Antivasospastic and antiinflammatory effects of caspase inhibitor in experimental subarachnoid hemorrhage
Antivasospastic and antiinflammatory effects of caspase inhibitor in experimental subarachnoid hemorrhage
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DOI：
10.3171/jns-07/07/0128
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发表时间：
2007-07-01
影响因子：
4.1
通讯作者：
Date, Isao
中科院分区：
文献类型：
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作者：
Iseda, Keiichi;Ono, Shigeki;Date, Isao
Object.蛛网膜下腔的炎症和动脉内皮细胞的凋亡与蛛网膜下腔出血后迟发性脑血管痉挛的发生有关。作者研究了N-苄基-氧羰基-Val-Ala-Asp-fluoromethylketone（Z-VAD-FMK）可能的抗血管痉挛作用的机制，Z-VAD-FMK是一种半胱天冬酶抑制剂，可抑制炎症和凋亡系统。在SAH的动物模型中。将家兔分为三组，每组8只动物，通过向枕大池注射血液进行SAH。实验在以下组中进行：仅SAH、SAH +媒介物和SAH + Z-VAD-FMK。在SAH诱导前鞘内给予Z-VAD-FMK（1 mg）或溶媒（5%二甲亚砜）。在SAH前和SAH后2天获得的血管造影片上测量基底动脉（BA）的直径。第2天的BA直径表示为SAH前的百分比。使用蛋白质印迹法检测脑脊液（CSF）中的白细胞介素（IL）-1 β，并对脑进行半胱天冬酶-1和IL-1 β的免疫组织化学检测。在另一项实验中，20只大鼠进行SAH，并对他们的大脑进行半胱天冬酶-1，IL-1 β和巨噬细胞的化学评估。Z-VAD-FMK能明显减轻兔脑血管痉挛（仅SAH组、SAH +溶媒组和SAH + Z-VAD-FMK组第2天的BA直径分别为基线的66.6 +/-3.2%、66.3 +/-3.7%和82.6 +/- 4.9%），并抑制IL-1 β释放到CSF中，还抑制浸润到蛛网膜下腔的巨噬细胞中半胱天冬酶- I和IL-1 β的免疫反应性。免疫组化结果显示，在大鼠浸润性巨噬细胞中观察到caspase- I和IL-1 β的免疫反应性。这些结果表明，caspase激活可能通过炎症反应参与了SAH诱导的血管痉挛的发展。
Object. Inflammation in the subarachnoid space and apoptosis of arterial endothelial cells have been implicated in the development of delayed cerebral vasospasm after subarachnoid hemorrhage (SAH). The authors investigated mechanisms of possible antivasospastic effects of N-benzyl-oxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK), a caspase inhibitor that can inhibit both inflammatory and apoptotic systems., in animal models of SAH.Methods. Rabbits were assigned to three groups of eight animals each and were subjected to SAH by injection of blood into the cisterna magna. The experiments were performed in the following groups: SAH only, SAH + vehicle, and SAH + Z-VAD-FMK. The Z-VAD-FMK (1 mg) or vehicle (5% dimethyl sulfoxide) was intrathecally administered before SAH induction. Diameters of the basilar artery (BA) were measured on angiograms obtained before and 2 days after SAH. The BA diameter on Day 2 was expressed as a percentage of that before SAH. Interleukin (IL)-1 beta in the cerebrospinal fluid (CSF) was examined using Western blotting, and brains were immunohistochemically examined for caspase-1 and IL-1 beta. In a separate experiment, 20 rats were subjected to SAH and their brains were immunohistochemically assessed for caspase-1, IL-1 beta, and macrophages.Results. In rabbits, Z-VAD-FMK significantly attenuated cerebral vasospasm (the BA diameter on Day 2 in SAH-only, SAH + vehicle, and SAH + Z-VAD-FMK groups was 66.6 +/- 3.2%, 66.3 +/- 3.7%, and 82.6 +/- 4.9% of baseline, respectively), and suppressed IL-1 beta release into the CSF and also suppressed immunoreactivities of caspase- I and IL-1 beta in macrophages infiltrating into the subarachnoid space. Immunoreactivities for caspase- I and IL-1 beta were observed in immunohistochemically proven infiltrating macrophages in rats.Conclusions. These results indicate that caspase activation may be involved in the development of SAH-induced vasospasm through inflammatory reaction.