Department of Neurology, Seoul National University Hospital, Seoul 03080, Republic of Korea; Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea; Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea; Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, 130000 Jilin, China.
Exp Neurol. 2018 Dec;310:22-32. doi: 10.1016/j.expneurol.2018.08.013. Epub 2018 Aug 29.
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.
核苷酸结合寡聚化结构域样受体家族富含吡喃结构域蛋白 3（NLRP3）炎性小体由 NLRP3 结构域、衔接子分子含 CARD（ASC）结构域的凋亡相关斑点样蛋白和前胱天蛋白酶-1 组成，在脑出血（ICH）引起的继发性损伤的免疫病理生理学中发挥重要作用。本研究旨在探讨血管紧张素 II 受体阻滞剂富马沙坦在缺血性脑卒中前治疗是否通过抑制 NLRP3 炎性小体的激活对 ICH 具有抗炎作用。将 Sprague-Dawley 大鼠分为五组：假手术组、假手术对照组、低剂量（0.5mg/kg）富马沙坦组、常规剂量（1.0 和 3.0mg/kg）富马沙坦组。这些大鼠在胶原酶诱导 ICH 诱导前治疗 30 天，并在手术后连续 3 天治疗。低剂量富马沙坦组的平均血压（BP）与对照组无显著差异，而常规剂量组的 BP 呈剂量依赖性下降。低剂量富马沙坦预处理可减轻 ICH 诱导的水肿并改善神经功能。低剂量富马沙坦显著降低 ICH 后 NLRP3/ASC/caspase-1 和 NF-κB 通路的激活。细胞双重免疫荧光染色显示富马沙坦处理后 NLRP3 与 Iba1（小胶质细胞标志物）阳性细胞的共定位明显减少。溶血物刺激的培养小胶质细胞显示炎性小体明显激活，富马沙坦可降低其激活。低剂量富马沙坦预处理可通过抑制 NLRP3 炎性小体减轻急性 ICH 后的脑损伤，而不降低 MBP。我们的研究表明，缺血性脑卒中前给予富马沙坦可能通过靶向炎性小体减轻 ICH 引起的继发性脑损伤。
