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PreprintCited by 0Neurological Disease Mechanisms and TreatmentsSphingolipid Metabolism and SignalingNeurogenesis and neuroplasticity mechanisms

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Danggui-Shaoyao-San modulates sphingolipid metabolism to promote oligodendrocyte differentiation and maturation in vascular dementia rats

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Su, Yue, Zhong, Yuying, Yuan, Ningning, Li, Xiang, Xu, Ying, Yang, Hui, Huang, Mengmeng, Zhang, Yafeng, Cheng, Xiaolan·2025·Chinese Medicine
DOI 10.21203/rs.3.rs-7241365/v1PMC PMC12777056

Preprint — published as 10.1186/s13020-025-01284-x · Paper page

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Abstract

Objective Vascular dementia (VaD) is a neurodegenerative disease primarily characterized by white matter injury and myelin degeneration, and currently, there is a lack of effective treatment options. This study aims to investigate the effects of the traditional Chinese medicine formula Danggui Shaoyao San (DSS) on cognitive function and myelin repair in VaD rats and to elucidate its underlying mechanisms. Methods The VaD rat model was established using the bilateral common carotid artery ligation (2VO) method. The effects of DSS on cognitive function, myelin regeneration, sphingolipid metabolism, and SPHK2/S1P/S1PR5 pathway was conducted using behavioral tests, histological staining, Western blot, lipidomics, qPCR, immunofluorescence, LC-MS/MS, and 16S rRNA sequencing. Besides, molecular docking and molecular dynamics simulation were carried out. Results DSS treatment significantly improved learning and memory abilities in VaD rats, reduced structural damage in the hippocampus and white matter, and promoted the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs). Lipidomics and molecular biological experiments indicated that DSS activated the SPHK2/S1P/S1PR5 pathway, ameliorated sphingolipid metabolic disorders and increased S1P levels, thereby promoting myelin repair. The specific SPHK2 inhibitor ABC294640 significantly weakened the neuroprotective effects of DSS, further confirming the central role of SPHK2/S1P/S1PR5 pathway. Antibiotic depletion experiments confirmed that the gut microbiota was not a key mediator of the therapeutic effects of DSS. Finally, molecular docking and molecular dynamics simulations indicated that the DSS components Albiflorin and Gallic acid form tighter and more stable interactions with SPHK2. Conclusion DSS improved VaD cognitive impairment by modulating sphingolipid metabolism and promote myelin regenerationa via activating the SPHK2/S1P/S1PR5/SOX10 signaling pathway. This study provides important experimental evidence for the clinical application of DSS in VaD.

