Specific caspase inhibitor Q-VD-OPh prevents neonatal stroke in P7 rat: a role for gender
Specific caspase inhibitor Q-VD-OPh prevents neonatal stroke in P7 rat: a role for gender
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DOI：
10.1111/j.1471-4159.2006.04269.x
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发表时间：
2007-02-01
影响因子：
4.7
通讯作者：
Charriaut-Marlangue, Christiane
中科院分区：
文献类型：
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作者：
Renolleau, Sylvain;Fau, Sebastien;Charriaut-Marlangue, Christiane
发育中的大脑缺氧缺血会导致脑损伤，并具有细胞凋亡的显着特征。在本研究中，第三代二肽基广谱半胱天冬酶抑制剂喹啉-Val-Asp(Ome)-CH2-O-苯氧基(Q-VDOPh)在7日龄大鼠单侧局部缺血再灌注模型中进行了测试。 Q-VD-OPh（1 mg/kg，腹腔注射）减少了细胞死亡，在恢复 48 小时时产生显着的神经保护作用（梗塞体积为 12.6 +/- 2.8 vs. 24.3 +/- 2.2%，p = 0.006）。缺血后 48 小时观察到的神经保护作用持续到生存期 21 天，并减轻了神经功能障碍。按性别分析显示，在左侧颈总动脉夹子移除后给予 Q-VD-OPh 时，女性受到强烈保护（6.7 +/- 3.3%，p < 0.006），而男性则没有显着效果。免疫印迹分析表明，Q-VD-OPh 在体内抑制 caspase 3 裂解为其 p17 活性形式以及 caspase 1 上调和裂解。 P7 大鼠缺血后，雄性和雌性在恢复的前 24 小时内表现出不同的时间过程和细胞色素 c 释放和活性 p17 caspase 3 的模式。相比之下，性别之间的 caspase 1 表达没有观察到显着差异。这些结果表明，缺血在再灌注后不久就会激活半胱天冬酶，并且动物的性别可能强烈影响新生儿脑损伤发病机制中的细胞凋亡途径。 Q-VD-OPh 的特异性、有效性和降低的毒性可能决定肽衍生的不可逆 caspase 抑制剂作为有前景的治疗药物的潜在用途。
Hypoxia-ischaemia in the developing brain results in brain injury with prominent features of apoptosis. In the present study, a third generation dipeptidyl broad-spectrum caspase inhibitor, quinoline-Val-Asp(Ome)-CH2-O-phenoxy (Q-VDOPh), was tested in a model of unilateral focal ischaemia with reperfusion in 7-day-old rats. Q-VD-OPh (1 mg/kg, i.p.) reduced cell death, resulting in significant neuroprotection at 48 h of recovery (infarct volume of 12.6 +/- 2.8 vs. 24.3 +/- 2.2%, p = 0.006). The neuroprotective effects observed at 48 h post- ischaemia hold up at 21 days of survival time and attenuate neurological dysfunction. Analysis by gender revealed that females were strongly protected (6.7 +/- 3.3%, p 0.006), in contrast to males in which there was no significant effect, when Q-VD-OPh was given after clip removal on the left common carotid artery. Immunoblot analysis demonstrated that Q-VD-OPh inhibits caspase 3 cleavage into its p17 active form and caspase 1 up-regulation and cleavage in vivo. Following ischaemia in P7 rats, males and females displayed different time course and pattern of cytochrome c release and active p17 caspase 3 during the first 24 h of recovery. In contrast, no significant difference was observed for caspase 1 expression between genders. These results indicate that ischaemia activates caspases shortly after reperfusion and that the sex of the animal may strongly influences apoptotic pathways in the pathogenesis of neonatal brain injury. The specificity, effectiveness, and reduced toxicity of Q-VD-OPh may determine the potential use of peptide-derived irreversible caspase inhibitors as promising therapeutics.