青蒿琥酯调控NLRP3/ASC/Caspase-1信号通路减轻脑出血小鼠炎症及保护神经功能的作用研究

doi:10.12114/j.issn.1007-9572.2023.0160

中国全科医学 ›› 2023, Vol. 26 ›› Issue (33): 4194-4202.DOI: 10.12114/j.issn.1007-9572.2023.0160

青蒿琥酯调控NLRP3/ASC/Caspase-1信号通路减轻脑出血小鼠炎症及保护神经功能的作用研究

李媛¹^,², 木艳玲¹^,², 薛孟周¹^,²^,^*()

1．450000　河南省郑州市，郑州大学第二附属医院脑血管疾病科
2．450000　河南省郑州市，郑州大学医学科学院

收稿日期:2023-03-10 修回日期:2023-04-13 出版日期:2023-11-20 发布日期:2023-04-27
通讯作者: 薛孟周
作者贡献：李媛提出研究目标，负责研究的构思、设计与实施，撰写论文；李媛、木艳玲进行数据的收集与整理、统计学处理，图表的绘制与展示，论文的修订；薛孟周负责文章的质量控制与审查，监督管理，对文章整体负责。
基金资助:
国家自然科学基金资助项目(8207052870); 国家自然科学基金重点国际（地区）合作研究项目(81520108011); 国家重点研发计划项目(2018YFC1312200)

Mechanism of Artesunate Regulating NLRP3/ASC/Caspase-1 Signaling Pathway to Reduce Inflammation and Protect Neurological Function in Mice with Intracerebral Hemorrhage

LI Yuan¹^,², MU Yanling¹^,², XUE Mengzhou¹^,²^,^*()

1. Department of Cerebrovascular Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
2. School of Medical Science, Zhengzhou University, Zhengzhou 450001, China

Received:2023-03-10 Revised:2023-04-13 Published:2023-11-20 Online:2023-04-27
Contact: XUE Mengzhou

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摘要/Abstract

摘要： 背景炎症反应是脑出血（ICH）病情进展的主要因素。青蒿琥酯（ART）具有抗菌和抗炎的药理活性，ART在脑内浓度较高，但对脑出血损伤的神经保护作用尚不清楚。目的观察ICH后ART对炎症反应的影响并探讨其机制。方法 2022年3月—2023年2月选取108只8~10周雄性SPF级C57BL/6小鼠，随机分为假手术组（Sham组，n=36）、ICH对照组（ICH+Vehicle组，n=36）、ART治疗组（ICH+ART组，n=36），建立ICH模型，ICH+ART组在造模后2 h腹腔注射ART溶液150 mg·kg-1·d-1，ICH+Vehicle组腹腔注射5%碳酸氢钠溶液，连续注射3 d。观察小鼠行为学指标，HE染色观察各组小鼠脑组织损伤情况，免疫组织化学染色检测白介素（IL）6、IL-1β、髓过氧化物酶（MPO）单位面积阳性细胞数，兔抗小胶质标志物（IBA1）免疫荧光染色观察小胶质细胞/巨噬细胞的激活情况，TUNEL/NeuN免疫荧光双染色观察神经元死亡情况，蛋白质印迹法比较小鼠MPO、IL-1β、肿瘤坏死因子α（TNF-α）、NOD样受体蛋白3（NLRP3）、凋亡相关颗粒样蛋白（ASC）和半胱氨酸天冬氨酸蛋白酶1（Caspase-1）水平。结果 ICH+Vehicle组改良神经系统严重程度评分、右转弯的百分比高于Sham组，ICH+ART组低于ICH+Vehicle组（P<0.05）。HE染色结果示Sham组纹状体周围有少量血液，水肿可忽略不计，ICH+Vehicle组脑组织严重损伤，细胞间隙增加、血管周围血肿、炎性细胞浸润增加；ICH+ART组上述症状均有明显改善。ICH+Vehicle组IL-6、IL-1β、MPO单位面积阳性细胞数均高于Sham组，ICH+ART组IL-6、IL-1β、MPO单位面积阳性细胞均低于ICH+Vehicle组（P<0.05）。ICH+Vehicle组小胶质细胞/巨噬细胞激活数高于Sham组，ICH+ART组低于ICH+Vehicle组（P<0.05）。3组小鼠神经元死亡数量比较，差异有统计学意义（P<0.05），其中ICH+Vehicle组高于Sham组，ICH+ART组低于ICH+Vehicle组（P<0.05）。ICH+Vehicle组MPO、IL-1β、TNF-α、NLRP3、ASC和Caspase-1水平均高于Sham组，ICH+ART组MPO、IL-1β、TNF-α、NLRP3、ASC和Caspase-1水平均低于ICH+Vehicle组（P<0.05）。结论 ICH后ART治疗可通过靶向调节NLRP3/ASC/Caspase-1信号通路减轻小鼠纹状体炎症反应，减少小胶质细胞激活，最终减轻纹状体神经元凋亡并改善脑水肿。

关键词: 脑出血, 炎症, 青蒿琥酯, NOD样受体蛋白3, 半胱氨酸天冬氨酸蛋白酶1, 小鼠

Abstract:

Background

The inflammatory response is a major factor in the progression of intracerebral hemorrhage (ICH). Artesunate (ART) has antibacterial and anti-inflammatory pharmacological activity with high concentrations in the brain, but its neuroprotective effect on cerebral hemorrhage injury remains unclear.

