geranylgeranylacetone and Brain-Infarction

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.

Topics: Androstadienes; Animals; Brain; Brain Infarction; Central Nervous System Agents; Decanoic Acids; Diazoxide; Diterpenes; Enzyme Inhibitors; Hydroxy Acids; Infarction, Middle Cerebral Artery; KATP Channels; Male; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Signal Transduction; Time Factors; Wortmannin

Previous studies have strongly suggested that heat shock protein 70 (HSP70) has protective effects in ischemia/reperfusion in tissues such as brain, heart, and liver. This study was performed to assess the efficacy of the HSP70 inducer geranylgeranylacetone (GGA) in experiments involving permanent middle cerebral artery (MCA) occlusion. Male Balb/c mice were subjected to permanent MCA occlusion by direct occlusion through small craniectomy. Vehicle or GGA (200 or 1000 mg/kg) was injected intraperitoneally 1 h prior to the onset of ischemia. Infarct volumes were evaluated at 24 h of ischemia by using 2,3,5-triphenyltetrazolium chloride (TTC) staining. The effect of GGA on the induction of HSP70 was studied at 3 h after ischemia with fluorescence immunocytochemistry. The percentage of infarct volume in the control mice (n=10) was 23.0+/-4.0% (mean+/-SD) of the contralateral hemisphere, while those in the treated groups were 22.6+/-7.3% (200 mg/kg group; n=5, P>0.05) and 15.7+/-3.8% (1000 mg/kg group; n=5, P<0.05). Pretreatments with 1000 mg/kg of GGA enhanced the ischemia-related induction of HSP in the neurons and astrocytes in the boundary zone of infarct. The results demonstrate that GGA significantly reduces infarct volume due to permanent MCA occlusion when given 1 h prior to the induction of ischemia.

Topics: Animals; Brain Infarction; Brain Ischemia; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Gene Expression Regulation; Glial Fibrillary Acidic Protein; HSP70 Heat-Shock Proteins; Immunohistochemistry; Male; Mice; Mice, Inbred BALB C; Neuroprotective Agents; Tetrazolium Salts