Abstract
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). Sinomenine (SIN), a bioactive alkaloid extracted from the Chinese medicinal plant Sinomenium acutum, has powerful anti-inflammatory and immunosuppressive therapeutic benefits. In our previous research, we found that SIN increased resistance to oxidative stress via the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in PC12 neuronal cells. However, whether SIN can improve the symptoms and pathological features of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, via the Nrf2 signaling pathway remains unclear. EAE was immunized followed by SIN treatment. Then we evaluated the effects of SIN in EAE. Subsequently, primary microglia were cultured to explore the effect of SIN on microglia activation. Further, the levels of Nrf2 and its downstream molecules were detected to assess the molecular mechanisms of SIN. We demonstrated that SIN effectively ameliorated the severity of EAE, accompanied by a reduction in the demyelination, axonal damage and inhibition of inflammatory cell infiltration. Mechanistically, SIN decreased the inflammatory cytokines expression, and suppressed microglia and astrocytes activation in EAE mice. Furthermore, SIN suppressed lipopolysaccharide (LPS)-induced microglial activation and the production of pro-inflammatory factors in vitro. Moreover, SIN inhibited oxidative stress via the activation of the Nrf2 signaling pathway. Our work proves that SIN exerts its neuroprotective effects by the Nrf2-dependent anti-oxidative stress and diminishing neuroinflammation, suggesting that the “antioxiflammation” effect of SIN is expected to be an ideal treatment strategy for MS/EAE.
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Data Availability
The datasets used and analyzed in the present study are available from the corresponding author on reasonable request.
Abbreviations
- ANOVA:
-
Analysis of variance
- AOPP:
-
Advanced oxidation protein products
- ARE:
-
Antioxidant-responsive elements
- BBB:
-
Blood-brain barrier
- BSA:
-
Bovine serum albumin
- cDNA:
-
Complementary DNA
- CNS:
-
Central nervous system
- COX-2:
-
Cyclooxygenase-2
- DAPI:
-
4′, 6-diamidino‐2‐phenylindole
- dHEt:
-
Dihydroethidium
- DMSO:
-
Dimethyl sulfoxide
- DNA:
-
Deoxyribonucleic acid
- EAE:
-
Experimental autoimmune encephalomyelitis
- Et:
-
Ethidium
- FITC:
-
Fluorescein isothiocyanate
- GFAP:
-
Glial fibrillary acidic protein
- GM-CSF:
-
Granulocyte-macrophage colony-stimulating factor
- H&E:
-
Hematoxylin and eosin
- HO-1:
-
Heme oxygenase-1
- i.p.:
-
Intraperitoneal injection
- Iba1:
-
Ionized calcium binding adaptor molecule 1
- IL:
-
Interleukin
- iNOS:
-
Inducible nitric oxide synthase
- LFB:
-
Luxol fast blue
- LPS:
-
Lipopolysaccharide
- MBP:
-
Myelin basic protein
- MCP-1:
-
Monocyte chemoattractant protein-1
- MDA:
-
Malondialdehyde
- MOG:
-
Myelin oligodendrocyte glycoprotein
- MS:
-
Multiple sclerosis
- NF:
-
Neurofilaments
- NO:
-
Nitric oxide
- NQO1:
-
NAD(P)H: quinone oxidoreductase 1
- Nrf2:
-
Nuclear factor erythroid 2-related factor 2
- NADPH:
-
Nicotinamide adenine dinucleotide phosphate
- PBS:
-
Phosphate-buffered saline
- PFA:
-
Paraformaldehyde
- qPCR:
-
Quantitative polymerase chain reaction
- RNA:
-
Ribonucleic acid
- ROS:
-
Reactive oxygen species
- SD:
-
Standard deviation of the mean
- SIN:
-
Sinomenine
- TBST:
-
Tris-buffered saline/0.1% Tween-20
- Th:
-
T helper
- TNF-α:
-
Tumor necrosis factor-α
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Acknowledgements
This work was supported by the National Nature Science Foundation of China (Grant nos. U1504808 and 81801201), the Henan Provincial Key R&D and Promotion Project (Grant no. 212102311042) and the Henan Provincial Science and Technology R&D Project (Grant no. 222103810048).
Funding
This work was supported by the National Nature Science Foundation of China (Grant nos. U1504808 and 81801201), the Henan Provincial Key R&D and Promotion Project (Grant no. 212102311042) and the Henan Provincial Science and Technology R&D Project (Grant no. 222103810048).
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Hua Fan, Yanhui Yang, and Dongmei Wang conceived and designed the experiments; Yang Yang, Qianqian Bai, Xiaofei Shi, and Lele Zhang performed the experiments; Yang Yang and Qianqian Bai analyzed the data; Hua Fan, Yang Yang, and Qianqian Bai wrote the paper.
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Fan, H., Yang, Y., Bai, Q. et al. Neuroprotective Effects of Sinomenine on Experimental Autoimmune Encephalomyelitis via Anti-Inflammatory and Nrf2-Dependent Anti-Oxidative Stress Activity. Neuromol Med 25, 545–562 (2023). https://doi.org/10.1007/s12017-023-08756-z
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DOI: https://doi.org/10.1007/s12017-023-08756-z