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NADPH ameliorates MPTP-induced dopaminergic neurodegeneration through inhibiting p38MAPK activation.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2018-05-16 , DOI: 10.1038/s41401-018-0003-0
Jing-Si Zhou 1 , Zhou Zhu 1 , Feng Wu 1, 2 , Ying Zhou 1 , Rui Sheng 1 , Jun-Chao Wu 1 , Zheng-Hong Qin 1
Affiliation  

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). Although the pathogenic mechanism underlying PD remains largely unknown, decreased nigral glutathione (GSH) in postmortem brains of PD patients supports the presence of oxidative stress in PD. We found that Nicotinamide adenine dinucleotide phosphate (NADPH), which is important for maintaining the level of GSH, protected dopaminergic (DA) neurons from neurotoxicity of MPTP/MPP+. In the present study, NADPH prevented DA neurons from MPTP toxicity with increased GSH and decreased reactive oxygen species (ROS) levels in the ventral midbrain of mice, and improved motor activity. Our present results demonstrated that NADPH inhibited the phosphorylation of p38MAPK, decreased the level of TP53 protein, and inhibited TP53 nuclear translocation in DA neurons of SNpc and in MES23.5 cells. Furthermore, NADPH decreased the protein level of TP53 target gene, Bax, cleavage of PARP, and nuclei condensation. Taken together, NADPH abrogated MPTP-induced p38MAPK phosphorylation, TP53 nuclear translocation, and Bax induction, and finally, MPTP/MPP+-induced apoptosis of DA neurons. This study suggests that NADPH may be a novel therapeutic candidate for PD.

中文翻译:

NADPH通过抑制p38MAPK激活来改善MPTP诱导的多巴胺能神经变性。

帕金森氏病(PD)是第二种最常见的神经退行性疾病,其特征是黑质致密部(SNpc)中的多巴胺能神经元选择性丢失。尽管PD的致病机制仍然未知,但是PD患者死后大脑中的谷胱甘肽(GSH)含量下降支持了PD中氧化应激的存在。我们发现烟酰胺腺嘌呤二核苷酸磷酸(NADPH)对维持GSH的水平很重要,可以保护多巴胺能(DA)神经元免受MPTP / MPP +的神经毒性。在本研究中,NADPH通过增加小鼠腹中脑的GSH含量和降低其活性氧(ROS)水平来防止DA神经元受到MPTP毒性。我们目前的结果表明,NADPH抑制p38MAPK的磷酸化,降低SNpc的DA神经元和MES23.5细胞中TP53蛋白的水平,并抑制TP53核易位。此外,NADPH降低了TP53靶基因的蛋白质水平,Bax,PARP的裂解和细胞核缩合。两者合计,NADPH废除了MPTP诱导的p38MAPK磷酸化,TP53核易位和Bax诱导,最后废除了MPTP / MPP +诱导的DA神经元凋亡。这项研究表明,NADPH可能是PD的新型治疗候选药物。MPTP / MPP +诱导DA神经元凋亡。这项研究表明,NADPH可能是PD的新型治疗候选药物。MPTP / MPP +诱导DA神经元凋亡。这项研究表明,NADPH可能是PD的新型治疗候选药物。
更新日期:2018-05-16
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