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Article(id=1308828795734418372, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308828670878376007, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2025-0783, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1751817600000, receivedDateStr=2025-07-07, revisedDate=1761408000000, revisedDateStr=2025-10-26, acceptedDate=null, acceptedDateStr=null, onlineDate=1789978701765, onlineDateStr=2026-09-21, pubDate=1773244800000, pubDateStr=2026-03-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789978701765, onlineIssueDateStr=2026-09-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789978701765, creator=13701087609, updateTime=1789978701765, updator=13701087609, issue=Issue{id=1308828670878376007, tenantId=1146029695717560320, journalId=1189982191388893191, year='2026', volume='61', issue='3', pageStart='677', pageEnd='1000', issueExtLink='null', onlineDate='null', pubDate='1773244800000', pubDateStr='2026-03-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789978671998, creator='13701087609', updateTime=1789984247322, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308852055549248371, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308828670878376007, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308852055549248372, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308828670878376007, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=802, endPage=812, ext={EN=ArticleExt(id=1308828796141265861, articleId=1308828795734418372, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=The antidepressant mechanisms of Schisandra chinensis lignans via mediating cannabinoid type Ⅰ receptors to regulate brain-derived neurotrophic factor, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Depression is a common mental disorder. Previous studies have found that Schisandra chinensis lignans (SCL) exhibit significant therapeutic effects on depression, though its antidepressant mechanisms remain incompletely understood. This study aims to elucidate the molecular mechanisms by which SCL exerts neuroprotective and antidepressant effects, based on SCL's modern pharmacological neuroprotective properties and the physiological function of cannabinoid type 1 receptor (CB1R) in neuronal protection. By establishing a chronic unpredictable mild stress (CUMS)-induced depression model and administering CB1R antagonist AM251 to CUMS-treated animals, we conducted pharmacobehavioral experiments to evaluate SCL's ability to improve depression-like behaviors in mice. Additionally, we employed Western blot, hematoxylin-eosin staining, immunohistochemistry, immunofluorescence, and molecular docking to investigate SCL's antidepressant mechanism through CB1R-mediated regulation of brain-derived neurotrophic factor (BDNF). The use of animals in this study was approved by the Ethics Committee of Shenyang Pharmaceutical University, with the approval number: SYPU-IACUC-C2021-11-3-115. Pharmacobehavioral results demonstrated that SCL alleviates depression-like behaviors in CUMS model mice. Hematoxylin-eosin staining revealed that SCL improves neuronal pathological damage and neuroplasticity impairment caused by CUMS in the model. Western blot analysis revealed that SCL upregulates BDNF and CB1R expression, activates the proBDNF-tPA-BDNF pathway to promote proBDNF cleavage, and exerts anti-apoptotic effects. It also activates BDNF-TrkB-MEK-ERK-PKA-CREB and PI3K-AKT pathways to reduce neuronal damage and exert antidepressant effects. Further experiments confirmed that AM251 antagonized SCL's antidepressant effects by inhibiting its depression-like behavior and modulation of BDNF-related pathways. Specifically, SCL activates proBDNF-tPA-BDNF via CB1R to enhance BDNF production and anti-apoptotic effects, while simultaneously activating the downstream classical pathway BDNF-TrkB-ERK-PI3K-AKT to protect neurons and exert antidepressant effects. Molecular docking revealed the binding sites of six major components in SCL for CB1R. The study revealed that SCL exerts antidepressant effects by regulating BDNF through CB1R to alleviate neuronal damage.

, authors=Zhen-feng GUO, Mei-yi HOU, Jing-xuan LI, Ying JIA, Ting-xu YAN*, authorsList=Zhen-feng GUO, Mei-yi HOU, Jing-xuan LI, Ying JIA, Ting-xu YAN, authorCompany=null, correspAuthors=Ting-xu YAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2026 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1308828800100688854, articleId=1308828795734418372, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=五味子木脂素基于大麻素Ⅰ型受体调控脑源性神经营养因子抗抑郁作用机制研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

抑郁症是一种常见的心理疾病。前期研究发现, 五味子木脂素(Schisandra chinensis lignans, SCL) 对抑郁症有明显的治疗作用, 但其抗抑郁机制探究尚不完全。本研究基于SCL神经保护的现代药理作用及大麻素Ⅰ型受体(cannabinoid type 1 receptor, CB1R) 保护神经元的生理功能, 旨在阐述SCL发挥神经保护、抗抑郁的分子作用机制。通过构建慢性不可预知性温和刺激(chronic unpredictable mild stress, CUMS) 诱导的抑郁模型, 以及CB1R拮抗剂AM251干预CUMS动物模型, 采用药理行为学实验考察SCL改善小鼠抑郁样行为能力, 并采用蛋白免疫印记法(Western blot)、苏木精-伊红(H&E) 染色、免疫组化检测(IHC)、免疫荧光检测、分子对接等实验方法, 研究SCL通过CB1R调控脑源性神经营养因子(brain-derived neurotrophic factor, BDNF) 发挥抗抑郁作用的机制。实验所用动物获得沈阳药科大学伦理委员会批准, 伦理审查编号: SYPU-IACUC-C2021-11-3-115。药理行为学实验结果表明, SCL可缓解CUMS模型小鼠抑郁样行为。H&E染色结果显示, SCL可减轻CUMS模型造成的小鼠神经元病理损伤及神经可塑性损伤。Western blot结果表明, SCL可上调BDNF和CB1R的表达, 激活proBDNF-tPA-BDNF通路促进proBDNF裂解, 发挥抗凋亡的作用, 激活BDNF-TrkB-MEK-ERK-PKA-CREB和PI3K-AKT通路减轻神经元损伤, 发挥抗抑郁作用。进一步实验结果证实, AM251拮抗了SCL所发挥的减缓抑郁样行为及对BDNF关联通路的调节作用, 即SCL通过CB1R激活proBDNF-tPA-BDNF, 促进BDNF的生成, 发挥抗凋亡作用, 同时激活下游经典通路BDNF-TrkB-ERK-PI3K-AKT, 保护神经元, 发挥抗抑郁的作用。分子对接结果显示了SCL中6种主要成分对CB1R发挥作用的位点。该研究揭示了SCL通过CB1R调控BDNF减轻神经元损伤, 发挥抗抑郁作用。

, authors=郭振凤, 侯美屹, 李京轩, 贾英, 颜廷旭*, authorsList=郭振凤, 侯美屹, 李京轩, 贾英, 颜廷旭, authorCompany=null, correspAuthors=颜廷旭, authorNote=

作者贡献:

