title: A Single Oral Dose of Geranylgeranylacetone Upregulates Vascular Endothelial Growth Factor and Protects against Kainic Acid-Induced Neuronal Cell Death: Involvement of the Phosphatidylinositol-3 Kinase/Akt Pathway.
abstract: BACKGROUND
  Previous studies demonstrated the cytoprotective effect of geranylgeranylacetone (GGA), a heat shock protein inducer, against ischemic insult or kainic acid (KA)-induced neuronal cell death. Phosphatidylinositol-3 kinase (PI3K)/Akt is thought to be an important factor that mediates neuroprotection. However, the signaling pathways in the brain in vivo after oral GGA administration remain unclear.
  
  
  METHODS
  We measured and compared hippocampal neuron density to investigate the effect of GGA on KA-induced cell death in rats. We evaluated the effects of pretreatment with wortmannin (Wort), a specific PI3K inhibitor, on GGA-induced neuroprotection against KA-induced cell death. To clarify the relationship between PI3K/Akt activation and neuroprotection, we used immunoblot analysis to determine the amounts of p-Akt and vascular endothelial growth factor (VEGF) proteins present after GGA administration with or without Wort treatment.
  
  
  RESULTS
  Neuroprotective effects of GGA (pretreatment with a single oral dose of GGA, 800 mg/kg, 48 h before KA injection) were prevented by Wort pretreatment, which indicates that the selective PI3K/Akt pathway may mediate the GGA-dependent protection. Oral GGA-induced p-Akt and VEGF, and GGA pretreatment enhanced KA-induced VEGF, both of which were prevented by Wort pretreatment.
  
  
  CONCLUSIONS
  These results suggest that a single oral dose of GGA induces p-Akt and that GGA plays an important role in neuroprotection against KA-induced neuronal cell death through VEGF induction.
authors.affiliation: Department of Neurosurgery, School of Medicine, Oita University, Oita, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Kawasaki
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujiki
authors.forename: Susumu
authors.initials: S
authors.lastname: Uchida
authors.forename: Masaki
authors.initials: M
authors.lastname: Morishige
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Momii
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ishii
mesh_terms: D000284:Administration, Oral; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D004224:Diterpenes / Q000008:administration & dosage*; D006624:Hippocampus / Q000378:metabolism; D007608:Kainic Acid / Q000009:adverse effects; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D058539:Phosphatidylinositol 3-Kinase / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000378:metabolism; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D004224:Diterpenes; D018696:Neuroprotective Agents; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D058539:Phosphatidylinositol 3-Kinase; C031049:geranylgeranylacetone; D007608:Kainic Acid; D000077191:Wortmannin
keywords: Geranylgeranylacetone; Kainic acid; Neuroprotection; PI3K/Akt pathway; Phosphatidylinositol-3 kinase; Vascular endothelial growth factor