiueh, CC
通过抑制单胺氧化酶B型（MAO-B），（-）-丙炔苯丙胺（司来吉兰）可防止1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）转化为毒性代谢物1-甲基-4-苯基吡啶离子（MPP+），并可防止动物模型中多巴胺能神经元的神经毒性。累积观察结果表明，司来吉兰也可能通过诱导促生存基因来保护MPP+诱导的神经毒性。我们已经观察到，硫氧还蛋白（Trx）介导的诱导线粒体锰超氧化物歧化酶（MnSOD）和Bcl-2在预处理诱导的兴奋效应。因此，我们研究了氧化还原蛋白Trx是否在司来吉兰对MPP+诱导的人SH-SY 5 Y神经母细胞瘤细胞和小鼠中脑多巴胺能神经元的原代神经元培养物的细胞毒性的神经保护机制中发挥任何作用。在证实司来吉兰保护免受MPP+诱导的细胞毒性后，我们进一步观察到司来吉兰在1 μ M或更低时诱导Trx以保护免受MPP+引起的氧化损伤。Trx的诱导被蛋白激酶A（PKA）抑制剂阻断，并由PKA敏感的促分裂原活化蛋白（MAP）激酶Erk 1/2和转录因子c-Myc的磷酸化激活介导。司来吉兰诱导的Trx和相关的神经保护作用同时被反义Trx mRNA阻断，而不是正义或反义突变体硫代磷酸寡核苷酸，不仅在人SH-SY 5 Y细胞中，而且在小鼠中脑多巴胺能神经元的原代神经元培养物中。此外，Trx的氧化还原循环可能介导了司来吉兰的保护作用，因为1-氯-2，4-二硝基苯抑制Trx还原酶改善了司来吉兰的作用。Trx（1 μ M）持续增加线粒体蛋白MnSOD和Bcl-2的表达，支持细胞存活（Andoh等，2002年）。总之，在不改变MAO-B活性的情况下，司来吉兰增强了Trx的基因诱导，导致抗氧化MnSOD和抗凋亡Bcl-2蛋白的表达升高，以保护免受MPP+诱导的神经毒性。
Through the inhibition of monoamine oxidase type B (MAO-B), (-)-deprenyl (selegiline) prevents the conversion of 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the toxic metabolite 1-methyl-4- phenylpyridinium ion (MPP+) and also prevents the neurotoxicity in the dopaminergic neurons in animal models. Cumulative observations suggest that selegiline may also protect against MPP+-induced neurotoxicity, possibly through the induction of pro-survival genes. We have observed that thioredoxin (Trx) mediates the induction of mitochondrial manganese superoxide dismutase (MnSOD) and Bcl-2 during preconditioning-induced hormesis. We therefore investigated whether the redox protein Trx plays any role in the neuroprotective mechanism of selegiline against MPP+-induced cytotoxicity in human SH-SY5Y neuroblastoma cells and also in primary neuronal cultures of mouse midbrain dopaminergic neurons. After confirming that selegiline protects against MPP+-induced cytotoxicity, we observed further that selegiline, at 1 mu M or less, induced Trx for protection against oxidative injury caused by MPP+. The induction of Trx was blocked by protein kinase A (PKA) inhibitor and mediated by a PKA-sensitive phospho-activation of mitogen-activated protein (MAP) kinase Erk1/2 and the transcription factor c-Myc. Selegiline-induced Trx and associated neuroprotection were concomitantly blocked by the antisense against Trx mRNA, but not the sense or antisense mutant phosphothionate oligonucleotides, not only in human SH-SY5Y cells but also in mouse primary neuronal culture of midbrain dopaminergic neurons. Furthermore, the redox cycling of Trx may mediate the protective action of selegiline because the inhibition of Trx reductase by 1-chloro-2,4-dinitrobenzene ameliorated the effect of selegiline. Trx (1 mu M) consistently increased the expression of mitochondrial proteins MnSOD and Bcl-2, supporting cell survival (Andoh et al., 2002). In conclusion, without modifying MAO-B activity, selegiline augments the gene induction of Trx, leading to elevated expression of antioxidative MnSOD and antiapoptotic Bcl-2 proteins for protecting against MPP+-induced neurotoxicity.