Pharmacological induction of heat shock protein exerts neuroprotective effects in experimental intracerebral hemorrhage.
Heat shock proteins (HSPs) are reported to reduce inflammation and apoptosis in a variety of brain insults. Geranylgeranylacetone (GGA), developed as an antiulcer in Japan, has been known to induce HSP70 and to exert cytoprotective effects. In this study, we investigated whether GGA, as a specific HSP inducer, exerts therapeutic effects in experimentally induced intracerebral hemorrhage (ICH). ICH was induced with male Sprague-Dawley rats via the collagenase infusion. GGA (800 mg/kg) was administered via oral tube according to various schedules of treatment. The treatment with GGA, beginning before the induction of ICH and continuing until day 3, showed the reduction of brain water content and the increased level of HSP70 protein, as compared to the treatment with vehicle, although GGA started after the induction of ICH or administered as a single dose before ICH failed to up-regulate HSP70 and to reduce brain edema. The rats treated with GGA exhibited better functional recovery than those treated with vehicle. In the pre- and post- treatment group, inflammatory cells and cell death in the perihematomal regions were found to have been decreased. The treatment of GGA inhibited the mRNA expression of MMP-9, uPA, IL-6 and MIP-1, with concomitant increment of eNOS and phosphorylated STAT3 and Akt after ICH. We demonstrated that GGA induced a reduction in the brain edema along with marked inhibitory effects on inflammation and cell death after ICH.
Sinn
Dong-In
DI
Stroke and Neural Stem Cell Laboratory in the Clinical Research Institute, Stem Cell Research Center, Department of Neurology, Seoul National University Hospital, Seoul, South Korea.
Chu
Kon
K
Lee
Soon-Tae
ST
Song
Eun-Cheol
EC
Jung
Keun-Hwa
KH
Kim
Eun-Hee
EH
Park
Dong-Kyu
DK
Kang
Kyung-Mook
KM
Kim
Manho
M
Roh
Jae-Kyu
JK
D000704:Analysis of Variance; D000818:Animals; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D016923:Cell Death / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004224:Diterpenes / Q000008:administration & dosage*; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D016207:Cytokines; D004224:Diterpenes; D018840:HSP70 Heat-Shock Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C031049:geranylgeranylacetone