Geranylgeranylacetone, a noninvasive heat shock protein inducer, induces protein kinase C and leads to neuroprotection against cerebral infarction in rats.
Previous studies demonstrated the cytoprotective effect of geranylgeranylacetone (GGA), a heat shock protein (HSP) inducer, against ischemic insult. Protein kinase C (PKC) is thought to be an important factor that mediates the expression of heat shock protein 70 (HSP70) in vitro. 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 (MCA) occlusion in rats. To clarify the relationship between PKC induction and HSP70 expression, we determined the amounts of HSP70 and PKC proteins after GGA administration by immunoblotting. We evaluated the effects of pretreatment with chelerythrine (CHE), a specific PKC inhibitor, on expressions of PKC and HSP70 proteins with immunoblotting. Neuroprotective effects of GGA (pretreatment with a single oral GGA dose (800 mg/kg) 48 h before ischemia) were prevented by CHE pretreatment, which indicates that PKC may mediate the GGA-dependent protection. Oral GGA-induced HSP70 expression induced PKC delta, and GGA pretreatment enhanced ischemia-induced HSP70, both of which were prevented by CHE pretreatment. These results suggest that a single oral dose of GGA induces PKC delta and promotes HSP70 expression in the brain and that GGA plays an important role in neuroprotection against cerebral ischemia.
Uchida
Susumu
S
Department of Neurosurgery, School of Medicine, Oita University, 1-1, Idaigaoka, Hasama-machi, 879-5593, Japan.
Fujiki
Minoru
M
Nagai
Yasuyuki
Y
Abe
Tatsuya
T
Kobayashi
Hidenori
H
D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D015153:Blotting, Western / Q000379:methods; D002544:Cerebral Infarction / Q000201:enzymology* / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004224:Diterpenes / Q000627:therapeutic use*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D015870:Gene Expression / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010617:Phenanthridines / Q000008:administration & dosage; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013778:Tetrazolium Salts; D013997:Time Factors
D000470:Alkaloids; D053119:Benzophenanthridines; D004224:Diterpenes; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D018696:Neuroprotective Agents; D010617:Phenanthridines; D013778:Tetrazolium Salts; C009591:triphenyltetrazolium; C016299:chelerythrine; D011493:Protein Kinase C; C031049:geranylgeranylacetone