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Fig. 1 DSS improved learning memory function of VaD rats. A Flowchart of the experimental procedure. B Body weight changes in rats throughout the experimental period. C Path traces during the morris water maze test. D Average swimming speed in the Morris water maze experiment (E) Times of platform crossings in the Morris water maze test. F Time spent in the target quadrant during the Morris water maze test. G Escape latency in the Morris water maze test
Fig. 1 DSS improved learning memory function of VaD rats. A Flowchart of the experimental procedure. B Body weight changes in rats throughout the experimental period. C Path traces during the morris water maze test. D Average swimming speed in the Morris water maze experiment (E) Times of platform crossings in the Morris water maze test. F Time spent in the target quadrant during the Morris water maze test. G Escape latency in the Morris water maze testCC BY · PubMed Central
Fig. 2 DSS improved the structural damage of hippocampal and white matter tissue. A Hematoxylin and eosin (HE) staining of the hippocampal CA1 region. B Luxol Fast Blue (LFB) staining of white matter. C Transmission electron microscopy (TEM) images displaying the ultrastructure of myelin sheaths. D G-ratio analysis of myelin sheaths. E–F Quantification of MAG and MBP expression in white matter of rats by RT-qPCR. G Western blot analysis of MAG and MBP expression in white matter of rats. H-I Quantification of MAG and MBP expression from Western blot data
Fig. 2 DSS improved the structural damage of hippocampal and white matter tissue. A Hematoxylin and eosin (HE) staining of the hippocampal CA1 region. B Luxol Fast Blue (LFB) staining of white matter. C Transmission electron microscopy (TEM) images displaying the ultrastructure of myelin sheaths. D G-ratio analysis of myelin sheaths. E–F Quantification of MAG and MBP expression in white matter of rats by RT-qPCR. G Western blot analysis of MAG and MBP expression in white matter of rats. H-I Quantification of MAG and MBP expression from Western blot dataCC BY · PubMed Central
Fig. 3 DSS promoted OPC differentiation in VaD rats. A–D Immunofluorescence staining for oligodendrocyte precursor cells (NG2) and mature oligodendrocytes (MBP). E–G Gene expression analysis of differentiation markers (p38MAPK, Sox10, Myrf) in white matter of rats by RT-qPCR. H–K Western blot analysis of p38MAPK, Sox10 and Myrf in white matter of rats
Fig. 3 DSS promoted OPC differentiation in VaD rats. A–D Immunofluorescence staining for oligodendrocyte precursor cells (NG2) and mature oligodendrocytes (MBP). E–G Gene expression analysis of differentiation markers (p38MAPK, Sox10, Myrf) in white matter of rats by RT-qPCR. H–K Western blot analysis of p38MAPK, Sox10 and Myrf in white matter of ratsCC BY · PubMed Central
Fig. 4 DSS improved sphingolipid metabolism levels in serum of VaD rats. A OPLS-DA score plots of lipid profiles in serum samples from three groups of rats. B The types and proportions of lipid metabolites in rat serum were detected using the LC–MS/MS method. C Volcano plot to visualize differential metabolites of significance between the sham/model group (left) and the model/H-DSS group (right). Metabolites with p value ≤ 0.05 are highlighted in red (up-regulated) and blue (down-regulated). D Types and ratios of lipid metabolites in sphingomyelin from rat serum. E-L Identification and quantification of sphingomyelins (Cer, SM, HerCer, S1P) between the three rat groups
Fig. 4 DSS improved sphingolipid metabolism levels in serum of VaD rats. A OPLS-DA score plots of lipid profiles in serum samples from three groups of rats. B The types and proportions of lipid metabolites in rat serum were detected using the LC–MS/MS method. C Volcano plot to visualize differential metabolites of significance between the sham/model group (left) and the model/H-DSS group (right). Metabolites with p value ≤ 0.05 are highlighted in red (up-regulated) and blue (down-regulated). D Types and ratios of lipid metabolites in sphingomyelin from rat serum. E-L Identification and quantification of sphingomyelins (Cer, SM, HerCer, S1P) between the three rat groupsCC BY · PubMed Central
Fig. 5 DSS activated the SPHK2/S1P/S1PR5 signaling in white matter of VaD rats. A–E Quantification of sphingolipid metabolites (S1P, Cer, SM, HexCer, Sph) in white matter using biochemical assays. F–J Gene expression analysis of sphingolipid metabolism enzymes and receptors (SPHK2, SPHK1, S1PR1, S1PR3, S1PR5). K–M Western blot analysis of sphingolipid-related proteins (SPHK2 and S1PR5)
Fig. 5 DSS activated the SPHK2/S1P/S1PR5 signaling in white matter of VaD rats. A–E Quantification of sphingolipid metabolites (S1P, Cer, SM, HexCer, Sph) in white matter using biochemical assays. F–J Gene expression analysis of sphingolipid metabolism enzymes and receptors (SPHK2, SPHK1, S1PR1, S1PR3, S1PR5). K–M Western blot analysis of sphingolipid-related proteins (SPHK2 and S1PR5)CC BY · PubMed Central
Fig. 6 SPHK2 inhibitor ABC294640 significantly diminished the improvement of DSS on cognitive impairment and sphingolipid metabolism in VaD rats. A–D Morris water maze test performance after SPHK2 inhibition. E–F Novel object recognition test after SPHK2 inhibition. G Luxol Fast Blue (LFB) staining of white matter after SPHK2 inhibition
Fig. 6 SPHK2 inhibitor ABC294640 significantly diminished the improvement of DSS on cognitive impairment and sphingolipid metabolism in VaD rats. A–D Morris water maze test performance after SPHK2 inhibition. E–F Novel object recognition test after SPHK2 inhibition. G Luxol Fast Blue (LFB) staining of white matter after SPHK2 inhibitionCC BY · PubMed Central
Fig. 7 The effect of SPHK2 inhibitor ABC294640 on DSS-induced promotion of oligodendrocyte differentiation. A Immunofluorescence staining of MBP (myelin basic protein) in white matter tissue. B Quantification of MBP-positive cells from immunofluorescence staining. C Immunofluorescence staining of NG2, OLG2 in white matter tissue. D Quantification of NG2-positive cells from immunofluorescence staining. E Immunofluorescence staining of EdU and CNPase in white matter tissue. F Quantification of EdU-positive and CNPase-positive cells from immunofluorescence staining
Fig. 7 The effect of SPHK2 inhibitor ABC294640 on DSS-induced promotion of oligodendrocyte differentiation. A Immunofluorescence staining of MBP (myelin basic protein) in white matter tissue. B Quantification of MBP-positive cells from immunofluorescence staining. C Immunofluorescence staining of NG2, OLG2 in white matter tissue. D Quantification of NG2-positive cells from immunofluorescence staining. E Immunofluorescence staining of EdU and CNPase in white matter tissue. F Quantification of EdU-positive and CNPase-positive cells from immunofluorescence stainingCC BY · PubMed Central
Fig. 8 Effect of DSS on gut microbiota and cognitive function in VaD rats. A Principal Coordinate Analysis (PCoA) of gut microbiota composition from 16S rRNA gene sequencing, showing separation of microbial communities among the groups. B Relative abundance of gut microbiota at the phylum level across the groups. C The proportions of the main phyla, including Firmicutes, Bacteroidota, and others, in each group. D Path tracing of rats in the Morris water maze test across the groups. E Escape latency in the Morris water maze test across the groups. F Time spent in the target quadrant during the Morris water maze test across the groups. G Number of platform crossings in the Morris water maze test across the groups. H Cognitive index in the novel object recognition test at 1 h across the groups. I Cognitive index in the novel object recognition test at 24 h across the groups
Fig. 8 Effect of DSS on gut microbiota and cognitive function in VaD rats. A Principal Coordinate Analysis (PCoA) of gut microbiota composition from 16S rRNA gene sequencing, showing separation of microbial communities among the groups. B Relative abundance of gut microbiota at the phylum level across the groups. C The proportions of the main phyla, including Firmicutes, Bacteroidota, and others, in each group. D Path tracing of rats in the Morris water maze test across the groups. E Escape latency in the Morris water maze test across the groups. F Time spent in the target quadrant during the Morris water maze test across the groups. G Number of platform crossings in the Morris water maze test across the groups. H Cognitive index in the novel object recognition test at 1 h across the groups. I Cognitive index in the novel object recognition test at 24 h across the groupsCC BY · PubMed Central
Fig. 9 Molecular docking analysis of DSS active components with SPHK2. A–E The docking poses of ligustrazine (− 5.5 kcal/mol), albiflorin (− 8.91 kcal/mol), ligustilide (− 7.39 kcal/mol), ferulic Acid (− 6.39 kcal/mol), and gallic acid (− 6.31 kcal/mol) with SPHK2
Fig. 9 Molecular docking analysis of DSS active components with SPHK2. A–E The docking poses of ligustrazine (− 5.5 kcal/mol), albiflorin (− 8.91 kcal/mol), ligustilide (− 7.39 kcal/mol), ferulic Acid (− 6.39 kcal/mol), and gallic acid (− 6.31 kcal/mol) with SPHK2CC BY · PubMed Central
Fig. 10 Molecular dynamics simulation results of DSS active components with SPHK2. A-D RMSD, Rg, RMSF and hydrogen bond number analysis for Ligustrazine-SPHK2 complex. E–H RMSD, Rg, RMSF and hydrogen bond number analysis for Albiflorin-SPHK2 complex. I-L RMSD, Rg, RMSF and hydrogen bond number analysis for Ligustilide-SPHK2 complex. M-P RMSD, Rg, RMSF and hydrogen bond number analysis for Ferulic Acid-SPHK2 complex. Q–T RMSD, Rg, RMSF and hydrogen bond number analysis for Gallic acid-SPHK2 complex
Fig. 10 Molecular dynamics simulation results of DSS active components with SPHK2. A-D RMSD, Rg, RMSF and hydrogen bond number analysis for Ligustrazine-SPHK2 complex. E–H RMSD, Rg, RMSF and hydrogen bond number analysis for Albiflorin-SPHK2 complex. I-L RMSD, Rg, RMSF and hydrogen bond number analysis for Ligustilide-SPHK2 complex. M-P RMSD, Rg, RMSF and hydrogen bond number analysis for Ferulic Acid-SPHK2 complex. Q–T RMSD, Rg, RMSF and hydrogen bond number analysis for Gallic acid-SPHK2 complexCC BY · PubMed Central
Fig. 11 Microscale Thermophoresis (MST) experiment. A–D The binding affinities of Gallic acid (A), Ferulic acid (B), Ligustrazine (C), and Albiflorin (D) to SPHK2 protein were assessed using MST
Fig. 11 Microscale Thermophoresis (MST) experiment. A–D The binding affinities of Gallic acid (A), Ferulic acid (B), Ligustrazine (C), and Albiflorin (D) to SPHK2 protein were assessed using MSTCC BY · PubMed Central