颜廷旭完成实验设计、论文修改; 郭振凤完成实验操作部分、论文初稿的写作、修改; 侯美屹、李京轩帮助论文初稿的完成; 贾英提供了方法理论支持和建议。

, correspAuthorsNote=
颜廷旭, Tel: 18842411904, E-mail:
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J Guangzhou Univ Tradit Chin Med (广州中医药大学学报), 2022, 39: 1129-1135., articleTitle=null, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1308834370102846201, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, xref=null, ext=[AuthorCompanyExt(id=1308834370119623418, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, companyId=1308834370102846201, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=College of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, China), AuthorCompanyExt(id=1308834370132206331, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, companyId=1308834370102846201, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=沈阳药科大学功能食品与葡萄酒学院, 辽宁 沈阳 110016)])], figs=[ArticleFig(id=1308834375022764831, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=EN, label=null, caption=null, figureFileSmall=xL1Jp+NmSPidr6NpHWqpoQ==, figureFileBig=UXNgcIHHxeQ6M+bGnCOxXw==, tableContent=null), ArticleFig(id=1308834375102456608, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=CN, label=Fig.1, caption=SCL alleviates neuronal damage and neuroplastic damage in CUMS model mice. A, B: Effects of SCL treatment on CUMS-induced histopathological changes in the brain (H&E staining, scale bar = 100 μm), number of abnormally shaped neurons in the mouse brain; C-F: The protein expressions of Bcl-2/Bax, cleaved caspase 3/caspase 3, cleaved caspase 9/caspase 9 were determined by Western blot; G, H: Expression of PSD95 was examined by Western blot. n = 3, x ± s. **P < 0.01, ***P < 0.001 vs control group; #P < 0.05, ##P < 0.01, ###P < 0.001 vs CUMS group. PSD95: Postsynaptic density protein 95, figureFileSmall=xL1Jp+NmSPidr6NpHWqpoQ==, figureFileBig=UXNgcIHHxeQ6M+bGnCOxXw==, tableContent=null), ArticleFig(id=1308834375198925601, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=EN, label=null, caption=null, figureFileSmall=xLxDPgLgzUbHD2HfdNtIRQ==, figureFileBig=KhlCunW9VQscw+xVZGQiNQ==, tableContent=null), ArticleFig(id=1308834376859869986, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=CN, label=Fig.2, caption=SCL promotes proBDNF hydrolysis to upregulate BDNF expression in the CUMS model of mice. A, B: Effect of SCL on the positive rate of BDNF in CUMS mice (IHC staining, scale bar = 100 μm); C-F: The protein expressions of proBDNF, tPA and BDNF were examined by Western blot. n = 3, x ± s. **P < 0.01, ***P < 0.001 vs control group; #P < 0.05, ##P < 0.01, ###P < 0.001 vs CUMS group, figureFileSmall=xLxDPgLgzUbHD2HfdNtIRQ==, figureFileBig=KhlCunW9VQscw+xVZGQiNQ==, tableContent=null), ArticleFig(id=1308834376926978851, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=EN, label=null, caption=null, figureFileSmall=sUq4HnaXGTZZw9CKoN0Vig==, figureFileBig=mQotkRd47tCMtVhuAaX2og==, tableContent=null), ArticleFig(id=1308834377023447844, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=CN, label=Fig.3, caption=SCL activates tropomyosin receptor kinase B (TrkB) related pathways to exert antidepressant effects. A-G: The protein expressions of p-TrkB, TrkB, p-MEK/MEK, p-ERK/ERK, PKA, p-CREB/CREB were determined by Western blot. n = 3, x ± s. *P < 0.05, **P < 0.01, ***P < 0.001 vs control group; #P < 0.05, ##P < 0.01, ###P < 0.001 vs CUMS group, figureFileSmall=sUq4HnaXGTZZw9CKoN0Vig==, figureFileBig=mQotkRd47tCMtVhuAaX2og==, tableContent=null), ArticleFig(id=1308834377107333925, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=EN, label=null, caption=null, figureFileSmall=uK2fBXob7aW9TIbaiYABLw==, figureFileBig=4+BYk3yjx5oBsZeNIBZL2g==, tableContent=null), ArticleFig(id=1308834377187025702, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=CN, label=Fig.4, caption=SCL activates the PI3K-AKT related pathways to exert antidepressant effects. A-C: The protein expressions of p-PI3K/PI3K and p-AKT/AKT were determined by Western blot. n = 3, x ± s. ***P < 0.001 vs control group; #P < 0.05, ##P < 0.01, ###P < 0.001 vs CUMS group, figureFileSmall=uK2fBXob7aW9TIbaiYABLw==, figureFileBig=4+BYk3yjx5oBsZeNIBZL2g==, tableContent=null), ArticleFig(id=1308834377266717479, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=EN, label=null, caption=null, figureFileSmall=V1nzF979FwcyclVpsrnZ8A==, figureFileBig=yhb+oJxehNuS5Y9jUHZh5A==, tableContent=null), ArticleFig(id=1308834377329632040, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=CN, label=Fig.5, caption=Effect of SCL on expression of cannabinoid type 1 receptor (CB1R) in CUMS model mice. The protein expression of CB1R was determined by Western blot. n = 3, x ± s. ***P < 0.001 vs control group; #P < 0.05, ##P < 0.01 vs CUMS group, figureFileSmall=V1nzF979FwcyclVpsrnZ8A==, figureFileBig=yhb+oJxehNuS5Y9jUHZh5A==, tableContent=null), ArticleFig(id=1308834377396740905, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=EN, label=null, caption=null, figureFileSmall=zCJ68xcTRChd+JNLdhQvnQ==, figureFileBig=aJ75eOhBB6N5I7bnwfsO8A==, tableContent=null), ArticleFig(id=1308834377455461162, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=CN, label=Fig.6, caption=SCL reduces the level of apoptosis in hippocampal neurons of CUMS mice via CB1R. A, B: Expression of CB1R was examined by Western blot; C-F: Expressions of Bcl-2/Bax, cleaved caspase 3/caspase 3 and cleaved caspase 9/caspase 9 were examined by Western blot. n = 3, x ± s. ***P < 0.001 vs control group; #P < 0.05, ###P < 0.001 vs CUMS group; $P < 0.05, $$$P < 0.001 vs SCL (H) group, figureFileSmall=zCJ68xcTRChd+JNLdhQvnQ==, figureFileBig=aJ75eOhBB6N5I7bnwfsO8A==, tableContent=null), ArticleFig(id=1308834377543541547, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=EN, label=null, caption=null, figureFileSmall=qIbfHZE57RnryXo7G/+lWQ==, figureFileBig=CAynjDn4jpIAzCsLNjaOEQ==, tableContent=null), ArticleFig(id=1308834377627427628, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=CN, label=Fig.7, caption=SCL activates multiple pathways through CB1R to regulate the effects of physiological processes and related protein expression in CUMS mice. A, B: Effect of SCL on the positive rate of BDNF in CUMS model mice (IHC staining, scale bar = 100 μm); C-F: The protein expressions of proBDNF, tPA and BDNF were examined by Western blot; G-J: Expressions of p-TrkB, TrkB and p-ERK/ERK were examined by Western blot; K-M: Expressions of p-PI3K/PI3K, p-AKT/AKT were examined by Western blot. n = 3, x ± s. **P < 0.01, ***P < 0.001 vs control group; #P < 0.05, ##P < 0.01, ###P < 0.001 vs CUMS group; $P < 0.05, $$P < 0.01, $$$P < 0.001 vs SCL (H) group, figureFileSmall=qIbfHZE57RnryXo7G/+lWQ==, figureFileBig=CAynjDn4jpIAzCsLNjaOEQ==, tableContent=null), ArticleFig(id=1308834377711313709, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=EN, label=null, caption=null, figureFileSmall=S0II0ZI6+TWqjTys/v+8Yg==, figureFileBig=8StCDfSbbby/bvSIWV1wVg==, tableContent=null), ArticleFig(id=1308834377782616878, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=CN, label=Fig.8, caption=The molecular docking diagram of six main active ingredients in SCL act on CB1R, figureFileSmall=S0II0ZI6+TWqjTys/v+8Yg==, figureFileBig=8StCDfSbbby/bvSIWV1wVg==, tableContent=null), ArticleFig(id=1308834377858114351, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
GroupSPT/%FST/sOFT/cm
Control51.68 ± 3.5096.17 ± 11.201 965.00 ± 378.09
CUMS42.67 ± 2.02***133.83 ± 7.78**1 301.67 ± 306.69**
SCL (L)52.87 ± 2.38###86.17 ± 12.01###1 901.67 ± 207.31##
SCL (H)53.76 ± 3.23###68.00 ± 16.71###2 078.33 ± 151.32###
Flu54.68 ± 4.51###68.83 ± 30.17###1 845.00 ± 302.57#
), ArticleFig(id=1308834377916834608, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=CN, label=Tab.1, caption=

