title: Poly (ADP-ribose) polymerase plays an important role in intermittent hypoxia-induced cell death in rat cerebellar granule cells.
abstract: BACKGROUND
  Episodic cessation of airflow during sleep in patients with sleep apnea syndrome results in intermittent hypoxia (IH). Our aim was to investigate the effects of IH on cerebellar granule cells and to identify the mechanism of IH-induced cell death.
  
  
  METHODS
  Cerebellar granule cells were freshly prepared from neonatal Sprague-Dawley rats. IH was created by culturing the cerebellar granule cells in the incubators with oscillating O2 concentration at 20% and 5% every 30 min for 1-4 days. The results of this study are based on image analysis using a confocal microscope and associated software. Cellular oxidative stress increased with increase in IH. In addition, the occurrence of cell death (apoptosis and necrosis) increased as the duration of IH increased, but decreased in the presence of an iron chelator (phenanthroline) or poly (ADP-ribose) polymerase (PARP) inhibitors [3-aminobenzamide (3-AB) and DPQ]. The fluorescence of caspase-3 remained the same regardless of the duration of IH, and Western blots did not detect activation of caspase-3. However, IH increased the ratio of apoptosis-inducing factor (AIF) translocation to the nucleus, while PARP inhibitors (3-AB) reduced this ratio.
  
  
  RESULTS
  According to our findings, IH increased oxidative stress and subsequently leading to cell death. This effect was at least partially mediated by PARP activation, resulting in ATP depletion, calpain activation leading to AIF translocation to the nucleus.
  
  
  CONCLUSIONS
  We suggest that IH induces cell death in rat primary cerebellar granule cells by stimulating oxidative stress PARP-mediated calpain and AIF activation.
authors.affiliation: Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.
authors.forename: Sheng-Chun
authors.initials: SC
authors.lastname: Chiu
authors.forename: Sung-Ying
authors.initials: SY
authors.lastname: Huang
authors.forename: Yu-Chieh
authors.initials: YC
authors.lastname: Tsai
authors.forename: Shee-Ping
authors.initials: SP
authors.lastname: Chen
authors.forename: Cheng-Yoong
authors.initials: CY
authors.lastname: Pang
authors.forename: Chih-Feng
authors.initials: CF
authors.lastname: Lien
authors.forename: Yu-Jou
authors.initials: YJ
authors.lastname: Lin
authors.forename: Kun-Ta
authors.initials: KT
authors.lastname: Yang
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D002154:Calpain / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects*; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D018384:Oxidative Stress; D010100:Oxygen / Q000008:administration & dosage; D010618:Phenanthrolines / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: C494831:Aifm1 protein, rat; D051033:Apoptosis Inducing Factor; D001549:Benzamides; D010618:Phenanthrolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C025160:3-aminobenzamide; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D002154:Calpain; D053148:Caspase 3; D010100:Oxygen