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Article(id=1198558168470090614, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198558165093675863, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.1164.2024.0202, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1693584000000, receivedDateStr=2023-09-02, revisedDate=null, revisedDateStr=null, acceptedDate=1696608000000, acceptedDateStr=2023-10-07, onlineDate=1763688135496, onlineDateStr=2025-11-21, pubDate=1724774400000, pubDateStr=2024-08-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763688135496, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763688135496, creator=13701087609, updateTime=1763688135496, updator=13701087609, issue=Issue{id=1198558165093675863, tenantId=1146029695717560320, journalId=1189873630562394117, year='2024', volume='49', issue='8', pageStart='855', pageEnd='976', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763688134691, creator=13701087609, updateTime=1763689174168, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1198562525043327039, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198558165093675863, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1198562525043327040, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198558165093675863, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=914, endPage=921, ext={EN=ArticleExt(id=1198558169451557757, articleId=1198558168470090614, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Promotion mechanism of astragaloside on axon repair and regeneration in experimental autoimmune encephalomyelitis mice, columnId=1190310110212751762, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Basic Research, runingTitle=null, highlight=null, articleAbstract=

Objective To investigate the effects of astragaloside Ⅳ (AS-Ⅳ) on axon growth inhibitory factor A (Nogo-A) and its downstream pathway protein RHO-associated coiled spiral kinase 2 (ROCK2) in experimental autoimmune encephalomyelitis (EAE) mice, and to explore the mechanism by which it promotes axon repair and regeneration. Methods EAE model was induced in C57BL/6 female mice by subcutaneous injection of myelin oligodendrocyte glycoprotein 35-55 (MOG35-55). Mice were randomly divided into EAE group and AS-Ⅳ group (n=8 per group). EAE group received intraperitoneal injection of PBS on the 3rd day post-immunization, while AS-Ⅳ group was administered AS-Ⅳ at a dosage of 30mg/(kg.d) once daily, 0.2 ml per injection, for 25 consecutive days. On the 28th day post-immunization, the expression levels of growth-associated protein 43 (GAP-43), neuronal core antigen (NeuN), microtubule associated protein 2 (MAP-2), glial fibroacidic protein (GFAP), and Iba1 in the spinal cord were detected using immunofluorescence assay. Real-time fluorescence quantitative PCR (qRT-PCR) was conducted to detect mRNA expression levels of GAP-43, Nogo-A, and Nogo receptor (NgR) genes. Western blotting was utilized to determine the expression levels of GAP-43, Nogo-A, ROCK2, phosphorylated myosin phosphatase (p-MYPT1), B-lymphoblastoma-2 (Bcl-2), and Bcl-2 associated X protein (Bax). Results Compared with EAE group, AS-Ⅳ treatment significantly reduced the positive cell expression rates of Iba1 microglia and GFAP astrocyte in spinal cord (P<0.01 and P<0.001,respectively), while it also increased the positive expression rates of NeuN and MAP-2 (P<0.001 and P<0.05, respectively). The treatment also upregulated the expression level of anti-apoptotic factor Bcl-2 (P<0.001) and downregulated the expression level of pro-apoptotic factor Bax (P<0.05), leading to an increase in Bcl-2/Bax ratio (P<0.05). Furthermore, AS-Ⅳ enhanced the expression of GAP-43 protein (P<0.05) and decreased the mRNA expression levels of neuroregeneration inhibitor Nogo receptor (NgR) and ROCK2 gene (P<0.001, P<0.05, respectively); as well as decreased the expression levels of Nogo-A, ROCK2 and p-MYPT1 proteins (P<0.05, P<0.001). Conclusion AS-IV may inhibit the activation of microglia and astrocytes and neuronal apoptosis in EAE mice by inhibiting Nogo-A and downstream pathway ROCK2, thereby promoting the expression of GAP-43, NeuN and MAP-2, alleviating neuronal damage, and facilitating axon repair and regeneration.

