Activation of the ATF2/CREB-PGC-1α pathway by metformin leads to dopaminergic neuroprotection

Abstract

Progressive dopaminergic neurodegeneration is responsible for the canonical motor deficits in Parkinson's disease (PD). The widely prescribed anti-diabetic medicine metformin is effective in preventing neurodegeneration in animal models; however, despite the significant potential of metformin for treating PD, the therapeutic effects and molecular mechanisms underlying dopaminergic neuroprotection by metformin are largely unknown.In this study, we found that metformin induced substantial proteomic changes, especially in metabolic and mitochondrial pathways in the substantia nigra (SN). Consistent with this data, metformin increased mitochondrial marker proteins in SH-SY5Y neuroblastoma cells. Mitochondrial protein expression by metformin was found to be brain region specific, with metformin increasing mitochondrial proteins in the SN and the striatum, but not the cortex. As a potential upstream regulator of mitochondria gene transcription by metformin, PGC-1α promoter activity was stimulated by metformin via CREB and ATF2 pathways. PGC-1α and phosphorylation of ATF2 and CREB by metformin were selectively increased in the SN and the striatum, but not the cortex. Finally, we showed that metformin protected dopaminergic neurons and improved dopamine-sensitive motor performance in an MPTP-induced PD animal model. Together these results suggest that the metformin-ATF2/CREB-PGC-1α pathway might be promising therapeutic target for PD.

Epigallocatechin-3-gallate confers protection against corticosterone-induced neuron injuries via restoring extracellular signal-regulated kinase 1/2 and phosphatidylinositol-3 kinase/protein kinase B signaling pathways

“…In hippocampal progenitor cells from a Down syndrome mouse model and cells derived from patients with Down’s syndrome, EGCG could also sustain and enhance mitochondrial functions by up-regulating PGC-1α/SIRT1/AMPK axis as well as increasing SIRT1-dependent PGC-1α deacetylation [ 64 , 66 ]. In addition, the most recent studies suggested that PGC-1α could interact or collaborate with critical cellular signaling pathways, such as NF-κB [ 70 ], ERK1/2 [ 71 ], PI3K/AKT [ 72 , 73 ], cAMP response element binding protein (CREB) [ 74 ] and AMPK [ 75 ] pathways, and collectively modulate mitochondrial functions in physiological and pathological conditions. So the modulation of intracellular pathways by EGCG, which ultimately restore mitochondrial functions, could explain, at least partly, the effects of such natural active substances in ameliorating the stress- or corticosterone- induced neural injuries.…”

Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation

“…Recent animal studies have further demonstrated that long‐term metformin pretreatment can obviously alleviate the damage of ischemic stroke to brain tissue 12, 13, 14. In addition, metformin is also effective in treating global cerebral ischemia,15 intracerebral hemorrhage,16 epilepsy,17 Parkinson disease,18, 19 and Huntington disease 20. However, whether and how metformin treatment is effective in reducing brain injury after CA remain uninvestigated.…”

Potential Therapeutic Drugs for Parkinson’s Disease Based on Data Mining and Bioinformatics Analysis

“…However, melbine (DMBG) could control blood glucose so as to reduce the probability of type 2 diabetes patients suffering PD [ 22 , 23 ]. Kang et al discovered that melbine (DMBG) could mediate ATF2/CREB-PGC-1 α pathway, induce proteomic change of metabolisms and mitochondria pathways in the substantia nigra, increase mitochondrial protein in the substantia nigra and the corpus striatum, protect dopaminergic neuron in the substantia nigra and the corpus striatum, and improve dyskinesia of PD [ 24 ]. Julia et al discovered that TRAP1 could adjust the mitochondrial function of downstream PINK1 and HTRA2, malfunction of TRAP1 increased free NADH, mitochondria was produced, unfolded protein reaction and membrane potential of mitochondria were triggered, the sensitivity of mitochondria elimination and apoptosis decreased, and PD patients suffered TRAP1 malfunction, while metformin hydrochloride could adjust energy metabolism, produce mitochondria, recover the mitochondrial membrane potential, reverse mitochondrial mitochondrial function arising from TRAP1 mutation of PD, and provide new ideas for mitochondrial pathological change and treatment of PD [ 22 , 25 , 26 ].…”