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医药导报  2019, Vol. 38 Issue (6): 700-705    DOI: 10.3870/j.issn.1004-0781.2019.06.003
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丹参酮ⅡA对神经病理性疼痛大鼠的影响*
沈亦萱1(),马玉清1(),马越2,张红1,霍斌1,王晓庆1
1.兰州大学第一医院麻醉科,兰州 730000
2.兰州大学第一临床医学院 2015级临床医学1班,兰州 730000
Effection of Tanshinone ⅡA on Neuropathic Pain Model of Rats
Yixuan SHEN1(),Yuqing MA1(),Yue MA2,Hong ZHANG1,Bin HUO1,Xiaoqing WANG1
1.Department of Anesthesiology, the First Hospital of Lanzhou University, Lanzhou 730000, China
2.Class One Grade 2015 Clinical Medicine, the First Clincial Medical College of Lanzhou University, Lanzhou 730000, China
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摘要 

目的 观察丹参酮ⅡA(Tan ⅡA)对神经病理性疼痛模型(SNL)大鼠脊髓组织高迁移率族蛋白B1(HMGB1)、Toll 样受体4(TLR4) 和肿瘤坏死因子-α(TNF-α)、白细胞介素1β(IL-l β)和白细胞介素10(IL-10)表达的影响,探讨Tan ⅡA对神经病理性疼痛的作用及其机制。方法 成年雄性SD大鼠54只,随机分为 3 组:假手术组、模型对照组和Tan ⅡA组(术后腹腔注射Tan ⅡA 30 mg·kg-1·d-1),分别于术前1 d,术后第3,7,14 天测试机械痛阈和热痛阈后,取 L4~L6 脊髓,置于液氮中迅速冷冻。实时荧光定量 PCR 和 Western blotting 检测脊髓 HMGB1、TLR4 mRNA 和蛋白的表达,酶联免疫吸附测定(ELISA) 法检测脊髓 TNF-α、IL-lβ和 IL-10 蛋白的表达情况。结果 与假手术组比较,模型对照组、Tan ⅡA组在术后第3,7,14 天机械痛阈和热痛阈降低,脊髓HMGB1,TLR4 mRNA 和蛋白表达上调(P<0.05)。与模型对照组比较,Tan ⅡA组在术后第3,7,14 天机械痛阈和热痛阈升高,脊髓HMGB1、TLR4 mRNA 和蛋白表达下调(P<0.05)。与假手术组比较,模型对照组、Tan ⅡA组在术后第3,7,14 天脊髓TNF-α、IL-1β表达上调(P<0.05),而IL-10表达下调(P<0.05)。与模型对照组比较,Tan ⅡA组在术后第3,7,14 天脊髓TNF-α、IL-1β表达下调(P<0.05),IL-10表达上调,行为学指标改善(P<0.05)。结论 丹参酮ⅡA 能减轻大鼠神经病理性疼痛,可能机制是在分子水平抑制 HMGB1-TLR4 信号通路及其下游的细胞因子,HMGB1-TLR4信号通路可能与神经病理性疼痛有关,是治疗神经病理性疼痛的靶点。

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沈亦萱
马玉清
马越
张红
霍斌
王晓庆
关键词 丹参酮ⅡA;疼痛神经病理性高迁移率族蛋白B1Toll 样受体4细胞因子    
Abstract