, correspAuthors=Cun-Gen Ma, authorNote=null, correspAuthorsNote=
E-mail:
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目的 观察黄芪甲苷(AS-Ⅳ)对实验性自身免疫性脑脊髓炎(EAE)小鼠轴突生长抑制因子A(Nogo-A)及其下游通路蛋白Rho相关卷曲螺旋激酶2(ROCK2)的影响，探究其对轴突修复和再生的促进作用机制。方法 采用髓鞘少突胶质细胞糖蛋白35-55多肽(MOG35-55)皮下注射C57BL/6雌性小鼠制备EAE 模型；将小鼠随机分为EAE组、AS-Ⅳ组，每组8只。于免疫后第3天开始，EAE组腹腔注射PBS；AS-Ⅳ组腹腔注射AS-Ⅳ 30 mg/(kg.d)，1次/d，0.2 ml/次，连续给药25 d。免疫后第28天，取小鼠脊髓，采用免疫荧光法检测脊髓中生长相关蛋白43(GAP-43)、神经元核心抗原(NeuN)、微管相关蛋白2(MAP-2)、胶质纤维酸性蛋白(GFAP)和离子钙结合衔接分子1(Iba1)的表达水平；实时荧光定量PCR(qRT-PCR)检测GAP-43、Nogo-A、Nogo 受体(NgR)基因mRNA 表达水平；Western blotting检测GAP-43、Nogo-A、ROCK2、磷酸化肌球蛋白磷酸酶(p-MYPT1)、B淋巴细胞瘤-2(Bcl-2)蛋白和Bcl-2关联X蛋白(Bax)表达水平。结果 与EAE组比较，AS-Ⅳ组小鼠脊髓中星形胶质细胞GFAP和小胶质细胞Iba1的阳性表达率均明显下降(P<0.01，P<0.001)；NeuN和MAP-2阳性表达率均增高(P<0.001，P<0.05)；抗凋亡因子Bcl-2表达水平增高(P<0.001)，促凋亡因子Bax表达水平降低(P<0.05)，Bcl-2/Bax比值升高(P<0.05)；GAP-43蛋白表达水平增高(P<0.05)；神经再生抑制因子NgR和ROCK2 基因mRNA表达水平均下调(P<0.001，P<0.05)；Nogo-A、ROCK2和p-MYPT1蛋白表达水平均降低(P<0.05或P<0.001)。结论 AS-Ⅳ可通过抑制Nogo-A及其下游通路分子ROCK2，抑制EAE小鼠小胶质细胞和星形胶质细胞的激活及神经元凋亡，进而促进GAP-43、NeuN及MAP-2的表达，减轻神经元损伤，促进轴突修复和再生。

, correspAuthors=马存根, authorNote=null, correspAuthorsNote=
马存根，E-mail：
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刘建春，理学硕士，教授，主要从事神经系统形态学方面的研究

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刘建春，理学硕士，教授，主要从事神经系统形态学方面的研究

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刘建春，理学硕士，教授，主要从事神经系统形态学方面的研究

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AS-Ⅳ. 黄芪甲苷；EAE. 实验性自身免疫性脑脊髓炎；GFAP. 胶质纤维酸性蛋白；Iba1. 离子钙结合衔接分子1；与EAE组比较，**P<0.01，***P<0.001

, figureFileSmall=A8UdDVMAxh9mawpRIx/upQ==, figureFileBig=4l7A8MMJRvO51kaA4vjtnw==, tableContent=null), ArticleFig(id=1198558176753840346, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558168470090614, language=EN, label=Fig.2, caption=The effects of AS-Ⅳ on neuronal damage and axonal loss induced by EAE in mice, figureFileSmall=k0GyljQYKsMltFnf1Ql6Lw==, figureFileBig=62pIZ4znOImT5Uio10jxtA==, tableContent=null), ArticleFig(id=1198558176854503648, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558168470090614, language=CN, label=图2, caption=AS-Ⅳ对EAE诱导的小鼠神经元损伤与轴突脱失的影响

AS-Ⅳ. 黄芪甲苷；EAE. 实验性自身免疫性脑脊髓炎；NeuN. 神经元核心抗原；MAP-2. 微管相关蛋白2；与EAE组比较，*P<0.05，***P<0.001

, figureFileSmall=k0GyljQYKsMltFnf1Ql6Lw==, figureFileBig=62pIZ4znOImT5Uio10jxtA==, tableContent=null), ArticleFig(id=1198558176992915684, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558168470090614, language=EN, label=Fig.3, caption=The effects of AS-Ⅳ on proteins related of neuron apoptosis induced by EAE in mice (Western blotting), figureFileSmall=PLiCqgtP79+I3v+z3wfgOw==, figureFileBig=oXt5mfby1aB8cMZvy3elww==, tableContent=null), ArticleFig(id=1198558178133766373, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558168470090614, language=CN, label=图3, caption=AS-Ⅳ对EAE诱导的小鼠神经元凋亡相关蛋白的影响(Western blotting)

EAE. 实验性自身免疫性脑脊髓炎；AS-Ⅳ. 黄芪甲苷；Bcl-2. B淋巴细胞瘤-2蛋白；Bax. Bcl-2关联X蛋白；GAPDH. 甘油醛-3-磷酸脱氢酶；A. Bcl-2与Bax蛋白相对表达水平；B. Bcl-2与Bax表达量的比值；与EAE组比较，*P<0.05，***P<0.001

, figureFileSmall=PLiCqgtP79+I3v+z3wfgOw==, figureFileBig=oXt5mfby1aB8cMZvy3elww==, tableContent=null), ArticleFig(id=1198558178242818282, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558168470090614, language=EN, label=Fig.4, caption=The effects of AS-Ⅳ on expression of GAP-43 protein in spinal cord of mice with EAE, figureFileSmall=kL6cFd/2tup0i/18LUxltA==, figureFileBig=n4wSNJYCpy80m1OMXehZYA==, tableContent=null), ArticleFig(id=1198558178410590450, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558168470090614, language=CN, label=图4, caption=AS-Ⅳ对EAE小鼠脊髓中GAP-43表达的影响

AS-Ⅳ. 黄芪甲苷；EAE. 实验性自身免疫性脑脊髓炎；GAP-43. 生长相关蛋白43；GAPDH. 甘油醛-3-磷酸脱氢酶；A. GAP-43阳性表达情况(免疫荧光)；B. GAP-43 mRNA相对表达水平(qRT-PCR)；C. GAP-43 蛋白表达水平(Western blotting)；与EAE组比较，*P<0.05，***P<0.001

