Pretreatment with low-dose fimasartan ameliorates NLRP3 inflammasome-mediated neuroinflammation and brain injury after intracerebral hemorrhage.
Pretreatment with low-dose fimasartan ameliorates NLRP3 inflammasome-mediated neuroinflammation and brain injury after intracerebral hemorrhage.
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DOI：
10.1016/j.expneurol.2018.08.013
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发表时间：
2018-12
影响因子：
5.3
通讯作者：
Yoon BW
中科院分区：
文献类型：
--
作者：
Yang X;Sun J;Kim TJ;Kim YJ;Ko SB;Kim CK;Jia X;Yoon BW
含核甘酸结合和寡聚化结构域样受体家族pyrin结构域3（NLRP 3）炎性小体由NLRP 3结构域、含CARD结构域的衔接分子凋亡相关斑点样蛋白（ASC）和半胱氨酸蛋白酶原-1（procaspase-1）组成，在脑出血继发性损伤的免疫病理生理中起重要作用。本研究旨在探讨卒中前使用血管紧张素II受体阻滞剂非马沙坦治疗是否通过抑制NLRP 3炎性体的激活对ICH具有抗炎作用。将Sprague-Dawley大鼠分为5组：假手术组、溶媒组、低剂量（0.5 mg/kg）和常规剂量（1.0和3.0 mg/kg）非马沙坦组。这些大鼠在诱导胶原酶诱导的ICH之前治疗30天，并在手术后连续治疗3天。非马沙坦低剂量组的平均血压（BP）与对照组无显著差异，常规剂量组的BP以剂量依赖方式降低。低剂量非马沙坦预处理可减轻ICH诱导的水肿，改善神经功能。小剂量非马沙坦可显著降低脑出血后NLRP 3/ASC/caspase-1和NF-κB通路的激活。脑细胞的双重免疫荧光染色显示，通过非马沙坦处理，NLRP 3与Iba 1（小胶质细胞标志物）阳性细胞的共定位显著降低。培养的小胶质细胞刺激的溶血产物表现出显着的炎性体的激活，这是减少了非马沙坦。低剂量非马沙坦预处理通过抑制NLRP 3炎性小体而不降低MBP来减轻急性ICH后的脑损伤。我们的研究表明，卒中前给予非马沙坦可能通过靶向炎性小体减轻ICH诱导的继发性脑损伤。
Nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which is composed of an NLRP3 domain, the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC) domain, and procaspase-1, plays an important role in the immune pathophysiology of the secondary damage induced by intracerebral hemorrhage (ICH). This study aims to investigate whether pre-stroke treatment with fimasartan, an angiotensin II receptor blocker, has anti-inflammatory effects on ICH by inhibiting the activation of the NLRP3 inflammasome. Sprague-Dawley rats were divided into five groups: sham, vehicle, low-dose (0.5 mg/kg) and regular-doses (1.0 and 3.0 mg/kg) fimasartan. These rats were treated for 30 days before the induction of collagenase-induced ICH and continuously 3 days after surgery. The mean blood pressure (BP) in the low-dose fimasartan group was not significantly different from that of control, and BP in the regular-dose groups was decreased in a dose-dependent manner. Pretreatment with low-dose fimasartan attenuated ICH-induced edema and improved neurological functions. Activation of the NLRP3/ASC/caspase-1 and the NF-κB pathways after ICH was markedly reduced by low-dose fimasartan. The double immunofluorescence staining of brain cells showed a significant decrease in the co-localization of NLRP3 with Iba1 (microglia marker) positive cells by fimasartan treatment. Cultured microglia cells stimulated by hemolysate demonstrated significant activation of the inflammasome, which was reduced by fimasartan. Pretreatment with a low-dose fimasartan alleviated brain damage after acute ICH by inhibiting the NLRP3 inflammasome without lowering MBP. Our study suggests pre-stroke administration of fimasartan could potentially attenuate ICH-induced secondary brain injury by targeting the inflammasome.
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影响因子：
11.2
作者：
Ma, Qingyi;Chen, Sheng;Hu, Qin;Feng, Hua;Zhang, John H.;Tang, Jiping
通讯作者：
Tang, Jiping
影响因子：
6.3
作者：
Abulafia, Denise P.;Vaccari, Juan Pablo de Rivero;Dietrich, W. Dalton
通讯作者：
Dietrich, W. Dalton
DOI：
10.1016/s1474-4422(12)70104-7
发表时间：
2012-08
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Keep RF;Hua Y;Xi G
通讯作者：
Xi G
影响因子：
9.3
作者：
Feng L;Chen Y;Ding R;Fu Z;Yang S;Deng X;Zeng J
通讯作者：
Zeng J
影响因子：
30.5
作者：
通讯作者：
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