Abstract
Ac2-26, a mimetic peptide of Annexin-A1, plays a vital role in the anti-inflammatory response mediated by astrocytes. In this study, we aimed to explore the underlying mechanisms of Ac2-26-mediated anti-inflammatory effect. Specifically, we investigated the inhibitory effects of Ac2-26 on lipopolysaccharide (LPS)-induced astrocyte migration and on pro-inflammatory cytokines and chemokines expressions, as well as one glutathione (GSH) reductase mRNA and total intracellular GSH levels in LPS-induced astrocytes. Additionally, we investigated whether mitogen-activated protein kinases (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathway were involved in this process. Finally, we evaluated the analgesic effect of Ac2-26 in complete Freund’s adjuvant (CFA)-induced inflammatory pain model. Our results demonstrated that Ac2-26 inhibited LPS-induced astrocytes migration, reduced the production of pro-inflammatory mediators [tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1α)] and upregulated GSH reductase mRNA and GSH levels in LPS-induced astrocytes in vitro. This process was mediated through the p38, JNK-MAPK signaling pathway, but not dependent on the NF-κB pathway. Furthermore, the p38 and JNK inhibitors mimicked the effects of Ac2-26, whereas a p38 and JNK activator anisomycin partially reversed its function. Finally, Ac2-26 treatment reduced CFA-induced activation of astrocytes and production of inflammatory mediators in the spinal cord. These results suggest that Ac2-26 attenuates pain by inhibiting astrocyte activation and the production of inflammatory mediators; thus, this work presents Ac2-26 as a potential drug to treat neuropathic pain.
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Acknowledgements
This work was supported by a research grant provided by Excellent Youth Foundation of Health and Family Planning Commission of Wuhan Municipality (WX17Q10), Open Research Fund Program of the State Key Laboratory of Virology of China (2016KF004), Research Fund of Hubei Province Public Health Bureau (WJ2015MB144) and Research Fund of Wuhan Public Health Bureau (WX15A12).
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ZL, HW, and SF carried out the molecular biology analysis, participated in the design of the study, and drafted the manuscript. LL and XL evaluated Ac2-26 analgesic effect on CFA-induced inflammatory pain, JS, MZ, and ZT participated in the data analysis, and performed the statistical analysis. ZL and ZL conceived of and designed the study, and participated in the data analysis and coordination, and helped to draft the manuscript. All authors read and approved the final manuscript.
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All animals were handled according to Huazhong University of Science and Technology guidelines for laboratory animals and the council for International Organization of Medical Sciences on Animal Experimentation (World Health Organization, Geneva, Switzerland).
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Luo, Z., Wang, H., Fang, S. et al. Annexin-1 Mimetic Peptide Ac2-26 Suppresses Inflammatory Mediators in LPS-Induced Astrocytes and Ameliorates Pain Hypersensitivity in a Rat Model of Inflammatory Pain. Cell Mol Neurobiol 40, 569–585 (2020). https://doi.org/10.1007/s10571-019-00755-8
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DOI: https://doi.org/10.1007/s10571-019-00755-8