, figureFileSmall=kL6cFd/2tup0i/18LUxltA==, figureFileBig=n4wSNJYCpy80m1OMXehZYA==, tableContent=null), ArticleFig(id=1198558178649665784, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558168470090614, language=EN, label=Fig.5, caption=The effects of AS-Ⅳ on expression of Nogo-A and ROCK2 in mice with EAE, figureFileSmall=28xVzbHFePuYngz+ycr8dQ==, figureFileBig=3GRcbwDdH1q7HzLMm9fGXw==, tableContent=null), ArticleFig(id=1198558178750329084, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558168470090614, language=CN, label=图5, caption=AS-Ⅳ对EAE小鼠Nogo-A和ROCK2表达的影响

EAE. 实验性自身免疫性脑脊髓炎；AS-Ⅳ. 黄芪甲苷；Nogo-A. 神经抑制因子A；NgR. Nogo 受体；ROCK2. Rho相关卷曲螺旋激酶2；p-MYPT1. 磷酸化肌球蛋白磷酸酶；GAPDH. 甘油醛-3-磷酸脱氢酶；A. mRNA相对表达水平(qRT-PCR)；B. 蛋白相对表达水平(Westernblotting)；与EAE组比较，*P<0.05，***P<0.001

, figureFileSmall=28xVzbHFePuYngz+ycr8dQ==, figureFileBig=3GRcbwDdH1q7HzLMm9fGXw==, tableContent=null), ArticleFig(id=1198558178863575295, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558168470090614, language=EN, label=Tab.1, caption=

Primer sequences for qRT-PCR

, figureFileSmall=null, figureFileBig=null, tableContent=
基因 引物序列

产物长
度(bp)
GAPDH 正向：5'-ATGGGTGTGAACCACGAGA-3' 229
反向：5'-CAGGGATGATGTTCTGGGCA-3'
ROCK2 正向：5'-GGATGGTTGTCATTGCCTGT-3' 180
反向：5'-TGTCTGGGTAACAGGTCGGA-3'
GAP-43 正向：5'-GCTACCACTGATAACTCCCCG-3' 221
反向：5'-CTTTCCTTAGGTTTGGCTTCG-3'
Nogo-A 正向：5'-CTATCCAGAAATCAGATGAAGGC-3' 198
反向：5'-TAAATACCCACATCAACACTGC-3'
NgR 正向：5'-AGCCCAAGGTAACAACAAG-3' 154
反向：5'-CACAGGATAGTGAGATTTCG-3'
), ArticleFig(id=1198558178981015813, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558168470090614, language=CN, label=表1, caption=

qRT-PCR引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
基因 引物序列

产物长
度(bp)
GAPDH 正向：5'-ATGGGTGTGAACCACGAGA-3' 229
反向：5'-CAGGGATGATGTTCTGGGCA-3'
ROCK2 正向：5'-GGATGGTTGTCATTGCCTGT-3' 180
反向：5'-TGTCTGGGTAACAGGTCGGA-3'
GAP-43 正向：5'-GCTACCACTGATAACTCCCCG-3' 221
反向：5'-CTTTCCTTAGGTTTGGCTTCG-3'
Nogo-A 正向：5'-CTATCCAGAAATCAGATGAAGGC-3' 198
反向：5'-TAAATACCCACATCAACACTGC-3'
NgR 正向：5'-AGCCCAAGGTAACAACAAG-3' 154
反向：5'-CACAGGATAGTGAGATTTCG-3'
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黄芪甲苷对EAE小鼠轴突修复和再生的促进作用机制
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刘建春 1 , 张红珍 1 , 王青 1 , 樊慧杰 1 , 宋丽娟 1 , 柴智 1 , 马存根 1, 2, *
解放军医学杂志 | 基础研究 2024,49(8): 914-921
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解放军医学杂志 | 基础研究 2024, 49(8): 914-921
黄芪甲苷对EAE小鼠轴突修复和再生的促进作用机制
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刘建春1, 张红珍1, 王青1, 樊慧杰1, 宋丽娟1, 柴智1, 马存根1, 2, *
作者信息
  • 1山西中医药大学神经生物学研究中心/国家中医药管理局多发性硬化益气活血重点研究室，山西晋中 030619
  • 2山西大同大学脑科学研究所，山西大同 037009

    • 刘建春，理学硕士，教授，主要从事神经系统形态学方面的研究

通讯作者:

马存根，E-mail：
Promotion mechanism of astragaloside on axon repair and regeneration in experimental autoimmune encephalomyelitis mice
Jian-Chun Liu1, Hong-Zhen Zhang1, Qing Wang1, Hui-Jie Fan1, Li-Juan Song1, Zhi Chai1, Cun-Gen Ma1, 2, *
Affiliations
  • 1Research Center of Neurobiology, Shanxi University of Chinese Medicine /Key Laboratory of Multiple Sclerosis Supplementing Qi and Promoting Blood Circulation of State Administration of Traditional Chinese Medicine, Jinzhong, Shanxi 030619, China
  • 2Institute of Brain Science, Shanxi Datong University, Datong, Shanxi 037009, China
出版时间: 2024-08-28 doi: 10.11855/j.issn.0577-7402.1164.2024.0202
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摘要
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目的 观察黄芪甲苷(AS-Ⅳ)对实验性自身免疫性脑脊髓炎(EAE)小鼠轴突生长抑制因子A(Nogo-A)及其下游通路蛋白Rho相关卷曲螺旋激酶2(ROCK2)的影响，探究其对轴突修复和再生的促进作用机制。方法 采用髓鞘少突胶质细胞糖蛋白35-55多肽(MOG35-55)皮下注射C57BL/6雌性小鼠制备EAE 模型；将小鼠随机分为EAE组、AS-Ⅳ组，每组8只。于免疫后第3天开始，EAE组腹腔注射PBS；AS-Ⅳ组腹腔注射AS-Ⅳ 30 mg/(kg.d)，1次/d，0.2 ml/次，连续给药25 d。免疫后第28天，取小鼠脊髓，采用免疫荧光法检测脊髓中生长相关蛋白43(GAP-43)、神经元核心抗原(NeuN)、微管相关蛋白2(MAP-2)、胶质纤维酸性蛋白(GFAP)和离子钙结合衔接分子1(Iba1)的表达水平；实时荧光定量PCR(qRT-PCR)检测GAP-43、Nogo-A、Nogo 受体(NgR)基因mRNA 表达水平；Western blotting检测GAP-43、Nogo-A、ROCK2、磷酸化肌球蛋白磷酸酶(p-MYPT1)、B淋巴细胞瘤-2(Bcl-2)蛋白和Bcl-2关联X蛋白(Bax)表达水平。结果 与EAE组比较，AS-Ⅳ组小鼠脊髓中星形胶质细胞GFAP和小胶质细胞Iba1的阳性表达率均明显下降(P<0.01，P<0.001)；NeuN和MAP-2阳性表达率均增高(P<0.001，P<0.05)；抗凋亡因子Bcl-2表达水平增高(P<0.001)，促凋亡因子Bax表达水平降低(P<0.05)，Bcl-2/Bax比值升高(P<0.05)；GAP-43蛋白表达水平增高(P<0.05)；神经再生抑制因子NgR和ROCK2 基因mRNA表达水平均下调(P<0.001，P<0.05)；Nogo-A、ROCK2和p-MYPT1蛋白表达水平均降低(P<0.05或P<0.001)。结论 AS-Ⅳ可通过抑制Nogo-A及其下游通路分子ROCK2，抑制EAE小鼠小胶质细胞和星形胶质细胞的激活及神经元凋亡，进而促进GAP-43、NeuN及MAP-2的表达，减轻神经元损伤，促进轴突修复和再生。

自身免疫性脑脊髓炎  /  黄芪甲苷  /  轴突生长抑制因子  /  凋亡  /  轴突再生

Objective To investigate the effects of astragaloside Ⅳ (AS-Ⅳ) on axon growth inhibitory factor A (Nogo-A) and its downstream pathway protein RHO-associated coiled spiral kinase 2 (ROCK2) in experimental autoimmune encephalomyelitis (EAE) mice, and to explore the mechanism by which it promotes axon repair and regeneration. Methods EAE model was induced in C57BL/6 female mice by subcutaneous injection of myelin oligodendrocyte glycoprotein 35-55 (MOG35-55). Mice were randomly divided into EAE group and AS-Ⅳ group (n=8 per group). EAE group received intraperitoneal injection of PBS on the 3rd day post-immunization, while AS-Ⅳ group was administered AS-Ⅳ at a dosage of 30mg/(kg.d) once daily, 0.2 ml per injection, for 25 consecutive days. On the 28th day post-immunization, the expression levels of growth-associated protein 43 (GAP-43), neuronal core antigen (NeuN), microtubule associated protein 2 (MAP-2), glial fibroacidic protein (GFAP), and Iba1 in the spinal cord were detected using immunofluorescence assay. Real-time fluorescence quantitative PCR (qRT-PCR) was conducted to detect mRNA expression levels of GAP-43, Nogo-A, and Nogo receptor (NgR) genes. Western blotting was utilized to determine the expression levels of GAP-43, Nogo-A, ROCK2, phosphorylated myosin phosphatase (p-MYPT1), B-lymphoblastoma-2 (Bcl-2), and Bcl-2 associated X protein (Bax). Results Compared with EAE group, AS-Ⅳ treatment significantly reduced the positive cell expression rates of Iba1 microglia and GFAP astrocyte in spinal cord (P<0.01 and P<0.001,respectively), while it also increased the positive expression rates of NeuN and MAP-2 (P<0.001 and P<0.05, respectively). The treatment also upregulated the expression level of anti-apoptotic factor Bcl-2 (P<0.001) and downregulated the expression level of pro-apoptotic factor Bax (P<0.05), leading to an increase in Bcl-2/Bax ratio (P<0.05). Furthermore, AS-Ⅳ enhanced the expression of GAP-43 protein (P<0.05) and decreased the mRNA expression levels of neuroregeneration inhibitor Nogo receptor (NgR) and ROCK2 gene (P<0.001, P<0.05, respectively); as well as decreased the expression levels of Nogo-A, ROCK2 and p-MYPT1 proteins (P<0.05, P<0.001). Conclusion AS-IV may inhibit the activation of microglia and astrocytes and neuronal apoptosis in EAE mice by inhibiting Nogo-A and downstream pathway ROCK2, thereby promoting the expression of GAP-43, NeuN and MAP-2, alleviating neuronal damage, and facilitating axon repair and regeneration.