Objective Detect the expression level of HMGB1,TLR4,TNF-α,IL-1β and IL-10 in spinal cord tissue of neuropathic pain model rat after tanshinone ⅡA treated to explore its effect on neuropathic pain and the mechanisms. Methods A total of 54 males Sprague-Dawley (SD) rats were randomly divided into three groups:sham-operated group , model control group, and Tan ⅡA group.Tan ⅡA was administered intraperitoneally to rats in Tan ⅡA group at a dose of 30 mg·kg-1 daily for 14 days after surgery.The pain threshold was measured 1 day before SNL (baseline) and 3, 7, and 14 days after surgery.The expressions of HMGB1, TLR4 mRNA and protein in lumbar spinal cord 4-6(L4-L6) were assessed by RT-PCR and Western blotting, respectively.The levels of TNF-α, IL-1β and IL-10 in the spinal cord were detected by ELISA. Results The paw withdrawl threshold (PWT) and paw withdrawl latency (PWL) were significantly decreased after SNL (P<0.05) .The expressions of TLR4, HMGB1 mRNA and protein were significantly increased (P<0.05),and the levels of TNF-α, IL-1β were significantly increased after SNL compared with those in the sham-operated group (P<0.05).After Tan ⅡA treatment, HMGB1 and TLR4 mRNA and protein levels were reduced significantly (P<0.05).TNF-α and IL-1β were downregulated, but IL-10 was upregulated in the spinal cords of SNL-induced rats (P<0.05),which was accompanied by improvement of pain behaviours in the Tan ⅡA group (P<0.05). Conclusion These results indicate Tanshinone ⅡA inhibited SNL-induced neuropathic pain via multiple effects, the possible mechanism is that HMGB1-TLR4 signal transduction pathway and its downstream cytokines are inhibited at the molecular level.It also suggesting that HMGB1-TLR4 signal transduction pathway may be related to neuropathic pain and is a target for the treatment of neuropathic pain.

Key wordsTanshinone ⅡA;    Neuropathic pain    High mobility group box 1 protein    Toll-like receptor 4    Proinflammatory cytokines
收稿日期: 2018-02-20      出版日期: 2019-06-11
基金资助:*甘肃省自然科学基金资助项目(1606RJZA125)
引用本文:   
沈亦萱,马玉清,马越,张红,霍斌,王晓庆. 丹参酮ⅡA对神经病理性疼痛大鼠的影响*[J]. 医药导报, 2019, 38(6): 700-705.
Yixuan SHEN,Yuqing MA,Yue MA,Hong ZHANG,Bin HUO,Xiaoqing WANG. Effection of Tanshinone ⅡA on Neuropathic Pain Model of Rats. Herald of Medicine, 2019, 38(6): 700-705.
链接本文:  
http://www.yydbzz.com/CN/10.3870/j.issn.1004-0781.2019.06.003      或      http://www.yydbzz.com/CN/Y2019/V38/I6/700
目的
基因
扩增
长度/bp
引物 序列
HMGB1 218 上游引物 5'AGC AAT CTG AAC GTC TGT CC 3'
下游引物 5'GTT CTT GTG ATA GCC TTC GC 3'
TLR4 356 上游引物 5'GCC GGA AAG TTA TTG TGG TGG T 3'
下游引物 5'ATG GGT TTT AGG CGC AGA GTT T 3'
β-actin 372 上游引物 5'GCC ATG TAC GTA GCC ATC CA 3'
下游引物 5'GAA CCG CTC ATT GCC GAT AG 3'
表1  目的基因引物、序列和长度
图1  3组大鼠不同时间PWT和PWL变化($\bar{x}±s$,n=6)
与假手术组比较,*1P<0.01;与模型对照组比较,*2P<0.01
图2  3组大鼠SNL术后不同时间点 HMGB1和 TLR4 mRNA表达($\bar{x}±s$,n=6)
与假手术组比较,*1P<0.05;与模型对照组比较,*2P<0.05
图3  3组大鼠SNL术后不同时间点HMGB1蛋白的表达变化
与假手术组比较,*1P<0.05;与模型对照组比较,*2P<0.05
图4  3组大鼠SNL术后不同时间点TLR4蛋白的表达($\bar{x}±s$,n=6)
与假手术组比较,*1P<0.05;与模型对照组比较,*2P<0.05
图5  3组SNL术后大鼠脊髓TNF-α、IL-1β和IL-10的表达变化($\bar{x}±s$,n=6)
与假手术组比较,*1P<0.05;与模型对照组比较,*2P<0.05
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