Metformin enhances nigrostriatal dopaminergic tone via activation of atypical protein kinase ζ

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease characterized by the progressive loss of the dopaminergic neurons in the substantia nigra leading to a decrease in the striatal dopamine. In our previous study, we demonstrated that metformin upregulated dopamine in the mouse brain, thus we designed this study to investigate the molecular mechanism behind such pharmacological effects. Here, we found that metformin enhanced the phosphorylation of tyrosine hydroxylase (TH) which was accompanied by increased expression of BDNF, GDNF, and activated their common signaling pathways in the nigrostriatal pathway. These effects were recapitulated in SH‐SY5Y cells suggesting a plausible role of neurotrophic factors in the activation of TH. Indeed, both BDNF and GDNF were essential for metformininduced TH activation. Importantly, we found that AMPK/aPKCζ/CREB pathway was required for metformin induced GDNF upregulation and TH activation. Our research is the first to reveal the critical role of DA‐upregulating effect of metformin via TH activation that critically requires neurotrophic factor induction. These results potentiate the candidacy of metformin not only as a neuroprotective agent but also as a restorative therapy for the treatment of PD.Support or Funding InformationThis research was supported by Basic Science Research Program through the Natonal Research Foundation of Korea funded by the Ministry of Education (2018R1D1A3B07049570).