autoimmune encephalomyelitis  /  astragaloside  /  axon growth inhibition factor  /  apoptosis  /  axon regeneration
刘建春, 张红珍, 王青, 樊慧杰, 宋丽娟, 柴智, 马存根. 黄芪甲苷对EAE小鼠轴突修复和再生的促进作用机制. 解放军医学杂志, 2024 , 49 (8) : 914 -921 . DOI: 10.11855/j.issn.0577-7402.1164.2024.0202
Jian-Chun Liu, Hong-Zhen Zhang, Qing Wang, Hui-Jie Fan, Li-Juan Song, Zhi Chai, Cun-Gen Ma. Promotion mechanism of astragaloside on axon repair and regeneration in experimental autoimmune encephalomyelitis mice[J]. Medical Journal of Chinese People’s Liberation Army, 2024 , 49 (8) : 914 -921 . DOI: 10.11855/j.issn.0577-7402.1164.2024.0202
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多发性硬化(multiple sclerosis，MS)是一种较常见的中枢神经系统炎性脱髓鞘病，其发病机制涉及自身免疫、神经胶质细胞和神经元的主要功能[1-2]。炎性脱髓鞘、胶质细胞增生及由此引起的神经元轴突损伤是MS患者的主要病理特征[3]。目前MS尚缺少治愈方法，临床治疗多使用免疫调节或免疫抑制药，可减少发作或延缓疾病进展，但长期应用不良反应较多[4]。越来越多的证据显示，损伤神经元周围存在的抑制微环境是导致轴突损伤修复困难的原因之一；轴突生长抑制因子(neurite outgrowth inhibitor，Nogo)-A是构成这种抑制微环境的重要成分，可通过与其下游分子结合激活Rho相关卷曲螺旋激酶2(Rho-associated kinase 2，ROCK2)，诱导生长锥塌陷，抑制神经轴突的生长，在MS神经损伤修复中起关键作用[5-6]。部分中药及其活性成分可通过Nogo调节其上游通路炎症级联因子和下游ROCK等信号通路相关因子的表达，发挥促神经再生作用[7]。
黄芪甲苷(astragalosides Ⅳ，AS-Ⅳ)是从中药黄芪中分离的天然皂苷分子。研究显示，AS-Ⅳ在中枢神经系统中可通过抗炎、抗氧化、抗凋亡保护神经细胞，促进轴突再生[8-9]。实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis，EAE)小鼠是MS相关研究的常用动物模型。本课题组前期研究显示，AS-Ⅳ可明显降低EAE小鼠的临床症状评分，减轻脊髓炎性浸润和髓鞘脱失[10]；但AS-IV对Nogo的作用报道较少。本研究采用EAE小鼠模型探究AS-Ⅳ对Nogo-A和轴突再生的作用，旨在为MS的临床治疗提供参考依据。
1 材料与方法
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1.1 实验动物
16只8~10周龄SPF级C57BL/6雌性小鼠，体重18~22 g，购自北京维通利华有限公司[实验动物生产许可证号：SCXK(京)2016-0006]。实验动物的饲养和处理遵守国际动物实验委员会的实验动物伦理原则。饲养条件为恒温(18~22 ℃)的无病原菌动物房，实验前小鼠自由饮食喂养1周。本研究经山西中医药大学伦理委员会审批(2022DW276)。
1.2 主要试剂与仪器
1.2.1 主要试剂
AS-IV [爱必信(上海)生物科技有限公司，abs47006065]；髓鞘少突胶质细胞糖蛋白35-55多肽(MOG35-55，上海强耀生物科技有限公司，9001)；结核分枝杆菌(Tuberculosis bacilli，TB)(美国Difco公司，231141)；弗氏佐剂(Freund，sAdjuvant，Complete)(美国Sigma公司，601103)；百日咳毒素(PTX，美国Alexis公司，12687-177)；RIPA裂解液、BCA试剂盒(北京索莱宝科技有限公司，R0010、PC0020)；SDS-PAGE凝胶配制试剂盒、蛋白质Marker(北京博泰斯生物技术有限公司，WB1102、WB1902S)；热稳定的反转录酶(HiScript reverse transcriptase)、核糖核酸酶H(RNase H)、SYBR Green Master Mix(南京诺唯赞医疗科技有限公司，R101-01/02、Q111-02)；抗GAPDH抗体(杭州贤至生物有限公司，AB-P-R 001)；抗Nogo-A抗体、HRP标记羊抗兔二抗(武汉博士德生物工程有限公司，BA1309、BA1054)；抗神经元核心蛋白(neuron-specific