title: The neuroprotective role of metformin in advanced glycation end product treated human neural stem cells is AMPK-dependent.
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.
authors.affiliation: Department of Internal Medicine, Cardinal Tien Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Ming-Min
authors.initials: MM
authors.lastname: Chung
authors.affiliation: Department of Pathology, Cardinal Tien Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Yen-Lin
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Cardinal Tien Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Dee
authors.initials: D
authors.lastname: Pei
authors.affiliation: Department of Biochemistry and Molecular Biology, Chang Gung University, Tao Yuan 333, Taiwan.
authors.forename: Yi-Chuan
authors.initials: YC
authors.lastname: Cheng
authors.affiliation: Institute of Neuroscience, Zhejiang University School of Medicine, Zhejiang, China.
authors.forename: Binggui
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Pathology and Molecular Medicine, Cancer Biology and Genetics Division, Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada; Department of Biomedical and Molecular Sciences (Pharmacology and Toxicology), Queen's University, Kingston, ON K7L 3N6, Canada.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Nicol
authors.affiliation: Department of International Business, Ming Chuan University, Taipei 111, Taiwan.
authors.forename: Chia-Hui
authors.initials: CH
authors.lastname: Yen
authors.affiliation: Graduate Institute of Applied Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan; Department of Life Science, Fu Jen Catholic University, New Taipei City 242, Taiwan.
authors.forename: Han-Min
authors.initials: HM
authors.lastname: Chen
authors.affiliation: Department of Life Science, Fu Jen Catholic University, New Taipei City 242, Taiwan.
authors.forename: Yao-Jen
authors.initials: YJ
authors.lastname: Liang
authors.affiliation: Department of Life Science, Fu Jen Catholic University, New Taipei City 242, Taiwan. Electronic address: cmcphd@gmail.com.
authors.forename: Ming-Chang
authors.initials: MC
authors.lastname: Chiang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D045304:Cytochromes c; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D053148:Caspase 3; D053453:Caspase 9
keywords: AGEs; AMPK; Metformin; hNSCs