Caspase inhibitors prevent endothelial apoptosis and cerebral vasospasm in dog model of experimental subarachnoid hemorrhage

被引:170
作者
Zhou, CM
Yamaguchi, M
Kusaka, G
Schonholz, C
Nanda, A
Zhang, JH [1 ]
机构
[1] Louisiana State Univ, Hlth Sci Ctr, Dept Neurosurg, Shreveport, LA 71105 USA
[2] Louisiana State Univ, Hlth Sci Ctr, Dept Radiol, Shreveport, LA 71105 USA
[3] Louisiana State Univ, Hlth Sci Ctr, Dept Mol & Cellular Physiol, Shreveport, LA 71105 USA
[4] Louisiana State Univ, Hlth Sci Ctr, Dept Pharmacol & Therapeut, Shreveport, LA 71105 USA
关键词
apoptosis; caspase inhibitor; cerebral vaso-spasm; subarachnoid hemorrhage;
D O I
10.1097/00004647-200404000-00007
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Apoptosis in the endothelium of major cerebral arteries may play a role in the initiation and maintenance of cerebral vasospasm after subarachnoid hemorrhage (SAH). We tested the therapeutic effect of caspase inhibitors on endothelial apoptosis and on cerebral vasospasm in an established dog double-hemorrhage model. Thirty-one mongrel dogs were divided into five groups: control; SAH; SAH treated with vehicle [DMSO]; SAH treated with Ac-DEVD-CHO [a specific caspase-3 inhibitor] and SAH treated with Z-VAD-FMK [a broad caspase inhibitor]. The inhibitors (100 muM) were injected into the cisterna magna daily front Day 0 through Day 3. Angiography was performed on Day 0 and Day 7. Histology, TUNEL staining, and immunohistochemistry were conducted on basilar arteries collected on Day 7 after SAH. Positive staining of TUNEL, poly(ADP)-ribose polymerase (PARP), caspase-3, and caspase-8 was observed in the endothelial cells of the spastic arteries. Double fluorescence labeling demonstrated colocalization of TUNEL with caspase-3 and TNFalpha-receptor-1 (TNFR I). Ac-DEVD-CHO and Z-VAD-FMK prevented endothelial apoptosis and reduced angiographic vasospasm. The mechanism of apoptosis in endothelial cells involves TNFR1 and the caspase-8 and caspase-3 pathways. Caspase inhibitors may have potential in the treatment of cerebral vasospasm..
引用
收藏
页码:419 / 431
页数:13
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