Comparison of depression-like behavior results in mice. n = 6, x ± s. **P < 0.01, ***P < 0.001 vs control group; #P < 0.05, ##P < 0.01, ###P < 0.001 vs CUMS group. SPT: Sucrose preference test; FST: Forced swimming test; OFT: Open field test; CUMS: Chronic unpredictable mild stress; SCL (L): 600 mg·kg-1 Schisandra chinensis lignans; SCL (H): 1 200 mg·kg-1 SCL; Flu: Fluoxetine

, figureFileSmall=null, figureFileBig=null, tableContent=
GroupSPT/%FST/sOFT/cm
Control51.68 ± 3.5096.17 ± 11.201 965.00 ± 378.09
CUMS42.67 ± 2.02***133.83 ± 7.78**1 301.67 ± 306.69**
SCL (L)52.87 ± 2.38###86.17 ± 12.01###1 901.67 ± 207.31##
SCL (H)53.76 ± 3.23###68.00 ± 16.71###2 078.33 ± 151.32###
Flu54.68 ± 4.51###68.83 ± 30.17###1 845.00 ± 302.57#
), ArticleFig(id=1308834377979749169, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
GroupSPT/%OFT/cm
Control85.78 ± 0.971 788.00 ± 223.76
CUMS63.39 ± 3.85***1 230.00 ± 185.61*
SCL (H)89.29 ± 1.17###2 242.00 ± 296.09###
AM25175.82 ± 2.12***1 170.00 ± 208.81***
AM251 + SCL (H)79.58 ± 4.40$$$1 448.00 ± 267.34$$$
WIN55212-275.85 ± 3.43###1 598.00 ± 223.65
), ArticleFig(id=1308834378059440946, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=CN, label=Tab.2, caption=

Comparison of depression-like behavior results in mice. n = 5, x ± s. *P < 0.05, ***P < 0.001 vs control group; ###P < 0.001 vs CUMS group; $$$P < 0.001 vs SCL (H) group

, figureFileSmall=null, figureFileBig=null, tableContent=
GroupSPT/%OFT/cm
Control85.78 ± 0.971 788.00 ± 223.76
CUMS63.39 ± 3.85***1 230.00 ± 185.61*
SCL (H)89.29 ± 1.17###2 242.00 ± 296.09###
AM25175.82 ± 2.12***1 170.00 ± 208.81***
AM251 + SCL (H)79.58 ± 4.40$$$1 448.00 ± 267.34$$$
WIN55212-275.85 ± 3.43###1 598.00 ± 223.65
), ArticleFig(id=1308834378378208051, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
ProteinActive ingredientBound energy/kal·mol-1Binding site
CB1RSchisandrol A-5.01LEU-133, THR-56
Schisandrol B-6.19LYS-148, GLU-160
Schisantherin A-6.39GLY-135, LEU-133
Schisantherin B-5.12ASN-33
Schizandrin A-5.55LEU-133, GLU-57, THR-56
Schizandrin B-6.41ILE-28
), ArticleFig(id=1308834378688586548, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308828795734418372, language=CN, label=Tab.3, caption=

Binding energies of active components in SCL and CB1R

, figureFileSmall=null, figureFileBig=null, tableContent=
ProteinActive ingredientBound energy/kal·mol-1Binding site
CB1RSchisandrol A-5.01LEU-133, THR-56
Schisandrol B-6.19LYS-148, GLU-160
Schisantherin A-6.39GLY-135, LEU-133
Schisantherin B-5.12ASN-33
Schizandrin A-5.55LEU-133, GLU-57, THR-56
Schizandrin B-6.41ILE-28
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五味子木脂素基于大麻素Ⅰ型受体调控脑源性神经营养因子抗抑郁作用机制研究
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郭振凤 , 侯美屹 , 李京轩 , 贾英 , 颜廷旭 *
药学学报 | 研究论文 2026,61(3): 802-812
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药学学报 |研究论文 2026 , 61 (3) : 802 -812
五味子木脂素基于大麻素Ⅰ型受体调控脑源性神经营养因子抗抑郁作用机制研究
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郭振凤, 侯美屹, 李京轩, 贾英, 颜廷旭*
作者信息
  • 沈阳药科大学功能食品与葡萄酒学院, 辽宁 沈阳 110016
通讯作者:
颜廷旭, Tel: 18842411904, E-mail:
作者简介:

作者贡献:

