geranylgeranylacetone and Cerebral-Hemorrhage

Previous studies have demonstrated that geranylgeranylacetone exerts neuroprotective effects in experimental intracerebral hemorrhage. This study is designed to explore the underlying mechanism.. One hundred and eighty male Sprague-Dawley rats were subjected to intracerebral hemorrhage by stereotactic injection of collagenase and were pretreated without or with different doses of geranylgeranylacetone. At 6 h, 24 h, 48 h, 72 h and 7 days after the operation, the neurological deficits were examined with the scoring scale method. To explore the underlying mechanism, wortmannin (Wort), a specific phosphatidylinositol-3 kinase (PI3K) inhibitor, was used. The protein expression of Akt was determined by Western blotting. The brain water content and the hematoma volume assessment were measured and compared among the different groups.. We first found that geranylgeranylacetone pretreatment significantly reduced neurological deficit in intracerebral hemorrhage rats, indicating its neuroprotective role. Then, we found wort treatment significantly decreased the geranylgeranylacetone-induced Akt expression level in intracerebral hemorrhage rats. Besides, wort not only reversed the effects of geranylgeranylacetone on neurological function, but also reversed the effects of geranylgeranylacetone on reducing brain edema and decreasing hematoma volume in intracerebral hemorrhage rats.. Geranylgeranylacetone exerts neuroprotective roles, at least partially, through medicating the PI3K/Akt signaling pathway in an experimental intracerebral hemorrhage rat model.

Topics: Animals; Behavior, Animal; Brain; Brain Edema; Cerebral Hemorrhage; Disease Models, Animal; Diterpenes; Hematoma; Male; Motor Activity; Neuroprotective Agents; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Proprioception; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction; Wortmannin

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.

Topics: Analysis of Variance; Animals; Brain Edema; Cell Death; Cerebral Hemorrhage; Cytokines; Disease Models, Animal; Diterpenes; Drug Administration Routes; Drug Administration Schedule; Functional Laterality; Gene Expression Regulation; HSP70 Heat-Shock Proteins; In Situ Nick-End Labeling; Male; Nerve Tissue Proteins; Neuroprotective Agents; PC12 Cells; Rats; Rats, Sprague-Dawley; Time Factors