2. Academic Validation
  3. Pyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection

Pyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection

  • Nat Commun. 2020 Feb 18;11(1):941. doi: 10.1038/s41467-020-14788-x.
Yao Wei  # 1,  Ming Lu  # 2,  Meng Mei  # 1,  Haoran Wang 2,  Zhitao Han 1,  Miaomiao Chen 2,  Hang Yao 2,  Nanshan Song 2,  Xiao Ding 1,  Jianhua Ding 2,  Ming Xiao 2,  Gang Hu 3 4 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
  • 2 Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
  • 3 Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China. ghu@njucm.edu.cn.
  • 4 Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, Jiangsu, 210029, China. ghu@njucm.edu.cn.
  • 5 Biomedical Functional Materials Collaborative Innovation Center, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, Jiangsu, 210023, China. ghu@njucm.edu.cn.
  • # Contributed equally.
PMID: 32071304 DOI: 10.1038/s41467-020-14788-x
Abstract

Oxidative stress is a major pathogenic mechanism in Parkinson's disease (PD). As an important cellular antioxidant, glutathione (GSH) balances the production and incorporation of free radicals to protect neurons from oxidative damage. GSH level is decreased in the brains of PD patients. Hence, clarifying the molecular mechanism of GSH deficiency may help deepen our knowledge of PD pathogenesis. Here we report that the astrocytic dopamine D2 receptor (DRD2) regulates GSH synthesis via PKM2-mediated Nrf2 transactivation. In addition we find that pyridoxine can dimerize PKM2 to promote GSH biosynthesis. Further experiments show that pyridoxine supplementation increases the resistance of nigral dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in wild-type mice as well as in astrocytic Drd2 conditional knockout mice. We conclude that dimerizing PKM2 may be a potential target for PD treatment.

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