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Paeonol ameliorates CFA-induced inflammatory pain by inhibiting HMGB1/TLR4/NF-κB p65 pathway

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Abstract

The enhanced release of inflammatory cytokines mediated by high mobility group box1 (HMGB1) leads to pain sensation, and has been implicated in the etiology of inflammatory pain. Paeonol (PAE), a major active phenolic component in Cortex Moutan, provides neuroprotective efficacy via exerting anti-inflammatory effect. However, the role and mechanism of PAE in inflammatory pain remain to be fully clarified. In this study, we showed that PAE treatment significantly ameliorated mechanical and thermal hyperalgesia of mice induced by complete Freund’s adjuvant (CFA). The analgesic effect of PAE administration was associated with suppressing the enhanced expression of HMGB1 as well as the downstream signaling molecules including toll-like receptor 4 (TLR4), the nuclear NF-κB p65, TNF-α and IL-1β after CFA insult in the anterior cingulate cortex (ACC), a key brain region responsible for pain processing. Furthermore, inhibition of HMGB1 activity by glycyrrhizin (GLY), an HMGB1 inhibitor, alleviated CFA-induced pain and also facilitated PAE-mediated analgesic effect in mice along with the decreased expression of TLR4, NF-κB p65, TNF-α and IL-1β upon CFA injury. Collectively, we showed PAE exerted analgesic effect through inhibiting the HMGB1/TLR4/NF-κB p65 pathway and subsequent generation of cytokines TNF-α and IL-1β in the ACC.

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Data availability

Datasets from this study are available from the corresponding author on reasonable request.

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Funding

This study was funded by Key International Cooperation Projects of Shaanxi Province (No. 2020KWZ-021), Military Medicine Promotion Projects (No. 2018jsts09), National Natural Science Foundation of China (No. 81571328 for Prof Wu, and No. 81701352 for Dr. Li), and Research Foundation from Social Development Science and Technology Project of Shaanxi Province for Mr Wang (No. 2020JQ-464).

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Author notes

  1. Chen Qiu and Liu-Di Yang contributed equally to this study.

Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi’an, Shaanxi Province, 710032, People’s Republic of China

    Chen Qiu, Liu-Di Yang, Wen Yu, Dan-Dan Tian, Mei-Rong Gao, Wen-Ju Wang, Xu-Bo Li, Yu-Mei Wu & Min Wang

  2. Department of Acupuncture-Moxibustion-Massage, Shaanxi University of Chinese Medicine, Xi’an, Shaanxi Province, 712000, People’s Republic of China

    Liu-Di Yang, Dan-Dan Tian & Mei-Rong Gao

Authors
  1. Chen Qiu
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  2. Liu-Di Yang
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  3. Wen Yu
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  7. Xu-Bo Li
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  9. Min Wang
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Contributions

Chen Qiu and Liu-Di Yang wrote the manuscript. Wen Yu and Wen-Ju Wang developed the model and performed part of the behavior test. Dan-Dan Tian and Mei-Rong Gao participated in the western blot and RT-PCR analysis. Liu-Di Yang and Min Wang was responsible for immunohistochemical experiments. Xu-Bo Li and Yu-Mei Wu analyzed the data. Chen Qiu and Min Wang designed and supervised whole experiments. All authors approved the final manuscript.

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Correspondence to Min Wang.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Qiu, C., Yang, LD., Yu, W. et al. Paeonol ameliorates CFA-induced inflammatory pain by inhibiting HMGB1/TLR4/NF-κB p65 pathway. Metab Brain Dis 36, 273–283 (2021). https://doi.org/10.1007/s11011-020-00645-9

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  • DOI: https://doi.org/10.1007/s11011-020-00645-9

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