Intranasal delivery of caspase-9 inhibitor reduces caspase-6-dependent axon/neuron loss and improves neurological function after stroke.
Intranasal delivery of caspase-9 inhibitor reduces caspase-6-dependent axon/neuron loss and improves neurological function after stroke.
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DOI：
10.1523/jneurosci.0698-11.2011
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发表时间：
2011-06-15
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影响因子：
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通讯作者：
Troy CM
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文献类型：
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作者：
Akpan N;Serrano-Saiz E;Zacharia BE;Otten ML;Ducruet AF;Snipas SJ;Liu W;Velloza J;Cohen G;Sosunov SA;Frey WH 2nd;Salvesen GS;Connolly ES Jr;Troy CM
尽管为治疗缺血性中风开发有效的神经保护策略进行了广泛的研究，但治疗选择仍然有限。虽然caspase依赖的死亡被认为在神经元损伤中起着突出的作用，但之前还没有直接证据表明中风中活跃的启动子caspase以及这一活动的功能相关性。利用体内无偏caspase捕获技术，我们从缺血再灌注1小时内的大鼠脑中分离到了活性caspase-9。在再灌注(HPR)后4小时，通过鼻腔给药一种新的细胞膜穿透性的高特异性活性caspase-9抑制物来显示活性caspase-9的致病相关性。药物抑制caspase-9提供了神经功能保护，并将caspase-6确立为其下游靶点。表达的时间和空间模式表明，神经元caspase-9活性诱导caspase-6激活，在12hpr后介导轴突丢失，随后在24hpr内神经元死亡。总而言之，这些结果支持选择性抑制这些特定的半胱氨酸天冬氨酸酶作为治疗中风的有效策略。
Despite extensive research to develop an effective neuroprotective strategy for the treatment of ischemic stroke, therapeutic options remain limited. While caspase-dependent death is thought to play a prominent role in neuronal injury, direct evidence of active initiator caspases in stroke and the functional relevance of this activity have not previously been shown. Employing an unbiased caspase-trapping technique in vivo, we isolated active caspase-9 from ischemic rat brain within 1 hour of reperfusion. Pathogenic relevance of active caspase-9 was shown by intranasal delivery of a novel cell membrane-penetrating highly specific inhibitor for active caspase-9 at 4 hours post-reperfusion (hpr). Pharmacologic caspase-9 inhibition provided neurofunctional protection and established caspase-6 as its downstream target. The temporal and spatial pattern of expression demonstrates that neuronal caspase-9 activity induces caspase-6 activation mediating axonal loss by 12hpr followed by neuronal death within 24hpr. Collectively, these results support selective inhibition of these specific caspases as an effective therapeutic strategy for stroke.