The phosphatidylinositol-3 kinase/Akt pathway mediates geranylgeranylacetone-induced neuroprotection against cerebral infarction in rats

Brain Res. 2010 May 12;1330:151-7. doi: 10.1016/j.brainres.2010.02.074. Epub 2010 Mar 3.


Previous studies demonstrated the cytoprotective effect of geranylgeranylacetone (GGA), a heat shock protein inducer, against ischemic insult. Phosphatidylinositol-3 kinase/Akt (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. We measured and compared infarction volumes to investigate the effect of GGA on cerebral infarction induced by permanent middle cerebral artery occlusion in rats. We evaluated the effects of pretreatment with 5-hydroxydecanoate (5HD), a specific mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel inhibitor; diazoxide (DZX), a selective mitoK(ATP) channel opener and wortmannin (Wort), a specific PI3K inhibitor of GGA-induced neuroprotection against infarction volumes. To clarify the relationship between PI3K/Akt activation and neuroprotection, we used immunoblot analysis to determine the amount of p-Akt proteins present after GGA administration with or without Wort treatment. Neuroprotective effects of GGA (pretreatment with a single oral GGA dose (800 mg/kg) 48 h before ischemia) were prevented by 5HD, DZX and Wort pretreatment, which indicates that the selective mitoK(ATP) channel and the PI3K/Akt pathway may mediate GGA-dependent protection. Oral GGA-induced p-Akt and GGA pretreatment enhanced ischemia-induced p-Akt, both of which were prevented by Wort pretreatment. These results suggest that a single oral dose of GGA induces p-Akt and that GGA plays an important role in neuroprotection against cerebral ischemia through the mitoK(ATP) channel opening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Brain Infarction / drug therapy*
  • Brain Infarction / metabolism
  • Brain Infarction / pathology
  • Central Nervous System Agents / pharmacology
  • Decanoic Acids / pharmacology
  • Diazoxide / pharmacology
  • Diterpenes / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Hydroxy Acids / pharmacology
  • Infarction, Middle Cerebral Artery / drug therapy*
  • Infarction, Middle Cerebral Artery / metabolism
  • Infarction, Middle Cerebral Artery / pathology
  • KATP Channels / agonists
  • KATP Channels / antagonists & inhibitors
  • KATP Channels / metabolism
  • Male
  • Neuroprotective Agents / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Time Factors
  • Wortmannin


  • Androstadienes
  • Central Nervous System Agents
  • Decanoic Acids
  • Diterpenes
  • Enzyme Inhibitors
  • Hydroxy Acids
  • KATP Channels
  • Neuroprotective Agents
  • Phosphoinositide-3 Kinase Inhibitors
  • 5-hydroxydecanoic acid
  • Proto-Oncogene Proteins c-akt
  • Diazoxide
  • geranylgeranylacetone
  • Wortmannin