颜廷旭完成实验设计、论文修改; 郭振凤完成实验操作部分、论文初稿的写作、修改; 侯美屹、李京轩帮助论文初稿的完成; 贾英提供了方法理论支持和建议。

The antidepressant mechanisms of Schisandra chinensis lignans via mediating cannabinoid type Ⅰ receptors to regulate brain-derived neurotrophic factor
Zhen-feng GUO, Mei-yi HOU, Jing-xuan LI, Ying JIA, Ting-xu YAN*
Affiliations
  • College of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, China
出版时间: 2026-03-12 doi: 10.16438/j.0513-4870.2025-0783
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抑郁症是一种常见的心理疾病。前期研究发现, 五味子木脂素(Schisandra chinensis lignans, SCL) 对抑郁症有明显的治疗作用, 但其抗抑郁机制探究尚不完全。本研究基于SCL神经保护的现代药理作用及大麻素Ⅰ型受体(cannabinoid type 1 receptor, CB1R) 保护神经元的生理功能, 旨在阐述SCL发挥神经保护、抗抑郁的分子作用机制。通过构建慢性不可预知性温和刺激(chronic unpredictable mild stress, CUMS) 诱导的抑郁模型, 以及CB1R拮抗剂AM251干预CUMS动物模型, 采用药理行为学实验考察SCL改善小鼠抑郁样行为能力, 并采用蛋白免疫印记法(Western blot)、苏木精-伊红(H&E) 染色、免疫组化检测(IHC)、免疫荧光检测、分子对接等实验方法, 研究SCL通过CB1R调控脑源性神经营养因子(brain-derived neurotrophic factor, BDNF) 发挥抗抑郁作用的机制。实验所用动物获得沈阳药科大学伦理委员会批准, 伦理审查编号: SYPU-IACUC-C2021-11-3-115。药理行为学实验结果表明, SCL可缓解CUMS模型小鼠抑郁样行为。H&E染色结果显示, SCL可减轻CUMS模型造成的小鼠神经元病理损伤及神经可塑性损伤。Western blot结果表明, SCL可上调BDNF和CB1R的表达, 激活proBDNF-tPA-BDNF通路促进proBDNF裂解, 发挥抗凋亡的作用, 激活BDNF-TrkB-MEK-ERK-PKA-CREB和PI3K-AKT通路减轻神经元损伤, 发挥抗抑郁作用。进一步实验结果证实, AM251拮抗了SCL所发挥的减缓抑郁样行为及对BDNF关联通路的调节作用, 即SCL通过CB1R激活proBDNF-tPA-BDNF, 促进BDNF的生成, 发挥抗凋亡作用, 同时激活下游经典通路BDNF-TrkB-ERK-PI3K-AKT, 保护神经元, 发挥抗抑郁的作用。分子对接结果显示了SCL中6种主要成分对CB1R发挥作用的位点。该研究揭示了SCL通过CB1R调控BDNF减轻神经元损伤, 发挥抗抑郁作用。

五味子木脂素  /  大麻素Ⅰ型受体  /  脑源性神经营养因子  /  抑郁症  /  神经保护

Depression is a common mental disorder. Previous studies have found that Schisandra chinensis lignans (SCL) exhibit significant therapeutic effects on depression, though its antidepressant mechanisms remain incompletely understood. This study aims to elucidate the molecular mechanisms by which SCL exerts neuroprotective and antidepressant effects, based on SCL's modern pharmacological neuroprotective properties and the physiological function of cannabinoid type 1 receptor (CB1R) in neuronal protection. By establishing a chronic unpredictable mild stress (CUMS)-induced depression model and administering CB1R antagonist AM251 to CUMS-treated animals, we conducted pharmacobehavioral experiments to evaluate SCL's ability to improve depression-like behaviors in mice. Additionally, we employed Western blot, hematoxylin-eosin staining, immunohistochemistry, immunofluorescence, and molecular docking to investigate SCL's antidepressant mechanism through CB1R-mediated regulation of brain-derived neurotrophic factor (BDNF). The use of animals in this study was approved by the Ethics Committee of Shenyang Pharmaceutical University, with the approval number: SYPU-IACUC-C2021-11-3-115. Pharmacobehavioral results demonstrated that SCL alleviates depression-like behaviors in CUMS model mice. Hematoxylin-eosin staining revealed that SCL improves neuronal pathological damage and neuroplasticity impairment caused by CUMS in the model. Western blot analysis revealed that SCL upregulates BDNF and CB1R expression, activates the proBDNF-tPA-BDNF pathway to promote proBDNF cleavage, and exerts anti-apoptotic effects. It also activates BDNF-TrkB-MEK-ERK-PKA-CREB and PI3K-AKT pathways to reduce neuronal damage and exert antidepressant effects. Further experiments confirmed that AM251 antagonized SCL's antidepressant effects by inhibiting its depression-like behavior and modulation of BDNF-related pathways. Specifically, SCL activates proBDNF-tPA-BDNF via CB1R to enhance BDNF production and anti-apoptotic effects, while simultaneously activating the downstream classical pathway BDNF-TrkB-ERK-PI3K-AKT to protect neurons and exert antidepressant effects. Molecular docking revealed the binding sites of six major components in SCL for CB1R. The study revealed that SCL exerts antidepressant effects by regulating BDNF through CB1R to alleviate neuronal damage.

