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Quetiapine ameliorates collagen-induced arthritis in mice via the suppression of the AKT and ERK signaling pathways

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Abstract

Objective and design

To investigate the amelioration effects of quetiapine on rheumatoid arthritis with RAW 264.7 macrophage and collagen-induced arthritis (CIA) DBA/1J mouse model.

Subjects

RAW 264.7 macrophage and DBA/1J mice.

Treatment

Lipopolysaccharide and collagen.

Methods

RAW 264.7 macrophages stimulated by lipopolysaccharide (LPS) followed by quetiapine treatments were investigated. Activations of CD80 and CD86 were analyzed by flow cytometry. Pro-inflammatory cytokines such as IL-6, TNF-α and IL-1β were analyzed by ELISA. Proteins involved in signaling pathways related to the formation of rheumatoid arthritis were assayed by Western blotting. Therapeutic efficacy of quetiapine in CIA mouse model was also assayed. 18F-FDG/micro-PET was used to monitor the inflammation status in the joints, and the severity of bone erosion was evaluated with micro-CT and H&E staining.

Results

The inhibition of pro-inflammatory cytokines by quetiapine was found through the ERK and AKT phosphorylation and subsequent NF-κB and CREB signaling pathways. Pro-inflammatory cytokines such as IL-17, IL-6 and IL-1β were decreased, while immunosuppressive factors such as TGF-β and IL-10 were increased in CIA mice treated with quetiapine. Notably, no uptake of 18F-FDG and bone erosion was found with micro-PET images on days 32 and 43 in the quetiapine-treated and normal control groups. However, significant uptake of 18F-FDG could be observed in the CIA group during the same time course. Similar results were further verified with ex vivo autoradiography.

Conclusion

Taken together, these results suggest that quetiapine is a potential anti-inflammatory drug, and may be used as an adjuvant for the treatment of rheumatoid arthritis.

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Acknowledgements

We thank Mr. Yen-Po Lee for carrying out the experiments of infiltration of pro-inflammatory macrophages, neutrophils and differentiation of osteoclasts. This study was supported by a grant (105FN19) from Far Eastern Memorial Hospital-National Yang-Ming University Joint Research Program. We thank Taiwan Mouse Clinic (MOST 103-2325-B-001-015) which is funded by the National Research Program for Biophamaceuticals (NRPB) at the Ministry of Science and Technology (MOST) of Taiwan for the technical support of animal imaging facilities; and Biophotonics & Molecular Imaging Research Center (BMIRC), National Yang-Ming University, Taipei, Taiwan.

Author information

Author notes

  1. Yi-Ju Pan and Wei-Hsun Wang contributed equally to this study.

Authors and Affiliations

  1. Department of Psychiatry, Far Eastern Memorial Hospital, Banciao, New Taipei City, 220, Taiwan

    Yi-Ju Pan

  2. Department of Orthopedic Surgery, Changhua Christian Hospital, Changhua, Taiwan

    Wei-Hsun Wang

  3. Department of Medical Imaging and Radiology, Shu-Zen Junior College of Medicine and Management, Kao-hsiung, Taiwan

    Wei-Hsun Wang

  4. Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan

    Tzu-Yao Huang, Wei-Hsiang Weng & Jeng-Jong Hwang

  5. Department of Psychiatry and Suicide Prevention Center, Mackay Memorial Hospital, No. 155, Sec.2, Li-Nong Street, Bei-tou, Taipei, 112, Taiwan

    Chun-Kai Fang

  6. Department of Radiation Oncology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan

    Yu-Chan Chen

  7. Biophotonics and Molecular Imaging Research Center, National Yang-Ming University, Taipei, Taiwan

    Jeng-Jong Hwang

  8. School of Medicine, National Yang-Ming University, Taipei, Taiwan

    Yi-Ju Pan

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Contributions

YJP, WHW, CKF and JJH have contributed to the conception and design of the study and approved the final version of manuscript. TYH and YCC developed methods and performed experiments. TYH and WHW analyzed data and drafted the manuscript. All authors have contributed to interpretation of results, as well as contributed to the final version of the manuscript.

Corresponding author

Correspondence to Jeng-Jong Hwang.

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All authors declare no conflict of interest.

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Responsible Editor: Yoshiya Tanaka.

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Pan, YJ., Wang, WH., Huang, TY. et al. Quetiapine ameliorates collagen-induced arthritis in mice via the suppression of the AKT and ERK signaling pathways. Inflamm. Res. 67, 847–861 (2018). https://doi.org/10.1007/s00011-018-1176-1

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  • DOI: https://doi.org/10.1007/s00011-018-1176-1

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