NADPH ameliorates MPTP-induced dopaminergic neurodegeneration through inhibiting p38MAPK activation

Jing-si Zhou1, Zhou Zhu1, Feng Wu1,2, Ying Zhou1, Rui Sheng1, Jun-chao Wu1, Zheng-hong Qin1
1 Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China
2 Department of Pharmacology, Nantong University School of Pharmaceutical Sciences, Nantong 226001, China
DOI: 10.1038/s41401-018-0003-0
Received: 25 August 2017
Accepted: 15 January 2018
Advance online: 16 May 2018


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.
Keywords: NADPH; PD; MPTP; ROS; P-p38MAPK; TP53

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