Schisandra chinensis lignans  /  cannabinoid type Ⅰ receptor  /  brain-derived neurotrophic factor  /  depression  /  neuroprotection
郭振凤, 侯美屹, 李京轩, 贾英, 颜廷旭. 五味子木脂素基于大麻素Ⅰ型受体调控脑源性神经营养因子抗抑郁作用机制研究. 药学学报, 2026 , 61 (3) : 802 -812 . DOI: 10.16438/j.0513-4870.2025-0783
Zhen-feng GUO, Mei-yi HOU, Jing-xuan LI, Ying JIA, Ting-xu YAN. The antidepressant mechanisms of Schisandra chinensis lignans via mediating cannabinoid type Ⅰ receptors to regulate brain-derived neurotrophic factor[J]. Acta Pharmaceutica Sinica, 2026 , 61 (3) : 802 -812 . DOI: 10.16438/j.0513-4870.2025-0783
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抑郁症是以长期的情绪低落、兴趣减退、思维迟缓等为主要表现的一种精神情感障碍性疾病[1], 伴有负性认知状态、顽固性睡眠障碍、自主神经功能紊乱等心理躯体症状[2]。此外, 患者常表现出明显的紧张、焦虑和烦躁情绪, 并伴随有自责、自罪及负面自杀思维或行为的趋向[3]。全球约有5%的成年人患有抑郁症, 到2030年, 它将成为最常见的致残原因[4]。
抑郁症的发生与持续的压力和神经功能的破坏有关。持续的压力会导致神经元萎缩, 包括突触的丧失以及海马和前额叶皮质的尺寸减小。这些改变与神经功能障碍有关, 包括情绪障碍、认知障碍和行为改变[5]。神经营养因子是一类对神经元的发育、存活和凋亡起重要作用的蛋白质, 脑源性神经营养因子(brain-derived neurotrophic factor, BDNF) 与抑郁症的严重程度存在密切的关系。低BDNF水平可能导致神经元退化、突触失去稳定性和神经可塑性下降, 进而影响到情绪和认知功能[6]。酪氨酸受体激酶B (tropomyosin receptor kinase B, TrkB) 是BDNF特异性受体, 在大脑皮质、海马、小脑等脑组织中广泛表达, BDNF主要通过BDNF-TrkB信号转导来激活下游通路发挥神经保护作用, 该信号通路上的分子被广泛认为是治疗神经退行性疾病和神经损伤的潜在靶点。BDNF与TrkB结合后可激活MEK-ERK、PIK3-AKT等多条信号通路, 促进神经元细胞发育、分化、再生及存活, 对突触可塑性形成起重要作用[7]。临床研究表明, 抑郁症患者中TrkB表达减少, 这在自杀者前额叶皮质和海马区表现尤为显著[8]。小鼠的体内实验证实, 抗抑郁药物用于治疗时先促进BDNF的释放, 激活TrkB的自磷酸化及其下游信号通路, 后增加BDNF的表达[9]。前体BDNF (precursor BDNF, proBDNF) 在内质网中合成, 转运到高尔基体内装配后, 由调节释放型囊泡包裹在轴突末端释放, proBDNF释放出来后在胞内胞外蛋白水解酶作用下裂解为成熟形式的BDNF[10]。有实验表明, 组织纤溶酶原激活物(tissue-type plasminogen activatort, tPA) 可以促进proBDNF裂解成为BDNF, 通过上调tPA表达增强内源性BDNF产生, 继发性激活TrkB影响神经元的存活, 成为发挥神经保护、实现抗抑郁的有效策略[11]。
近年来研究表明, 内源性大麻素系统在神经保护及免疫调控中发挥作用[12]。大麻素Ⅰ型受体(cannabinoid type 1 receptor, CB1R) 与抑郁症中神经元功能失调和损伤关系最为密切。CB1R活性的减弱会导致啮齿类动物产生抑郁和焦虑样行为的作用。研究表明, 使用CB1R拮抗剂AM251拮抗CB1R能下调海马中BDNF蛋白表达, 并导致啮齿类动物的认知功能、情绪调节和运动协调能力受到严重损伤[13]。使用CB1R激动剂WIN55212-2激活CBIR受体, 可以增强其抗抑郁行为。因此, 基于CB1R探究神经保护作用在抗抑郁治疗中的应用极具意义。
五味子为木兰科植物五味子Schisandra chinensis (Turcz.) Baill.的干燥成熟果实, 具有收敛固涩、益气生津、补肾宁心的功效[14]。五味子包含多种化学成分, 其中五味子木脂素(Schisandra chinensis lignans, SCL) 具有抗炎、抗菌、抗肿瘤等多种作用, 并具有调节神经递质、抑制神经炎症反应、抑制细胞凋亡、保护中枢神经系统的功能, 被认为是治疗抑郁症、焦虑和阿尔茨海默病等神经类疾病的主要活性成分[15]。课题组前期研究证实[16], 五味子提取物可上调模型诱导降低的BDNF的表达, 而SCL通过激活CB2R-STAT6通路促进小胶质细胞极化至M2表型, 减缓炎症反应, 抑制神经元损伤, 促进神经元新生, 发挥神经保护作用; 同时, SCL回调CB1R水平。但SCL对BDNF的影响以及CB1R与BDNF在神经保护中的关联尚未明确。
因此, 本文主要研究基于SCL神经保护的药理作用、CB1R保护神经元的生理功能, 采用慢性不可预知性温和刺激(chronic unpredictable mild stress, CUMS) 构建抑郁模型、CB1R拮抗剂AM251干预CUMS动物模型, 探究SCL发挥抗抑郁作用的具体机制。
材料与方法
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药材与试剂  五味子药材购自沈阳市同仁堂药店, 经沈阳药科大学功能食品与葡萄酒学院贾英教授鉴定为木兰科植物五味子Schisandra chinensis (Turcz.) Baill.的干燥成熟果实; SDS-PAGE凝胶快速配制试剂盒、超敏ECL发光剂、BCA蛋白定量/浓度测定试剂盒(大连美仑生物技术有限公司); RIPA裂解液、磷酸化蛋白酶抑制剂、PMSF、PSD95 antibody、Bax antibody (武汉塞维尔生物科技有限公司); Bcl-2 antibody、tPA antibody (Proteintech Group公司); BDNF antibody、ERK antibody、p-ERK antibody、MEK antibody、p-MEK antibody、PKA antibody、CREB antibody、p-CREB antibody、cleaved caspase 3 antibody、caspase 3 antibody、TrkB antibody (杭州华安生物科技有限公司); PI3K antibody、cleaved caspase 9 antibody、caspase 9 antibody (成都正能生物技术有限责任公司); p-PI3K antibody、CB1R antibody (Affinity公司); p-AKT antibody (万类生物科技有限公司); AKT antibody (Cell Signaling Technology公司); p-TrkB antibody (Novus Biologicals公司); proBDNF antibody (Santa Cruz公司); H&E染色(hematoxylin-eosin staining) 试剂盒(武汉蛋白美生物科技有限公司); 羧甲基纤维素钠(国药集团化学试剂有限公司); 甲醇、无水乙醇(分析纯, 天津市大茂化学试剂厂); AM251、WIN55212-2 (MedChemExpress公司)。
