title: Epidermal growth factor receptor transactivation is necessary for glucagon-like peptide-1 to protect PC12 cells from apoptosis.
abstract: OBJECTIVE
  Patients with long-standing diabetes commonly develop diabetic encephalopathy, which is characterized by cognitive impairment and dementia. To identify potential treatments for diabetic encephalopathy, we focused on the protective action of glucagon-like peptide-1 (GLP-1) against neural cell apoptosis. In this study, we evaluated whether exposure of cells to GLP-1 leads to epidermal growth factor receptor (EGFR) transactivation and signaling through the PI3K/Akt/mTOR/GCLc/redox pathway, which we previously reported.
  
  
  METHODS
  We monitored the phosphorylation of EGFR and Akt in PC12 cells exposed to MG and GLP-1 that had been first incubated in the presence or absence of various inhibitors of EGFR transactivation.
  
  
  RESULTS
  DAPI staining revealed that pretreatment of cells with BiPS, HB-EGF and anti-TGF-α neutralization antibodies or AG1478 abrogated the ability of GLP-1 to rescue cells from MG-induced apoptosis. We show that exposure of PC12 cells to GLP-1 induces EGFR phosphorylation and that this effect was inhibited by prior exposure of the cells to BiPS, HB-EGF and anti-TGF-α neutralization antibodies or AG1478. Interestingly, these agents also diminished the capacity of GLP-1 to protect cells from MG-induced apoptosis. Moreover, these agents reduced GLP-1-induced phosphorylation of Akt. EGF itself also protected the cells from MG-induced apoptosis and induced phosphorylation of Akt, which was inhibited by LY294002.
  
  
  CONCLUSIONS
  The neuroprotective effects of GLP-1 against MG-induced apoptosis are mediated by EGFR transactivation, which signals through the PI3K/Akt/mTOR/GCLc/redox pathway in PC12 cells.
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. CQR00501 @ nifty.com
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kimura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okouchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kato
authors.forename: Kenro
authors.initials: K
authors.lastname: Imaeda
authors.forename: Naotsuka
authors.initials: N
authors.lastname: Okayama
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Asai
authors.forename: Takashi
authors.initials: T
authors.lastname: Joh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001928:Brain Diseases, Metabolic / Q000209:etiology / Q000517:prevention & control; D019610:Cytoprotection / Q000187:drug effects; D048909:Diabetes Complications / Q000209:etiology / Q000517:prevention & control; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D011765:Pyruvaldehyde / Q000633:toxicity; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects*; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D016211:Transforming Growth Factor alpha; D011765:Pyruvaldehyde; D052216:Glucagon-Like Peptide 1; D011494:Protein Kinases; D066246:ErbB Receptors