Gallic Acid Alleviates Neuropathic Pain Behaviors in Rats by Inhibiting P2X7 Receptor-Mediated NF-κB/STAT3 Signaling Pathway.

Runan Yang,Yuting Zou,Zijing Li,Xiumei Xu,Lin Li,Changshui Xu,Shangdong Liang,Shuangmei Liu,Hong Nie,Guilin Li,Jingjian Yang,Günther Schmalzing

doi:10.3389/fphar.2021.680139

Runan Yang, Yuting Zou + Show 10 more

Open Access

https://doi.org/10.3389/fphar.2021.680139

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Abstract

Neuropathic pain is a complex disease with high incidence. Adenosine triphosphate (ATP) and its activated P2X7 receptor are involved in the signal transmission of neuropathic pain. Gallic acid (3,4,5-trihydroxybenzoic acid) is a traditional Chinese medicine obtained from natural plants that exhibit anti-inflammatory, analgesic, and antitumor effects. However, the underlying mechanism for gallic acid in analgesia remains unknown. This study aims to reveal how gallic acid alleviates neuropathic pain behaviors in a rat model with chronic constriction injury (CCI). Real-time PCR, western blotting, double-label immunofluorescence, molecular docking, and whole-cell patch clamp technology were used to explore the therapeutic action of gallic acid on neuropathic pain. The results showed that after CCI rats were treated with gallic acid for 1 week, the mechanical withdrawal threshold and thermal withdrawal latency were increased, accompanied by inhibition of the upregulated expression of P2X7 and TNF-α at both mRNA and protein levels, and reduced NF-κB and phosphorylated-STAT3 in the dorsal root ganglia. At the same time, gallic acid significantly decreased the coexpression of P2X7 and glial fibrillary acidic protein in the dorsal root ganglia. In addition, gallic acid could suppress ATP-activated current in human embryonic kidney 293 (HEK293) cells transfected with the plasmid expressing P2X7 but had no effect on ATP activation current of P2X7-mutant plasmid (with the point mutation sequence of the key site where gallic acid binds to the P2X7 receptor). Therefore, our work suggests that gallic acid may alleviate neuropathic pain in CCI rats by inhibiting the P2X7 receptor and subsequent activation of the TNF-α/STAT3 signaling pathway.

Highlights

The latest definition for pain by the International Association for the Study of Pain (IASP) is displayed as an unpleasant feeling and emotional experience, which is related to actual or potential tissue injury (Raja et al, 2020)
In a rat model of neuropathic pain established by chronic constriction injury (CCI), Tumor necrosis factor-α (TNF-α) can activate nuclear factor kappa-B (NF-κB), and activation of the NF-κB/Signal transducer and activator of transcription 3 (STAT3) signaling pathway may participate in pain regulation (Guo et al, 2018; Chu et al, 2020)
These results revealed that gallic acid could significantly alleviate mechanical and thermal hyperalgesia in CCI rats

Summary

Introduction

The latest definition for pain by the International Association for the Study of Pain (IASP) is displayed as an unpleasant feeling and emotional experience, which is related to actual or potential tissue injury (Raja et al, 2020). Neuropathic pain can cause the activation of satellite glial cells in dorsal root ganglia (DRG) and promote signal transduction between neuronal synapses and the release of cytokines, chemokines, and various inflammatory factors, eventually leading to an increase in the abnormal discharge of neurons and resulting in hyperalgesia or allodynia (Liu et al, 2020). Signal transducer and activator of transcription 3 (STAT3) can be activated by different cytokines. There is evidence that the TNF-α/STAT3 signaling pathway is activated in neuropathic pain (Ding et al, 2019). In a rat model of neuropathic pain established by chronic constriction injury (CCI), TNF-α can activate nuclear factor kappa-B (NF-κB), and activation of the NF-κB/STAT3 signaling pathway may participate in pain regulation (Guo et al, 2018; Chu et al, 2020)

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