动物  7周龄雄性C57BL/6小鼠(16~20 g) 购自沈阳药科大学动物管理中心, 生产许可证号: SCXK (辽) 2020-0001, 伦理审查编号: SYPU-IACUC-C2021-11-3-115。
提取物的制备及CB1R拮抗剂、激动剂的配制  取1 000 g五味子药材, 粉碎过20目筛, 加95%乙醇加热回流提取3次, 每次2 h, 8层纱布过滤, 收集滤液, 减压浓缩至浸膏状态。按大孔树脂∶浸膏= 1∶10的比例称取AB-8型大孔树脂, 用95%乙醇处理后湿法装柱。用30%乙醇以每小时1 BV流速洗脱, Molish法检测为阴性后, 用70%乙醇洗脱。收集70%乙醇洗脱液, 减压回收得到SCL浸膏, 浸膏得取率为2.7%。用0.5% CMC-Na溶液溶解后用于动物给药。CB1R拮抗剂AM251由10% DMSO、40% PEG300、5% Tween-80和45% saline配制而成。CB1R激动剂WIN55212-2由WIN55212-2粉末溶于DMSO配制而成。
CUMS模型的建立  CUMS抑郁模型的建立主要包括以下几种不同的应激因子: ①昼夜颠倒12 h/12 h; ②禁食、禁水12 h; ③潮湿垫料12 h; ④夹尾(用止血钳在距尾尖端1 cm处夹1 min); ⑤冷水游泳(12 ℃) 5 min; ⑥电击足底4 s; ⑦高温环境(烘箱45 ℃ 5 min); ⑧陌生气味2 h; ⑨倾斜鼠笼(45° 12 h); ⑩摇晃鼠笼(10 min) 等。在动物造模7周内选择不同的应激刺激进行造模, 顺序随机, 连续两天不能出现同一刺激。
动物分组与给药方案  选用60只雄性C57BL/6小鼠研究SCL基于神经保护发挥抗抑郁作用的机制, 分5组, 每组12只, 每组给药基于生药剂量设定。小鼠适应性饲养1周后, 对除control组小鼠的所有小鼠连续造模7周, 在造模第4周时同时连续给药4周。其中, control组不做处理, 模型组灌胃给予0.5% CMC-Na, 低剂量组每天灌胃给予600 mg·kg-1 SCL, 高剂量组每天灌胃给予1 200 mg·kg-1 SCL, 阳性药组腹腔注射给予10 mg·kg-1氟西汀(fluoxetine, Flu)。在治疗阶段结束后, 进行行为评估。
另外选用60只雄性C57BL/6小鼠研究SCL通过CB1R调节BDNF发挥抗抑郁作用机制, 分6组, 每组10只。小鼠适应性饲养1周后, 对除control组小鼠外的所有小鼠造模, 连续造模7周, 在造模3周后进行给药, SCL (1 200 mg·kg-1)、AM251 (3 mg·kg-1)、AM251 (3 mg·kg-1) + SCL (1 200 mg·kg-1) 联合给药、WIN55212-2 (0.5 mg·kg-1) 连续给予4周。在治疗阶段结束后, 进行全面的行为评估。
行为学实验
蔗糖偏好实验(sucrose preference test, SPT) 蔗糖偏好实验可以评估小鼠对奖励的敏感性, 用于评估抑郁水平, 当小鼠抑郁后对于蔗糖的喜爱度下降[17]。每只小鼠提供2瓶1%蔗糖水, 12 h后换成2瓶纯净水, 次日禁水, 第3天进行实验, 每只小鼠分别获得1瓶1%蔗糖水和纯净水, 12 h后取出2个瓶子称重, 计算消耗量。蔗糖偏好率=蔗糖水消耗量/(纯净水消耗量+蔗糖水消耗量) × 100%。
强迫游泳实验(forced swimming test, FST) 强迫游泳实验模拟了抑郁小鼠因无法脱离困境而放弃挣扎的绝望感, 小鼠在水箱中的静止不动时间与其绝望感和抑郁水平呈正比[18]。将小鼠单独放入装有20 cm左右水(24 ± 2 ℃) 的透明水桶(直径10 cm, 高度25 cm) 中, 每只鼠测试6 min, 前2 min适应环境, 记录后4 min的不动时间。
旷场实验(open field test, OFT) 旷场实验是基于探索的行为学测试手段, 反映了小鼠在陌生环境中的独立和探索行为[19], 抑郁小鼠对旷场环境的好奇心弱、探索欲低, 其运动总距离、平均速度等相关指标明显减少。将小鼠单独放入旷场(50 cm × 50 cm × 30 cm) 正中央, 进行3 min自由探索后正式实验, 记录每只小鼠5 min内的轨迹。每次测试后, 用75%乙醇清洁设备, 去除残留气味。实验在隔音、光照和温度适宜的实验室进行。
H&E染色  处死小鼠后取全脑, 4%多聚甲醛固定24 h, 脱水, 石蜡包埋组织, 切片(5 μm), 65 ℃烘干, 二甲苯脱蜡2次, 每次10 min, PBS溶液冲洗3、4次, 每次5 min, 用H&E染色, 用显微镜观察和分析。
免疫组化检测  处死小鼠取全脑, 4%多聚甲醛固定, 石蜡包埋切成薄片, 载玻片贴取。60 ℃烘干, 二甲苯脱蜡2次, 每次10 min, PBS冲洗3次, 每次5 min, 于枸橼酸钠修复液中修复2次, 每次30 min, PBS冲洗, 滴加3%山羊血清封闭, 室温孵育10 min后去除多余液体, 加一抗, 4 ℃孵育过夜, PBS清洗, 加入与一抗特异性结合的二抗, 室温孵育, PBS清洗, 显微镜下观察。
Western blot  取小鼠海马组织称重, 1∶10加RIPA缓冲液裂解, 用组织破碎机匀浆, 冷冻离心取上清, BCA法测蛋白浓度。制备凝胶, 上样、电泳、转膜、用PBST配制5%脱脂奶粉封闭1.5 h。按照比例稀释PSD95 (1∶500)、BDNF (1∶800)、TrkB (1∶500)、p-TrkB (1∶500)、Bcl-2 (1∶1 000)、Bax (1∶500)、caspase 3 (1∶1 000)、cleaved caspase 3 (1∶500)、caspase 9 (1∶1 000)、cleaved caspase 9 (1∶500)、ERK (1∶1 000)、p-ERK (1∶1 000)、MEK (1∶500)、p-MEK (1∶500)、PKA (1∶500)、CREB (1∶500)、p-CREB (1∶500)、PI3K (1∶500)、p-PI3K (1∶500)、AKT (1∶500)、p-AKT (1∶500)、CB1R (1∶500)、proBDNF (1∶200)、tPA (1∶500) 等抗体。将封闭后的NC膜孵育相应的一抗4 ℃过夜, TBST洗脱3次, 每次12 min, 室温孵二抗2 h, TBST洗脱后在发光图像分析仪上扫描, 以β-actin作为参照, 用Image-Pro Plus 6.0软件定量分析。
分子对接  检索PDB数据库和PubChem数据库, 分别获取PDB格式的CB1R蛋白质结构(PDB ID为6wsk) 及SCL 6种活性成分(schisandrol A、schisandrol B、schisantherin A、schisantherin B、schizandrin A、schizandrin B) 的3D结构。采用PyMol 3.0.3软件去除蛋白3D结构的配体和水分子结构, 通过AutoDockTools 1.5.6进行加氢、计算电荷等预处理, 确定受体蛋白对接区域活性口袋后进行分子对接, 获得结合能及对接文件, 选取对接后结合能最低的复合物, 通过PyMol 3.0.3软件进行可视化分析。