protein，NeuN)、微管相关蛋白2(MAP-2)抗体(美国 Millipore公司，NG1857584、NG1853418)；抗胶质纤维酸性蛋白(GFAP)、磷酸化肌球蛋白磷酸酶(p-MYPT1)抗体(美国CST公司，3670、4563)；抗离子钙结合衔接分子 1 (Iba1)抗体(美国Santa Cruz公司，批号A1218)；β肌动蛋白(β-actin，4870S)；抗生长相关蛋白43(growth associated protein-43，GAP-43)、ROCK2抗体(英国Abcam公司，ab75810、ab125025)；抗B淋巴细胞瘤-2(Bcl-2)和Bcl-2关联X蛋白(Bax)抗体(武汉三鹰生物技术有限公司，12789-1-AP、50599-2-Ig)。ECL化学发光试剂盒(上海碧云天生物技术有限公司)。
1.2.2 仪器
PVDF膜(德国Millpore公司)；冷冻LEICA切片机(德国LEICA公司，CM1950)；光学显微镜(日本Olympus公司)；凝胶成像分析仪(美国Bio-Rad公司)；凝胶电泳设备(北京六一仪器厂)；全自动酶标仪(美国 BioTek 公司)；PCR仪(北京东胜创新生物科技有限公司，型号EDC-810)。
1.3 方法
1.3.1 EAE小鼠模型制备、分组及给药
EAE模型制备严格按照文献[8]的方法：用生理盐水配制MOG35-55，用完全弗氏佐剂(FCA)配制TB，然后使用针管混合器将MOG35-55溶液和TB溶液按等比例充分混合，反复抽推，制成油包水样抗原乳剂；按每只小鼠0.1 ml的剂量于脊柱腰骶膨大处两侧皮下分4 个点注射抗原乳剂。将免疫当天记为免疫后的第0天。为加强免疫，在免疫后第0天和免疫后的第2天，分别给每只小鼠腹腔注射PTX 300 ng。
采用随机数字表法按体重分层，将造模后的C57BL/6小鼠随机分为EAE组与AS-Ⅳ组，每组8只。于免疫后第3天开始对小鼠进行如下处理：EAE组腹腔注射PBS 0.2 ml/d；AS-Ⅳ组腹腔注射AS-IV 30 mg/(kg.d)[11]；1次/d，连续给药至免疫后第27天。
1.3.2 标本制备
免疫后第28 天，每组随机取4 只小鼠，麻醉后剪开胸腔，暴露心脏，从心尖处推注PBS进行心脏灌注，同时在冰上快速取脊髓置于液氮中，之后保存在-80 ℃冰箱，用于 Western blotting 和qRT-PCR检测。各组其余4 只小鼠推注PBS至肝脏发白，改用4% 多聚甲醛溶液推注进行组织固定；然后迅速冰上分离脊髓组织，脱水后用 OCT 胶包埋，于液氮中冷冻，制作冷冻切片，厚度10 μm，用于免疫荧光染色。
1.3.3 免疫荧光染色检测小鼠脊髓GAP-43、NeuN、MAP-2、GFAP和Iba1蛋白表达水平
脊髓冷冻切片经室温自然晾干后，置于湿盒中，PBS洗3次×5 min；加入一抗[GAP-43(1:1000)、抗NeuN(1:1000)、抗MAP-2(1:1000)、抗GFAP(1:1000)和抗Iba1(1:1000)]，4 ℃冰箱中孵育过夜；次日PBS洗3次×5 min；加入Alexa Fluor® 488 或Alexa Fluor® 594标记的荧光二抗(1:1000)，室温湿盒避光孵育2 h；PBS洗3次；50%甘油封片，荧光显微镜采集图片，用ImageJ软件分析荧光抗体阳性表达率。
1.3.4 qRT-PCR 检测GAP-43、Nogo-A、NgR基因mRNA表达水平
取-80℃冰箱中保存的新鲜冷冻脊髓组织，采用Trizol试剂提取两组脊髓总RNA，用微量分光光度计测定OD260、OD280以及OD260/OD280值，测定并计算RNA的纯度和浓度。然后取一定量的RNA用HiScript reverse transcriptase (RNase H)试剂反转录成cDNA。以GAPDH作为内参，引物由上海生工生物工程公司设计合成，引物序列见表1。在PCR仪上进行基因片段扩增。PCR反应体系：cDNA(2 μl)，正向引物(10 μmol/L)(1 μl)，反向引物(10 μmol/L)(1μl)，SYBR Green Master Mix(5 μl)，50×ROX Reference Dye 2(0.2 μl)，ddH2O(0.8 μl)。反应条件：50 °C 2 min；95°C 10 min，95 °C 30 s ，60 °C 30 s，进行40个循环，每个样品设3个重复，对各组样品的Ct值进行测定，最终数据用2-ΔΔCt计算各组mRNA相对表达量。
1.3.5 Western blotting检测小鼠脊髓GAP-43、Nogo-A、ROCK2、p-MYPT1、Bcl-2和Bax蛋白表达水平
