Abstract
Andrographolide (Andro), a labdane diterpene, possesses anti-inflammatory properties and has been used to treat numerous inflammatory diseases. Novel findings revealed that Andro might be vital in regulating pain. However, the contribution of Andro to chronic inflammatory pain has yet to be determined, and its underlying mechanism of action remains unknown. In this study, we observed that Andro attenuated mechanical allodynia in inflammatory pain mice induced by injecting complete Freund’s adjuvant (CFA) into the right hind paws. This analgesic effect of Andro is mainly dependent on its inhibition of microglial overactivation and the release of proinflammatory cytokines (TNF and IL-1β) in lumbar spinal cords of inflammatory pain model mice. More importantly, our data in vivo and in vitro revealed a negative role for Andro in regulating the TLR4/NF-κB signaling pathway, which might contribute to the inhibition of spinal microglial activation and proinflammatory cytokines production, and the improvement of paw withdrawal thresholds in a mouse model of chronic inflammatory pain evoked by CFA. We further found the potential interaction of Andro with TLR4/myeloid differentiation factor 2 heterodimer using molecular modeling, implying that TLR4 might be a potential target for Andro to exert an analgesic effect. Taken together, our findings demonstrated that the modulation of spinal microglial activation by Andro might be substantially conducive to managing chronic pain triggered by neuroinflammation.
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Data Availability
Datasets from this study are available from the corresponding author on reasonable request.
Abbreviations
- Andro:
-
Andrographolide
- CFA:
-
Complete Freund’s adjuvant
- CNS:
-
Central nervous system
- NF-κB:
-
Nuclear factor-kappa B
- TLR4:
-
Toll-like receptor 4
- LPS:
-
Lipopolysaccharide
- DMSO:
-
Dimethyl sulfoxide
- BW:
-
Body weight
- PWTs:
-
Paw withdrawal thresholds
- IHC:
-
Immunohistochemistry
- MD2:
-
Myeloid differentiation factor 2
- SD:
-
Standard deviation
- Iba-1:
-
Ionized calcium-binder adapter molecule 1
- i.p.:
-
Intraperitoneal
- qPCR:
-
Quantitative PCR
- RA:
-
Rheumatoid arthritis
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Funding
This research received financial support from Traditional Chinese Medicine Science and Technology Planning Project of Zhejiang Province (2022ZB336), Medical science and technology project of Ningbo (2022Y51) and Natural Science Foundation of Zhejiang Province (LY22H090008).
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Dan Wang, Zhengbing Lv and Qing Sheng designed the experiment. Dan Wang, Yongjian Zheng, Junjing Xie, Zhongteng Lu, Yanling Hu, Jianyuan Fu done the experiments. Dan Wang and Yongjian Zheng wrote the paper. Wenping Zhang and Wenwen Yu prepared the final draft of the paper.
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Wang, D., Zheng, Y., Xie, J. et al. Andrographolide inhibits the activation of spinal microglia and ameliorates mechanical allodynia. Metab Brain Dis 39, 115–127 (2024). https://doi.org/10.1007/s11011-023-01325-0
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DOI: https://doi.org/10.1007/s11011-023-01325-0