Objective

To observe the effect of ART on inflammatory response after intracerebral hemorrhage and explore its mechanism.

Methods

From March 2022 to February 2023, 108 male C57BL/6 mice aged 8 to 10 weeks were selected and randomly divided into the sham-operated group (Sham group, n=36), ICH control group (ICH+Vehicle group, n=36) and ART treatment group (ICH+ART group, n=36). ICH model was established. The mice in the ICH+ART group were intraperitoneally injected with 150 mg·kg^-1·d^-1 2 h after modeling, and the mice in the ICH+Vehicle group were intraperitoneally injected with 5% sodium bicarbonate solution for 3 consecutive days. The behavioral indicators of mice were observed. The brain tissue damage of mice in each group was observed by HE staining; the number of positive cells per unit area of interleukin (IL) 6, IL-1β and myeloperoxidase (MPO) were detected by immunohistochemical staining; the activation of microglia/macrophages was observed by IBA1 immunofluorescence staining. TUNEL/NeuN immunofluorescence double staining was performed to observe neuronal death. The levels of MPO, IL-1β, tumor necrosis factor α (TNF-α), Nod-like receptor protein 3 (NLRP3), apoptosis-related granuloid protein (ASC) and cysteine aspartic protease 1 (Caspase-1) were compared by western blotting.

Results

The modified neurological severity scores and percentages of right turn of mice were higher in the ICH+Vehicle group than the Sham group, and lower in the ICH+ART group than the ICH+Vehicle group (P<0.05). HE staining results showed that there was a small amount of blood around the striatum in the Sham group and negligible edema. In the ICH+Vehicle group, brain tissue was seriously damaged, with increased intercellular space, perivascular hematoma and inflammatory cell infiltration. All of the above symptoms were significantly improved in the ICH+ART group. The numbers of IL-6, IL-1β and MPO positive cells in the ICH+Vehicle group were higher than the Sham group, the numbers of IL-6, IL-1β and MPO positive cells in the ICH+ART group were lower than the ICH+Vehicle group (P<0.05). The number of activated microglia/macrophages in the ICH+Vehicle group was higher than the Sham group, the number of activated microglia/macrophages in the ICH+ART group was lower than the ICH+Vehicle group (P<0.05). The number of neuron death in the ICH+Vehicle group was higher than the Sham group, and lower in the ICH+ART group than the ICH+Vehicle group (P<0.05). The levels of MPO, IL-1β, TNF-α, NLRP3, ASC and Caspase-1 in the ICH+Vehicle group were higher than the Sham group, the levels of MPO, IL-1β, TNF-α, NLRP3, ASC and Caspase-1 in the ICH+ART group were lower than the ICH+Vehicle group (P<0.05) .

Conclusion

ART therapy after ICH attenuates the inflammatory response of striatum and the activation of microglia in mice through targeted regulation of NLRP3/ASC/Caspase-1 signaling pathway, and ultimately reduces striatal neuronal apoptosis and improves brain edema.

Key words: Cerebral hemorrhage, Inflammation, Artesunate, NOD-like receptor 3, Caspase-1, Mouse

李媛,木艳玲,薛孟周. 青蒿琥酯调控NLRP3/ASC/Caspase-1信号通路减轻脑出血小鼠炎症及保护神经功能的作用研究[J]. 中国全科医学, 2023, 26(33): 4194-4202. DOI: 10.12114/j.issn.1007-9572.2023.0160.
LI Yuan,MU Yanling,XUE Mengzhou. Mechanism of Artesunate Regulating NLRP3/ASC/Caspase-1 Signaling Pathway to Reduce Inflammation and Protect Neurological Function in Mice with Intracerebral Hemorrhage[J]. Chinese General Practice, 2023, 26(33): 4194-4202. DOI: 10.12114/j.issn.1007-9572.2023.0160.