脊髓组织称重，按照说明书加入组织裂解液在4 ℃下充分裂解，12 000 r/min 4 ℃下离心5 min，提取蛋白，用BCA法测定蛋白含量。加入上样缓冲液制备蛋白上样缓冲液样品，用微量加样器将制备好的蛋白样品和marker加入上样孔。用10% SDS-PAGE凝胶电泳分离蛋白。然后用湿式转移法将分离的蛋白凝胶转移到硝酸纤维(PVDF)膜(稳流220 mA，2 h)。洗膜，5%脱脂奶粉封闭2 h，按照说明书加入一抗稀释液抗ROCK2(1:5000)、p-MYPT1(1:5000)、抗GAP-43(1:5000)、抗Bcl-2(1:1000)、抗Bax(1:1000)、抗Nogo-A(1:200)和抗GADPH(1:1000)，4 ℃孵育过夜；次日洗膜后，加入相应的HRP标记二抗稀释液，37 ℃摇床室温孵育2 h。洗膜后进行化学发光反应，用Bio-RAD凝胶成像分析仪成像，用ImageJ 图像分析系统测定各蛋白条带的灰度值，将目的蛋白与内参的灰度值比较，并进行统计学分析。
1.4 统计学处理
采用 Graph Pad Prism 5.0软件进行统计分析。计量数据均符合正态分布，以$\bar{x}±s$表示，组间比较采用t检验。P<0.05为差异有统计学意义。
2 结果
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2.1 AS-Ⅳ对EAE小鼠脊髓中小胶质细胞和星形胶质细胞活化的影响
免疫荧光染色显示，与EAE组比较，AS-Ⅳ组星形胶质细胞GFAP和小胶质细胞Iba1阳性表达率均明显下降(P<0.01，P<0.001，图1)。
2.2 AS-Ⅳ对EAE诱导的神经元损伤、轴突脱失及神经元凋亡的影响
免疫荧光染色结果显示，与EAE组比较，AS-Ⅳ组小鼠脊髓神经元NeuN和MAP-2阳性表达率均明显增高[(21.94±1.76)% vs. (5.2±0.84)%，P<0.001；(21.79±3.27)% vs. (12.97±2.64)%，P<0.05](图2)。Western blotting检测结果显示，与EAE组比较，AS-Ⅳ组抗凋亡因子Bcl-2蛋白表达水平明显增高(P<0.001)，促凋亡因子Bax蛋白表达水平明显降低(P<0.05，图3A)，Bcl-2/Bax比值明显升高(P<0.05，图3B)。
2.3 AS-Ⅳ对EAE小鼠脊髓中GAP-43表达的影响
免疫荧光染色结果显示，与EAE组比较，AS-Ⅳ组小鼠脊髓中GAP-43阳性表达率明显增高[(20.39±2.96)% vs. (13.86±1.12)%，P<0.05，图4A)；qRT-PCR检测结果显示，与EAE组比较，AS-Ⅳ组小鼠脊髓中GAP-43 mRNA表达水平差异无统计学意义(P>0.05，图4B)；Western blotting检测结果显示，与EAE 组比较，AS-Ⅳ组小鼠脊髓中GAP-43蛋白表达水平明显增高(P<0.001，图4C)。
2.4 AS-IV对EAE小鼠脊髓中神经抑制因子及ROCK2表达的影响
qRT-PCR 检测结果显示，与EAE组比较，AS-Ⅳ组小鼠脊髓中神经再生抑制因子Nogo-A、NgR和ROCK2 的mRNA表达水平明显下调(P<0.05或P<0.001，图5A)。Western blotting检测结果显示，与EAE 组比较，AS-Ⅳ组小鼠脊髓中Nogo-A、ROCK2和P-MYPT1蛋白表达水平均明显降低(P<0.05或P<0.001，图5B)。
3 讨论
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MS/EAE呈现炎性脱髓鞘病变，并伴有神经元轴突变性和损伤，给患者、家庭及社会带来较大负担，目前尚无满意的治疗措施。黄芪是经典的补益中药[12]，已有研究显示，黄芪及其有效成分对神经系统疾病有较好的预防和治疗作用[8,11,13-14]。本研究以MS相关的EAE小鼠模型为研究对象，探讨AS-Ⅳ对EAE小鼠轴突生长抑制因子Nogo-A及下游通路ROCK2的影响。
MS和EAE的主要病理变化是激活的免疫细胞浸润中枢神经系统，引发少突胶质细胞缺失，小胶质细胞和星形胶质细胞增生，继而发生髓鞘脱失，最终导致神经变性，神经元功能缺失[15]。炎性因子和髓鞘碎片刺激小胶质细胞向M1型极化，局灶性募集在脱髓鞘病变的周围；神经炎症同时也刺激了星形胶质细胞的活化，这两种细胞的活化分泌更多的炎性因子，又会加剧髓鞘脱失，加重MS的严重程度[16-19]。本研究免疫荧光染色结果显示，EAE组小鼠脊髓中星形胶质细胞活化的标志物GFAP和小胶质细胞Iba1阳性细胞表达率较高，AS-Ⅳ干预后，两种细胞的活化受到抑制，GFAP和Iba1阳性表达率明显下降。
NeuN是成熟神经元特异抗原的标志物。MAP-2是神经元骨架蛋白的主要成分，对神经元胞体的发育、突起的发生起着重要作用，可用来标记神经元轴突[20-21]。本研究采用免疫荧光染色观察脊髓NeuN和MAP-2的表达，结果显示，EAE组小鼠脊髓中NeuN标记的神经元退行性变较严重，轴突缺失，阳性表达率较低；AS-Ⅳ组NeuN形态完好，阳性表达率明显增高，MAP-2标记的轴突较长，形态较完整。Bcl-2和Bax同属Bcl-2家族，促凋亡蛋白与抗凋亡蛋白的平衡决定了细胞的生存或死亡命运，因此Bcl-2与Bax的比值是评估细胞凋亡倾向的较好指标[22-23]。本研究结果还显示，EAE小鼠脊髓中Bax表达水平明显升高，AS-Ⅳ干预可提高Bcl-2表达水平，降低Bax的表达，提升Bcl-2/Bax比值。这些结果提示，AS-Ⅳ可上调Bcl-2、下调Bax凋亡因子的表达，调节Bcl-2与Bax的比例，减轻EAE病程中神经元的凋亡，抑制神经元损伤与轴突脱失。
