Neutrophil elastase inhibitor attenuates hippocampal neuronal damage after transient forebrain ischemia in rats
Neutrophil elastase inhibitor attenuates hippocampal neuronal damage after transient forebrain ischemia in rats
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DOI：
10.1016/j.brainres.2008.12.070
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发表时间：
2009-03-09
期刊：
影响因子：
2.9
通讯作者：
Sakabe, Takefumi
中科院分区：
文献类型：
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作者：
Matayoshi, Hiroaki;Hirata, Takao;Sakabe, Takefumi
在实验动物脑缺血后，已知炎症反应有助于神经元损伤的发展。此外，血浆中的中性粒细胞弹性蛋白酶活性在急性脑梗死患者中升高。为了阐明中性粒细胞弹性蛋白酶是否分布到脑实质中并加剧缺血后的神经元损伤，我们研究了特异性中性粒细胞弹性蛋白酶抑制剂ONO-5046对海马CA 1区神经元死亡的影响，这些影响与血浆中中性粒细胞弹性蛋白酶活性及其在脑中的分布以及caspase-3/7活性有关。在大鼠前脑缺血8分钟后给予ONO-5046（5和10 mg/kg）或盐水（对照组）。缺血后7天海马CA 1中存活神经元的比率（中位数，[范围]）在ONO-5046 5 mg/kg组（31% [12-57%]）和10 mg/kg组（69% [39-76%]）中显著高于对照组（3.2% [0-10%]）。ONO-5046 10 mg/kg组中的血浆中性粒细胞弹性蛋白酶活性显著低于对照组（14 [11-25] vs.41（35-68）nmol/ml）。在对照组中，中性粒细胞弹性蛋白酶分布在海马CA 1神经元层的细胞外空间中，而在ONO-5046 10 mg/kg组中，仅在内皮中检测到痕量的中性粒细胞弹性蛋白酶。在对照组中，在缺血超过8小时后，Caspase-3/7活性升高，而在ONO-5046 10 mg/kg组中，未观察到升高。结果表明，中性粒细胞弹性蛋白酶可能有助于前脑缺血后海马CA 1区神经元死亡，中性粒细胞弹性蛋白酶抑制剂减弱神经元死亡。(C)2009 Elsevier B. V.保留所有灯光。
Inflammatory responses have been known to contribute to the development of neuronal damage after brain ischemia in experimental animals. Also, neutrophil elastase activity in the plasma has been elevated in the patients with acute cerebral infarction. In order to clarify whether neutrophil elastase distributes into the brain parenchyma and exacerbates neuronal damage following ischemia, we examined the effects of specific neutrophil elastase inhibitor, ONO-5046, on hippocampal CA1 neuronal death in relation to neutrophil elastase activity in the plasma and its distribution in the brain and to caspase-3/7 activity. ONO-5046 (5 and 10 mg/kg) or saline (control group) was administrated after 8 min of forebrain ischemia in rats. Ratio of surviving neurons (median, [range]) in hippocampal CA1 seven days after ischemia was significantly higher in the ONO-5046 5 mg/kg (31% [12-57%]), and 10 mg/kg groups (69% [39-76%]) than in the control group (3.2% [0-10%]). Plasma neutrophil elastase activity in the ONO-5046 10 mg/kg group was significantly lower than in the control group (14 [11-25] vs. 41 (35-68) nmol/ml). Neutrophil elastase distributed in the extracellular space in the hippocampal CA1 neuronal layer in the control group, while, in the ONO-5046 10 mg/kg group, trace of neutrophil elastase was detected only in the endothelium. Caspase-3/7 activity was elevated after ischemia over 8 h in the control group, while, in the ONO-5046 10 mg/kg group, no elevation was observed. The results suggest that neutrophil elastase may contribute to neuronal death in hippocampal CA1 following forebrain ischemia and that neutrophil elastase inhibitor attenuates neuronal death. (C) 2009 Elsevier B.V. All lights reserved.