The neuroprotective role of metformin in advanced glycation end product treated human neural stem cells is AMPK-dependent

Biochim Biophys Acta. 2015 May;1852(5):720-31. doi: 10.1016/j.bbadis.2015.01.006. Epub 2015 Jan 13.

Abstract

Diabetic neuronal damage results from hyperglycemia followed by increased formation of advanced glycosylation end products (AGEs), which leads to neurodegeneration, although the molecular mechanisms are still not well understood. Metformin, one of the most widely used anti-diabetic drugs, exerts its effects in part by activation of AMP-activated protein kinase (AMPK). AMPK is a critical evolutionarily conserved enzyme expressed in the liver, skeletal muscle and brain, and promotes cellular energy homeostasis and biogenesis by regulating several metabolic processes. While the mechanisms of AMPK as a metabolic regulator are well established, the neuronal role for AMPK is still unknown. In the present study, human neural stem cells (hNSCs) exposed to AGEs had significantly reduced cell viability, which correlated with decreased AMPK and mitochondria associated gene/protein (PGC1α, NRF-1 and Tfam) expressions, as well as increased activation of caspase 3 and 9 activities. Metformin prevented AGEs induced cytochrome c release from mitochondria into cytosol in the hNSCs. Co-treatment with metformin significantly abrogated the AGE-mediated effects in hNSCs. Metformin also significantly rescued hNSCs from AGE-mediated mitochondrial deficiency (lower ATP, D-loop level, mitochondrial mass, maximal respiratory function, COX activity, and mitochondrial membrane potential). Furthermore, co-treatment of hNSCs with metformin significantly blocked AGE-mediated reductions in the expression levels of several neuroprotective genes (PPARγ, Bcl-2 and CREB). These findings extend our understanding of the molecular mechanisms of both AGE-induced neuronal toxicity, and AMPK-dependent neuroprotection by metformin. This study further suggests that AMPK may be a potential therapeutic target for treating diabetic neurodegeneration.

Keywords: AGEs; AMPK; Metformin; hNSCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Blotting, Western
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cytochromes c / metabolism
  • Gene Expression / drug effects
  • Glycation End Products, Advanced / pharmacology*
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Metformin / pharmacology*
  • Mitochondria / drug effects
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Neural Stem Cells / drug effects*
  • Neural Stem Cells / metabolism
  • Nuclear Respiratory Factor 1 / genetics
  • Nuclear Respiratory Factor 1 / metabolism
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Glycation End Products, Advanced
  • Hypoglycemic Agents
  • NRF1 protein, human
  • Nuclear Respiratory Factor 1
  • PPAR gamma
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Proto-Oncogene Proteins c-bcl-2
  • Transcription Factors
  • Cytochromes c
  • Metformin
  • AMP-Activated Protein Kinases
  • Caspase 3
  • Caspase 9