图/表 10

表1 3组小鼠行为学结果比较

Table 1 Comparison of behavioral results among three groups of mice

组别	只数	mNSS评分〔M（P₂₅，P₇₅），分〕	右转弯的百分比（%）
Sham组	6	0.5（0，1.0）^a	49.44±9.38^a
ICH+Vehicle组	6	8.0（5.0，8.0）	71.67±12.95
ICH+ART组	6	3.0（3.0，4.0）^a	53.33±7.67^a
H值		15.059	24.192
P值		<0.001	<0.001

图1 3组小鼠脑组织HE染色结果（×40，×200）注：ICH=脑出血，ART=青蒿琥酯；Sham组=假手术组，ICH+Vehicle组=ICH对照组，ICH+ART组=ART治疗组。

Figure 1 HE staining results of brain tissue among the 3 groups of mice

图2 3组小鼠免疫组织化学染色结果（×100）注：MPO=髓过氧化物酶，IL-1β=白介素1β，IL-6=白介素6。

Figure 2 Immunohistochemical staining results among the 3 groups of mice

表2 3组小鼠IL-6、IL-1β、MPO单位面积阳性细胞数比较（个/mm2）

Table 2 Comparison of the number of positive cells of IL-6，IL-1β and MPO per unit area among the three groups

组别	只数	MPO	IL-6	IL-1β
Sham组	6	6.06±2.56^a	24.11±2.91^a	17.06±4.37^a
ICH+Vehicle组	6	25.11±3.23	58.78±4.65	37.28±4.42
ICH+ART组	6	20.28±3.34^a	39.06±2.67^a	35.00±3.48^a
F值		188.317	439.284	130.575
P值		<0.001	<0.001	<0.001

图3 3组小鼠IBA1免疫荧光染色结果（×200）注：DAPI=4'，6-二脒基-2-苯基吲哚，IBA1=小胶质标记物。

Figure 3 IBA1 immunofluorescence staining results among the 3 groups of mice

表3 3组小鼠小胶质细胞/巨噬细胞激活数比较（个/mm2）

Table 3 Comparison of the numbers of activated microglia/macrophages among the 3 groups of mice

分组	只数	小胶质细胞/巨噬细胞激活数
Sham组	6	29.44±4.87^a
ICH+Vehicle组	6	47.67±6.63
ICH+ART组	6	35.72±2.99^a
F值		60.414
P值		<0.001

图4 3组小鼠TUNEL/NeuN免疫荧光双染色结果（×200）

Figure 4 TUNEL/NeuN immunofluorescence double staining results among the 3 groups of mice

表4 3组小鼠神经元死亡数量比较（个/mm2）

Table 4 Comparison of neuronal death among the 3 groups of mice

分组	只数	神经元死亡数量
Sham组	6	6.06±2.80^a
ICH+Vehicle组	6	20.44±2.87
ICH+ART组	6	10.22±4.11^a
F值		89.779
P值		<0.001

图5 3组小鼠MPO、IL-1β、TNF-α、NLRP3、ASC和Caspase-1蛋白表达情况注：A表示3组小鼠MPO、IL-1β、TNF-α蛋白表达情况，B表示3组小鼠NLRP3、ASC、Caspase-1蛋白表达情况；TNF-α=肿瘤坏死因子α，ASC=ASC=含CARD结构域的凋亡相关颗粒样蛋白，Caspase-1=半胱氨酸天冬氨酸蛋白酶1，Actin=肌动蛋白。

Figure 5 Expressions of MPO，IL-1β，TNF-α，NLRP3，ASC and Caspase-1 among the 3 groups of mice

表5 3组小鼠MPO、IL-1β、TNF-α、NLRP3、ASC和Caspase-1水平比较

Table 5 Comparison of the levels of MPO，IL-1β，TNF-α，NLRP3，ASC and Caspase-1 among the 3 groups of mice

分组	只数	MPO	IL-1β	TNF-α	NLRP3	ASC	Caspase-1
Sham组	5	1.00±0^a	1.00±0^a	1.00±0^a	1.00±0^a	1.00±0^a	1.00±0^a
ICH+Vehicle组	5	4.28±0.15	3.30±0.16	4.30±0.19	2.46±0.15	2.12±0.18	4.10±0.14
ICH+ART组	5	2.58±0.19^a	2.00±0.16^a	2.56±0.11^a	1.28±0.08^a	1.40±0.07^a	1.72±0.15^a
F值		684.102	399.000	851.625	300.200	130.595	940.048
P值		<0.001	<0.001	<0.001	<0.001	<0.001	<0.001

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青蒿琥酯调控NLRP3/ASC/Caspase-1信号通路减轻脑出血小鼠炎症及保护神经功能的作用研究

Mechanism of Artesunate Regulating NLRP3/ASC/Caspase-1 Signaling Pathway to Reduce Inflammation and Protect Neurological Function in Mice with Intracerebral Hemorrhage

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