数据分析  所有数据呈现为x ± s形式。数据分析采用GraphPad Prism 9.0软件, 通过单因素方差分析和t检验来评估各组间数据的显著性。P < 0.05表示数据有统计学差异。
结果
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1　SCL缓解CUMS模型小鼠抑郁样行为
行为学实验结果如表1所示, SPT中, 与CUMS组相比, SCL (L)、SCL (H) 和Flu治疗4周后小鼠的蔗糖偏好率显著上升。FST中, CUMS组小鼠的静止时间呈现显著的上升趋势, 而SCL (L)、SCL (H) 和Flu治疗4周后显著逆转由CUMS造成小鼠不动时间增长。OFT中, CUMS组小鼠穿格总距离明显低于control组, 而SCL (L)、SCL (H) 和Flu组给药后明显逆转这一变化, 说明模型组小鼠自主活动能力明显下降, 而SCL和Flu可调节抑郁小鼠自主活动能力, 改善小鼠抑郁样行为。
2　SCL减轻CUMS模型小鼠脑内神经元损伤及神经可塑性损伤
实验结果如图1A、B所示, control组小鼠海马区神经元细胞无明显皱缩呈正常形态, CUMS组小鼠神经元细胞明显皱缩, 染色变深, 胞核与胞质界限分明, 在SCL (H) 及Flu组中, 大部分神经元细胞形态恢复正常, 仅有少量细胞皱缩, 染色变深。以上结果说明, 高剂量SCL能够改善CUMS小鼠脑内神经元损伤。
使用Western blot考察SCL对海马中神经元凋亡蛋白的影响。如图1C~F所示, 与control组相比, CUMS组Bcl-2/Bax比值明显下调, cleaved caspase 3/caspase 3和cleaved caspase 9/caspase 9的比值显著上调, 经过SCL (L)、SCL (H) 和Flu治疗后, 上述结果均被显著逆转。以上结果表明, SCL可以明显减少CUMS小鼠海马神经元凋亡。此外, 为探讨SCL给药后海马神经突触可塑性是否受到影响, 本研究检测了标志性蛋白PSD95的表达水平。如图1G、H所示, 与control组相比, CUMS组小鼠PSD95的表达明显下降; 而SCL (L)、SCL (H) 及Flu组回调了CUMS模型小鼠PSD95的表达水平, 表明SCL可改善CUMS模型小鼠的神经可塑性损伤。
3　SCL促进proBDNF水解, 上调CUMS模型小鼠BDNF的表达
BDNF在海马中高度表达, 参与大脑中神经元增殖、神经可塑性、神经元存活, 发挥神经保护作用。本研究使用免疫组化检测对各组小鼠海马的BDNF表达进行了考察。阳性信号呈黄褐色, 深浅不一, 均为胞浆染色。如图2A、B所示, 与control组相比, CUMS组BDNF阳性率显著降低, 而SCL (H) 组中阳性率明显提升。以上结果表明, SCL可以上调CUMS小鼠海马中BDNF的表达。
此外, proBDNF经蛋白水解加工成BDNF, 而tPA是纤溶系统激活的关键物质, 故tPA纤溶酶系统在BDNF转化中起着重要作用。检测proBDNF、tPA、BDNF的表达, 结果如图2C~F所示, 与control组相比, CUMS组小鼠tPA、BDNF的表达均降低, proBDNF的表达水平显著增高, 经过SCL治疗4周后, SCL (H) 组中tPA、BDNF的表达明显升高, 而proBDNF的表达水平显著下降, 结果表明SCL可能通过proBDNF的酶切反应增加BDNF的表达。
4　SCL激活TrkB相关信号通路发挥抗抑郁作用
TrkB-MEK-ERK信号通路是细胞命运的重要调节因子, MEK和ERK的激活对于细胞存活与生长至关重要。因此本研究考察了相关蛋白的变化, 采用Western blot检测小鼠海马组织中TrkB、p-TrkB、MEK、p-MEK、ERK、p-ERK、PKA、p-CREB、CREB蛋白的表达水平。结果如图3A~G所示, 与control组相比, CUMS组小鼠海马组织中TrkB、p-TrkB、PKA的表达和p-MEK/MEK、p-ERK/ERK、p-CREB/CREB的比值显著降低, 经过给药后发现, SCL (H) 可以显著逆转上述变化。结果表明, SCL可能通过TrkB-MEK-ERK通路激活PKA, 促进BDNF的分泌, 从而发挥保护神经元的作用。
5　SCL激活PI3K-AKT通路发挥抗抑郁作用
研究表明, 激活的BDNF-TrkB会刺激中枢神经系统中广泛表达的下游通路信号PI3K-AKT, 从而促进神经元细胞的存活与增殖。图4A~C所示, 与control组相比, CUMS组中p-PI3K/PI3K、p-AKT/AKT比值均下降, 而经过SCL治疗后p-PI3K/PI3K、p-AKT/AKT的比值显著提高, 表明SCL可能通过增强PI3K-AKT信号传导途径来发挥有效保护神经元的作用。
6　SCL通过CB1R降低CUMS小鼠海马神经元凋亡水平
CB1R是中枢神经系统中最丰富的大麻素受体, 主要分布于脑、脊髓和外周神经系统中, 高表达于脑内的基底神经核, 广泛参与学习记忆、认知和运动行为的调控。临床研究和动物模型表明, 内源性大麻素系统信号的衰减与焦虑、抑郁和精神分裂症等精神障碍的发展相关[20]。与BDNF相同, CB1R具有防止神经元损伤、发挥神经保护的作用。本研究利用Western blot检测了CB1R蛋白表达, 如图5A、B所示, 与control组相比, CUMS组CB1R蛋白表达下降, 经过SCL (H) 治疗后CB1R蛋白表达上调。
CB1R药理拮抗模型的行为学实验结果如表2所示, 在SPT中, 与control组相比, CUMS组小鼠与AM251组小鼠对蔗糖的喜爱度显著降低。经过4周药物治疗后, SCL (H) 组和WIN55212-2组中小鼠对于蔗糖的喜爱度明显提升; 与SCL (H) 组相比, SCL (H) 和AM251共同给药组小鼠对蔗糖的偏好率明显下降, 说明AM251抑制了SCL提高蔗糖偏好率的作用, 即SCL通过CB1R逆转CUMS模型小鼠的低SPT水平。在OFT中, 与control组小鼠相比, CUMS组小鼠与AM251组小鼠穿越格子距离明显降低, 经过SCL (H) 4周治疗后小鼠的运动总距离明显提高, 自主能力变强; 与SCL (H) 组相比, SCL (H) 和AM251共同给药组小鼠的运动总距离明显下降。以上实验结果可以表明, AM251抑制了SCL增加CUMS模型小鼠OFT穿格总距离, 即SCL通过CB1R缓解CUMS抑郁小鼠焦虑样行为的作用。
加入拮抗剂AM251后探究SCL对CB1R的影响。结果如图6A、B所示, SCL (H) 可上调CUMS诱导降低的CB1R蛋白表达, 而SCL (H) 和AM251共同处理后, CB1R的表达量显著低于SCL (H) 组。
SCL通过CB1R对神经元存活的影响结果如图6C~F所示, 与control组相比, CUMS组小鼠与AM251组小鼠的Bcl-2/Bax比值明显下调, cleaved caspase 3/caspase 3、cleaved caspase 9/caspase 9的表达显著上调, 经过SCL 4周治疗后, 上述结果被逆转; 与SCL (H) 组相比, SCL (H) 和AM251共同处理组中Bcl-2/Bax的表达被显著抑制, cleaved caspase 3/caspase 3、cleaved caspase 9/caspase 9的表达显著上调。结果表明, SCL通过CB1R改善CUMS诱导的神经元凋亡。