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Metadata

Authors
Su, Y., Zhong, Y., Yuan, N., Li, X., Xu, Y., Yang, H., Huang, M., Zhang, Y., & Cheng, X.
Affiliations
  • Nanjing University of Chinese Medicine (CN)
  • Nanjing University of Chinese Medicine
Corresponding author
Cheng, Xiaolan
ORCID
Venue
Chinese Medicine
Publisher
Springer Science and Business Media LLC
Published
2025-08-12
Volume
21
Issue
1
Pages
11-11
ISSN
1749-8546 (ISSN-L)
DOI
10.21203/rs.3.rs-7241365/v1
PMC
PMC12777056
OpenAlex
W7119109165
Cited by
0
References
1
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Chinese Medicine (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (82274218)
Topics
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
Danggui Shaoyao San, vascular dementia, sphingolipid metabolism, oligodendrocyte differentiation, remyelination, sphingosine-1-phosphate, oligodendrocyte precursor cells, cognitive impairment, albiflorin, gallic acid, traditional Chinese medicine formula, bilateral common carotid artery occlusion, gut microbiota

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Su, Y., Zhong, Y., Yuan, N., Li, X., Xu, Y., Yang, H., Huang, M., Zhang, Y., & Cheng, X. (2025). Danggui-Shaoyao-San modulates sphingolipid metabolism to promote oligodendrocyte differentiation and maturation in vascular dementia rats. Chinese Medicine. https://doi.org/10.21203/rs.3.rs-7241365/v1

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