Uchida Susumu, Fujiki Minoru, Nagai Yasuyuki, Abe Tatsuya, Kobayashi Hidenori
Department of Neurosurgery, School of Medicine, Oita University, 1-1, Idaigaoka, Hasama-machi, 879-5593, Japan.
Neurosci Lett. 2006 Apr 3;396(3):220-4. doi: 10.1016/j.neulet.2005.11.065. Epub 2006 Jan 6.
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.
先前的研究表明，热休克蛋白（HSP）诱导剂香叶基香叶基丙酮（GGA）对缺血性损伤具有细胞保护作用。蛋白激酶C（PKC）被认为是在体外介导热休克蛋白70（HSP70）表达的一个重要因素。然而，口服GGA后体内大脑中的信号通路仍不清楚。我们测量并比较了梗死体积，以研究GGA对大鼠永久性大脑中动脉（MCA）闭塞诱导的脑梗死的影响。为了阐明PKC诱导与HSP70表达之间的关系，我们通过免疫印迹法测定了GGA给药后HSP70和PKC蛋白的含量。我们用免疫印迹法评估了特异性PKC抑制剂白屈菜红碱（CHE）预处理对PKC和HSP70蛋白表达的影响。CHE预处理可阻止GGA的神经保护作用（在缺血前48小时单次口服GGA剂量（800 mg/kg）进行预处理），这表明PKC可能介导了GGA依赖性保护作用。口服GGA诱导的HSP70表达诱导了PKCδ，并且GGA预处理增强了缺血诱导的HSP70，这两者均被CHE预处理所阻止。这些结果表明，单次口服GGA可诱导PKCδ并促进大脑中HSP70的表达，并且GGA在抗脑缺血的神经保护中起重要作用。
