Activation of AMPK/aPKCζ/CREB pathway by metformin is associated with upregulation of GDNF and dopamine.

Parkinson's disease (PD) is the second most common neurodegenerative disease, which is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, leading to a decrease in striatal dopamine. There is no antiparkinsonian therapy that offers a true disease-modifying treatment till date and there is an urgent need for a safe and effective neuroprotective or neurorestorative therapy. Our previous study demonstrated that metformin upregulated dopamine in the mouse brain and provided significant neuroprotection in animal model of PD. Therefore, we designed this study to investigate the molecular mechanism underlying such pharmacological effect of metformin. Herein, we found that metformin enhanced the phosphorylation of tyrosine hydroxylase (TH) which was accompanied by increase in brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and activation of their downstream signaling pathways in the mouse brain and SH-SY5Y cells. We further investigated the role of the neurotrophic factors in the activation of TH and observed that both BDNF and GDNF-induction were essential for metformin-induced TH activation. We found that the AMPK/aPKCζ/CREB pathway was essential for metformin-induced GDNF upregulation and TH activation. Thus, this study reveals the TH-activating property of metformin in the brain via induction of neurotrophic factors along with the signaling mechanism. These results potentiate the candidacy of metformin not only as a neuroprotective agent, but also as restorative therapy for the treatment of PD.