Regulation of enhanced cerebrovascular expression of proinflammatory mediators in experimental subarachnoid hemorrhage via the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway.
Regulation of enhanced cerebrovascular expression of proinflammatory mediators in experimental subarachnoid hemorrhage via the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway.
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DOI：
10.1186/1742-2094-9-274
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发表时间：
2012-12-21
影响因子：
9.3
通讯作者：
Edvinsson L
中科院分区：
文献类型：
--
作者：
Maddahi A;Povlsen GK;Edvinsson L
蛛网膜下腔出血（SAH）与高发病率和死亡率相关。研究表明，相关炎症是通过丝裂原激活蛋白激酶（MAPK）途径的激活介导的，该途径在 SAH 后迟发性脑缺血的发病机制中发挥着至关重要的作用。本研究的目的首先是调查 SAH 后脑动脉壁中促炎细胞因子和基质金属蛋白酶表达改变的时间过程。其次，我们研究了 SAH 后 6 小时给予特定的丝裂原激活蛋白激酶激酶 (MEK)1/2 抑制剂 U0126 是否可以防止 MEK/细胞外信号调节激酶 1/2 通路的激活和脑血管炎症介质的上调并改善神经功能。通过将250μl自体血液注射到基底池中来诱导大鼠SAH。使用两种治疗方案经脑池给予U0126：(A)在SAH后6、12、24和36小时进行治疗，并在SAH后48小时终止实验，或(B)在SAH后6、12和24小时进行治疗，并在SAH后72小时终止实验。收获脑动脉并通过免疫组织化学研究白介素 (IL)-6、IL-1β、肿瘤坏死因子 α (TNF)α、基质金属蛋白酶 (MMP)-9 和磷酸化 ERK1/2 (pERK1/2) 水平。通过蛋白质印迹法测量 pERK1/2 的早期激活。还分析了 SAH 后的功能性神经学结果。脑动脉中IL-1β、IL-6、MMP-9和pERK1/2蛋白的表达水平随着时间的推移而升高，早期升高出现在SAH后6小时左右，晚期高峰出现在SAH后48至72小时。脑动脉中 TNFα 的表达增强从 24 小时开始，一直增加到 96 小时。此外，蛛网膜下腔出血还会导致动物感觉运动和自发行为缺陷。 SAH 后 6 小时开始使用 U0126 治疗可防止 MEK-ERK1/2 信号传导的激活。此外，U0126 显着降低 SAH 后 48 和 72 小时炎症蛋白的上调，并改善神经功能。我们发现治疗方案 A 和 B 之间没有差异。这些结果表明 SAH 诱导脑动脉壁 MEK-ERK1/2 通路的早期激活，这与促炎细胞因子和 MMP-9 的上调有关。从 SAH 后 6 小时开始，U0126 对 MEK-ERK1/2 通路的抑制可防止脑血管中细胞因子和 MMP-9 的上调，并改善神经系统结果。
Subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. It is suggested that the associated inflammation is mediated through activation of the mitogen-activated protein kinase (MAPK) pathway which plays a crucial role in the pathogenesis of delayed cerebral ischemia after SAH. The aim of this study was first to investigate the timecourse of altered expression of proinflammatory cytokines and matrix metalloproteinase in the cerebral arteries walls following SAH. Secondly, we investigated whether administration of a specific mitogen-activated protein kinase kinase (MEK)1/2 inhibitor, U0126, given at 6 h after SAH prevents activation of the MEK/extracellular signal-regulated kinase 1/2 pathway and the upregulation of cerebrovascular inflammatory mediators and improves neurological function. SAH was induced in rats by injection of 250 μl of autologous blood into basal cisterns. U0126 was given intracisternally using two treatment regimens: (A) treatments at 6, 12, 24 and 36 h after SAH and experiments terminated at 48 h after SAH, or (B) treatments at 6, 12, and 24 h after SAH and terminated at 72 h after SAH. Cerebral arteries were harvested and interleukin (IL)-6, IL-1β, tumor necrosis factor α (TNF)α, matrix metalloproteinase (MMP)-9 and phosphorylated ERK1/2 (pERK1/2) levels investigated by immunohistochemistry. Early activation of pERK1/2 was measured by western blot. Functional neurological outcome after SAH was also analyzed. Expression levels of IL-1β, IL-6, MMP-9 and pERK1/2 proteins were elevated over time with an early increase at around 6 h and a late peak at 48 to 72 h post-SAH in cerebral arteries. Enhanced expression of TNFα in cerebral arteries started at 24 h and increased until 96 h. In addition, SAH induced sensorimotor and spontaneous behavior deficits in the animals. Treatment with U0126 starting at 6 h after SAH prevented activation of MEK-ERK1/2 signaling. Further, U0126 significantly decreased the upregulation of inflammation proteins at 48 and 72 h following SAH and improved neurological function. We found no differences between treatment regimens A and B. These results show that SAH induces early activation of the MEK-ERK1/2 pathway in cerebral artery walls, which is associated with upregulation of proinflammatory cytokines and MMP-9. Inhibition of the MEK-ERK1/2 pathway by U0126 starting at 6 h post-SAH prevented upregulation of cytokines and MMP-9 in cerebral vessels, and improved neurological outcome.
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影响因子：
2.5
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