Role of protein kinase C in neuroprotective effect of geranylgeranylacetone, a noninvasive inducing agent of heat shock protein, on delayed neuronal death caused by transient ischemia in rats.
Role of protein kinase C in neuroprotective effect of geranylgeranylacetone, a noninvasive inducing agent of heat shock protein, on delayed neuronal death caused by transient ischemia in rats.
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DOI：
10.1089/neu.2006.23.1164
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发表时间：
2006-07
影响因子：
4.2
通讯作者：
M. Fujiki;T. Hikawa;T. Abe;Susumu Uchida;M. Morishige;Kenji Sugita;Hidenori Kobayashi
中科院分区：
文献类型：
--
作者：
M. Fujiki;T. Hikawa;T. Abe;Susumu Uchida;M. Morishige;Kenji Sugita;Hidenori Kobayashi
本实验观察了热休克蛋白（HSP）诱导剂和抗溃疡剂香叶基香叶基丙酮（GGA）对短暂性双侧颈总动脉（CCA）阻断和低血压所致海马神经元迟发性死亡的保护作用（40 mm Hg）持续10分钟。为了检验口服GGA会诱导蛋白激酶C（PKC）的假设，为了诱导HSP 70的表达和对迟发性神经元死亡（DND）的保护作用，我们在双侧CCA阻断前以不同的方案给大鼠口服GGA，并在短暂缺血后7天定量评估海马CA 1区DND的程度。在缺血前48小时单次口服800 mg/kg GGA可显著减轻DND（20.0 +/- 3.81 vs. 321.0 +/- 11.01 mm（3）; p < 0.05）。在缺血前2、4或8天给予GGA时，神经元保留程度相似。GGA的这些神经保护作用可被PKC特异性抑制剂白屈菜红碱（CHE）预处理所阻断，表明PKC可能介导GGA依赖性的缺血性DND保护作用。口服GGA诱导的HSP 70表达引起PKC δ的表达，GGA预处理增强缺血诱导的HSP 70表达，这两种作用都被CHE预处理所阻止。提示单次口服GGA可诱导脑内PKC δ的表达，促进HSP 70的表达，GGA在DND的神经保护中起重要作用。单次口服GGA预处理为探讨短暂性脑缺血后海马神经元DND的保护机制提供了重要工具。
We evaluated the neuroprotective effect of geranylgeranylacetone (GGA), an antiulcer agent and inducing agent of heat-shock protein (HSP), against the delayed death of hippocampal neurons induced by transient bilateral occlusion of the common carotid artery (CCA) and hypotension (40 mm Hg) lasting for 10 min. To test the hypothesis that orally administered GGA would induce protein kinase C (PKC), leading to the expression of HSP70 and protection against delayed neuronal death (DND), we gave GGA orally to rats in various regimens prior to bilateral occlusion of the CCA, and quantitatively assessed the extent of DND in region CA1 of the hippocampus at 7 days after transient ischemia. Pretreatment with a single oral dose of GGA of 800 mg/kg at 48 h before ischemia significantly attenuated DND (20.0 +/- 3.81 vs. 321.0 +/- 11.01 mm(3); p < 0.05). A similar degree of neuron sparing occurred when GGA was given 2, 4, or 8 days before ischemia. These neuroprotective effects of GGA were prevented by pretreatment with chelerythrine (CHE), a specific inhibitor of PKC, indicating that PKC may mediate GGA-dependent protection against ischemic DND. Oral GGA-induced expression of HSP70 elicited the expression of PKCdelta, and pretreatment with GGA enhanced the ischemia-induced expression of HSP70, both of which effects were prevented by pretreatment with CHE. These results suggest that a single oral dose of GGA induces the expression of PKCdelta and promotes the expression of HSP70 in the brain, and that GGA plays an important role in neuroprotection against DND. Pretreatment with a single oral dose of GGA provides an important tool for exploring the mechanisms of neuroprotection against DND of hippocampal neurons after transient ischemia.