title: Repeated Glucose Deprivation/Reperfusion Induced PC-12 Cell Death through the Involvement of FOXO Transcription Factor.
abstract: BACKGROUND
  Cognitive impairment and brain damage in diabetes is suggested to be associated with hypoglycemia. The mechanisms of hypoglycemia-induced neural death and apoptosis are not clear and reperfusion injury may be involved. Recent studies show that glucose deprivation/reperfusion induced more neuronal cell death than glucose deprivation itself. The forkhead box O (FOXO) transcription factors are implicated in the regulation of cell apoptosis and survival, but their role in neuronal cells remains unclear. We examined the role of FOXO transcription factors and the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt and apoptosis-related signaling pathways in PC-12 cells exposed to repeated glucose deprivation/reperfusion.
  
  
  METHODS
  PC-12 cells were exposed to control (Dulbecco's Modified Eagle Medium [DMEM] containing 25 mM glucose) or glucose deprivation/reperfusion (DMEM with 0 mM glucose for 6 hours and then DMEM with 25 mM glucose for 18 hours) for 5 days. MTT assay and Western blot analysis were performed for cell viability, apoptosis, and the expression of survival signaling pathways. FOXO3/4',6-diamidino-2-phenylindole staining was done to ascertain the involvement of FOXO transcription factors in glucose deprivation/reperfusion conditions.
  
  
  RESULTS
  Compared to PC-12 cells not exposed to hypoglycemia, cells exposed to glucose deprivation/reperfusion showed a reduction of cell viability, decreased expression of phosphorylated Akt and Bcl-2, and an increase of cleaved caspase-3 expression. Of note, FOXO3 protein was localized in the nuclei of glucose deprivation/reperfusion cells but not in the control cells.
  
  
  CONCLUSIONS
  Repeated glucose deprivation/reperfusion caused the neuronal cell death. Activated FOXO3 via the PI3K/Akt pathway in repeated glucose deprivation/reperfusion was involved in genes related to apoptosis.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Onhospital, Busan, Korea.
authors.forename: Na
authors.initials: N
authors.lastname: Han
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.
authors.forename: You Jeong
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.
authors.forename: Su Min
authors.initials: SM
authors.lastname: Park
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.
authors.forename: Seung Man
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Paik Institute for Clinical Research, Molecular Therapy Lab, Inje University, Busan, Korea.
authors.forename: Ji Suk
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Paik Institute for Clinical Research, Molecular Therapy Lab, Inje University, Busan, Korea.
authors.forename: Hye Sook
authors.initials: HS
authors.lastname: Jung
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.
authors.forename: Tae Kyoon
authors.initials: TK
authors.lastname: Kim
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.
authors.forename: Tae Nyun
authors.initials: TN
authors.lastname: Kim
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Kwon
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.
authors.forename: Soon Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.; Paik Institute for Clinical Research, Molecular Therapy Lab, Inje University, Busan, Korea.
authors.forename: Mi-Kyung
authors.identifier: 0000-0003-1111-9122
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.
authors.forename: Byoung Doo
authors.initials: BD
authors.lastname: Rhee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.; Paik Institute for Clinical Research, Molecular Therapy Lab, Inje University, Busan, Korea.
authors.forename: Jeong Hyun
authors.identifier: 0000-0002-0045-4438
authors.initials: JH
authors.lastname: Park
keywords: Apoptosis; Forkhead box O; PC-12 cell; Phosphatidylinositol 3-kinase/Akt pathway; Reperfusion