Role of interleukin-1beta in early brain injury after subarachnoid hemorrhage in mice.
Role of interleukin-1beta in early brain injury after subarachnoid hemorrhage in mice.
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DOI：
10.1161/strokeaha.109.549592
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发表时间：
2009-07
期刊：
影响因子：
8.3
通讯作者：
Zhang JH
中科院分区：
文献类型：
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作者：
Sozen T;Tsuchiyama R;Hasegawa Y;Suzuki H;Jadhav V;Nishizawa S;Zhang JH
白细胞介素（IL）-1β在蛛网膜下腔出血（SAH）后早期脑损伤（EBI）中的作用尚不清楚，尽管IL-1β在脑和脑脊液中的含量已被多次报道增加。本研究的目的是检测IL-1β失活对小鼠SAH后EBI的影响。制备SAH血管内穿孔模型，将112只小鼠分为假手术组、SAH+溶媒组和SAH+ N-Ac-Tyr-Val-Ala-Asp-氯甲基酮（Ac-YVAD-CMK，6和10 mg/kg）组。SAH后1小时腹腔内给予Ac-YVAD-CMK（IL-1β转化酶的选择性抑制剂）或溶媒。根据SAH后24 h内的死亡率、神经功能评分、24 h和72 h的脑含水量、Evans蓝染料外渗和Western blot检测SAH后24 h的IL-1β、c-Jun N-末端激酶（JNK）、基质金属蛋白酶（MMP）-9和闭合小带（ZO）-1评估EBI。与溶剂组相比，高剂量（10 mg/kg）治疗组显著改善了神经功能评分、死亡率、脑含水量和伊文思蓝染料外渗，但低剂量（6 mg/kg）治疗组没有改善。两个剂量的Ac-YVAD-CMK均能抑制IL-1β的成熟诱导，但只有高剂量组能显著抑制JNK磷酸化、MMP-9的诱导和ZO-1的降解。IL-1β的激活可能在SAH后EBI的发病机制中起重要作用。Ac-YVAD-CMK的神经血管保护作用可能是通过抑制JNK介导的MMP-9诱导和随后保护紧密连接蛋白ZO-1来提供的。
The role of interleukin (IL)-1β remains unknown in early brain injury (EBI) after subarachnoid hemorrhage (SAH), although IL-1β has been repeatedly reported to increase in the brain and cerebrospinal fluid. The aim of this study is to examine the effects of IL-1β inactivation on EBI after SAH in mice. The endovascular perforation model of SAH was produced and 112 mice were assigned to sham, SAH+ vehicle, and SAH+ N-Ac-Tyr-Val-Ala-Asp-chloromethyl ketone (Ac-YVAD-CMK, 6 and 10 mg/kg) groups. Ac-YVAD-CMK, a selective inhibitor of IL-1β converting enzyme, or vehicle was administered intraperitoneally 1 hour post-SAH. EBI was assessed in terms of mortality within 24 hours, neurological scores, brain water content at 24 and 72 hours, Evans blue dye extravasation and Western blot for IL-1β, c-Jun N-Terminal kinase (JNK), matrix metalloproteinase (MMP)-9 and zonula occludens (ZO)-1 at 24 hours after SAH. High-dose (10mg/kg), but not low-dose (6mg/kg) treatment group significantly improved neurological scores, mortality, brain water content and Evans blue dye extravasation compared with the vehicle group. Although both dosages of Ac-YVAD-CMK attenuated the mature IL-1β induction, only high-dose treatment group significantly inhibited the phosphorylation of JNK, MMP-9 induction and ZO-1 degradation. IL-1β activation may play an important role in the pathogenesis of EBI after SAH. The neurovascular protection of Ac-YVAD-CMK may be provided by the inhibition of JNK-mediated MMP-9 induction and the consequent preservation of tight junction protein ZO-1.