MS的轴突丧失是疾病进展和永久性神经系统残疾的关键组成部分，GAP-43是轴突生长锥的主要蛋白，也是轴突再生的主要标志物，与神经元发育、轴突再生及可塑性密切相关[24-25]。中枢神经系统损伤后，促进GAP-43表达有利于轴突再生和突触生长[26]。研究发现，AS-Ⅳ可以显著上调GAP-43在再生神经组织的表达，促进神经的修复和再生[27]。与上述研究结果一致，本研究中免疫荧光染色及Western blotting检测结果均显示，AS-Ⅳ干预可明显增加EAE小鼠脊髓中GAP-43表达量；qRT-PCR检测结果也显示，AS-Ⅳ治疗可上调脊髓中GAP-43 mRNA的相对表达水平。
良好的神经微环境是改善受损神经、促进轴突修复再生的基础。在中枢神经系统中，胶质瘢痕、轴突生长抑制因子Nogo等，会形成抑制性微环境，从而限制受损神经元的结构可塑性，阻碍神经元再生[28-30]。Nogo-A作为轴突再生的主要障碍备受关注，主要在少突胶质细胞表达。Nogo-A可与其受体结合来转导细胞内信号，激活RhoA/ROCK通路，抑制轴突生长，阻碍神经再生和修复[31-33]。研究显示，Nogo-A/NgR及ROCK信号通路参与了MS/EAE的发生。在MS/EAE中枢神经组织中Nogo-A和RhoA表达上调[34-35]。在MS脱髓鞘病变边缘存活的少突胶质细胞中，Nogo-A的表达明显升高，而在损伤部位的反应性星形胶质细胞和小胶质细胞中，NgR的表达明显升高[36]。本研究中，AS-Ⅳ干预可明显下调EAE小鼠中神经再生抑制因子NgR和ROCK2 mRNA的表达，降低EAE小鼠脊髓中Nogo-A、ROCK2及p-MYPT1蛋白表达水平。与上述结果一致。这表明AS-Ⅳ可抑制在轴突和髓鞘病变中产生的大量抑制因子及其下游ROCK信号通路。
综上所述，本研究结果显示，AS-Ⅳ可能通过抑制EAE小鼠脊髓中Nogo-A及下游通路ROCK2，抑制小胶质细胞和星形胶质细胞的激活，减少神经元凋亡，进而促进GAP-43、NeuN及MAP-2的表达，减轻神经元损伤，促进轴突修复和再生。AS-Ⅳ有望为MS的治疗提供新的方向，但相关机制仍需进一步验证。
基金
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  • 国家自然科学基金(81903596)
  • 山西省科技创新青年人才团队项目(202204051001028)
  • 山西省卫健委医学科技领军团队项目(2020TD05)
  • 山西中医药大学科技创新培育计划“太行本草”专项(2022PY-TH-31)
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2024年第49卷第8期
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doi: 10.11855/j.issn.0577-7402.1164.2024.0202
  • 接收时间：2023-09-02
  • 首发时间：2025-11-21
  • 出版时间：2024-08-28
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  • 收稿日期：2023-09-02
  • 录用日期：2023-10-07
基金
National Natural Science Foundation of China(81903596)
国家自然科学基金(81903596)
Shanxi Science and Technology Innovation Young Talent Team Project(202204051001028)
山西省科技创新青年人才团队项目(202204051001028)
Medical Science and Technology Leading Team Project of Shanxi Health Commission(2020TD05)
山西省卫健委医学科技领军团队项目(2020TD05)
"Taihang Materia Medica" Special Project of Science and Technology Innovation Cultivation Plan of Shanxi University of Chinese Medicine(2022PY-TH-31)
山西中医药大学科技创新培育计划“太行本草”专项(2022PY-TH-31)
作者信息
    1山西中医药大学神经生物学研究中心/国家中医药管理局多发性硬化益气活血重点研究室，山西晋中 030619
    2山西大同大学脑科学研究所，山西大同 037009

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