7　SCL通过CB1R促进proBDNF水解上调BDNF的表达
验证SCL是否通过CB1R影响BDNF的表达, 通过免疫组化检测考察给予AM251后小鼠脑内BDNF的表达情况。结果如图7A、B所示, 与control组相比, CUMS组与AM251组小鼠脑内BDNF的阳性率显著下降, 而经过SCL (H) 治疗后BDNF阳性率显著上升; 与SCL (H) 相比, SCL (H) 和AM251共同给药组小鼠脑内BDNF阳性率表达降低。以上结果说明, SCL通过CB1R影响BDNF的表达。
抑制CB1R后探究SCL对proBDNF-tPA-BDNF的影响。结果如图7C~F所示, 与SCL (H) 相比, SCL (H) 和AM251共同处理后, tPA、BDNF的表达量显著低于SCL (H) 组, proBDNF的表达量显著高于SCL (H) 组。以上结果表明, AM251拮抗了SCL促进proBDNF酶切反应的作用。
8　SCL通过CB1R激活TrkB和PI3K-AKT信号通路发挥抗抑郁作用
抑制CB1R后探究SCL对小鼠海马中BDNF-TrkB-ERK的影响。结果如图7G~J所示, 与SCL (H) 组相比, SCL (H) 和AM251联合用药后, 小鼠海马中p-TrkB和TrkB表达以及p-ERK/ERK比值显著下调, 表明AM251抑制了SCL对CUMS抑郁小鼠海马BDNF-TrkB-ERK通路的激活。
抑制CB1R后探究SCL对小鼠海马中PI3K-AKT的影响。结果如图7K~M所示, 与control组相比, CUMS组和AM251组p-PI3K/PI3K和pAKT/AKT比值显著下降, 经过SCL治疗后, 上述结果被逆转; 与SCL (H) 组相比, SCL (H) 和AM251联合用药后, 小鼠海马中p-PI3K/PI3K和p-AKT/AKT的比值显著下调, 表明AM251抑制了SCL对CUMS抑郁小鼠海马PI3K-AKT通路的激活。
9　分子对接
本研究利用分子对接技术, 探讨实验室前期证实的SCL中的6种成分与CB1R之间结合的分子作用关系。结果如表3所示, 结合能均小于-5.0 kal·mol-1。当活性成分与靶点蛋白结合形成稳定构象时, 能量越低, 结构越稳定, 即schisantherin A、schizandrin B与CB1R之间的结合能较低, 结构较稳定。其中, schisantherin A与CB1R在GLY-135、LEU-133处形成2个氢键, schizandrin B与CB1R在ILE-28处形成1个氢键。分子对接图如图8所示。
讨论
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抑郁症是由神经再生、神经内分泌和神经生物化学功能失调引起的心理健康障碍, 常导致认知功能障碍和紊乱。对抑郁症致病机制的研究已经成为现代医学发展面临的巨大难关, 其有效防治已成为亟待解决的公共卫生问题[21]。目前, 治疗抑郁症的方法层出不穷, 不管是药物治疗、心理治疗、物理治疗, 还是多种治疗手段联合, 但由于抑郁症是一种具有显著异质性的疾病, 治疗效果在不同患者身上差异极大。临床中多采用西医传统抗抑郁药进行干预, 虽有一定疗效, 但起效与治疗时间较长, 停药后易复发、成瘾性、自杀率高等弊端亦不容忽视[22]。市售药物一般针对5-羟色胺再摄取这个单一靶点。选用中药防治抑郁症, 可发挥多成分、多靶点、多途径的作用特点[23], 且成瘾性及毒副作用小。五味子为补虚固本中药, 可收敛固涩、益气生津、宁心安神, 其中提取的SCL已被证实具有镇静催眠、改善认知的作用[24]。本研究以SCL为研究对象, 通过体内实验对其抗抑郁作用的具体机制进行研究。
抑郁样行为产生的重要原因之一是长期暴露在慢性压力环境之下, 本研究选用CUMS构建抑郁样行为小鼠模型, 通过行为学实验观察SCL对CUMS模型小鼠的干预作用, 行为结果证实SCL可以改善小鼠抑郁样行为。H&E染色结果显示, CUMS模型能够造成小鼠神经元病理损伤, 而SCL可以逆转上述结果, 同时促进神经可塑性及细胞存活。
BDNF是一种脑神经营养因子, 通过促进神经元存活和分化来维持神经元功能。本研究也证实了这一点, SCL上调BDNF的表达可以减轻神经细胞的损伤, 发挥神经保护作用。proBDNF是BDNF前体, 经过tPA剪切生成BDNF, Western blot结果表明SCL可激活proBDNF-tPA-BDNF通路促进proBDNF裂解, 发挥抗凋亡及神经保护的作用。BDNF-TrkB通路是学习和记忆、情绪调节、神经发育等行为的重要调节通路, 其信号途径涉及多种信号分子与通路, 如PI3K/AKT等, 这些通路可能与BDNF的合成或发挥生理作用相关。本研究考察了相关通路, 发现SCL可以通过激活BDNF-TrkB-MEK-ERK-PKA-CREB和PI3K-AKT通路来改善神经元损伤, 发挥抗抑郁作用。
研究表明, 小鼠脑内CB1R与BDNF表达之间存在密切联系。本实验通过构建CB1R拮抗剂AM251干预动物模型, 发现AM251拮抗了SCL缓解抑郁样行为的作用, 且抑制了SCL对神经元凋亡的改善作用, 证实了SCL通过CB1R调控BDNF改善神经元损伤。免疫组化检测结果表明, AM251拮抗了SCL对BDNF的调节作用。Western blot结果表明, AM251拮抗了SCL对proBDNF-tPA-BDNF通路的激活, 减弱了SCL对BDNF-TrkB-ERK和PI3K-AKT通路的激活作用。分子对接结果显示了SCL对CB1R发挥作用的可能位点, 即6种主要成分与CB1R分别在LEU-133、THR-56、LYS-148、GLY-135、GLU-57、GLU-160、ASN-33、ILE-28处形成氢键, 且其与CB1R之间的结合能均小于-5.0 kal·mol-1, 结构较稳定, 验证了SCL活性成分与CB1R有较强的结合能力。综上, SCL可以介导CB1R激活proBDNF-tPA-BDNF促进BDNF的生成, 发挥抗凋亡作用, 同时激活下游经典通路BDNF-TrkB-ERK-PI3K-AKT保护神经元, 发挥抗抑郁的作用。
本研究证明了SCL介导CB1R调控BDNF改善神经元损伤、发挥抗抑郁作用的具体机制。

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2026年第61卷第3期
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doi: 10.16438/j.0513-4870.2025-0783
  • 接收时间：2025-07-07
  • 首发时间：2026-09-21
  • 出版时间：2026-03-12
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  • 收稿日期：2025-07-07
  • 修回日期：2025-10-26
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    沈阳药科大学功能食品与葡萄酒学院, 辽宁 沈阳 110016

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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