Zhiqiao Gancao Decoction Ameliorates Hyperalgesia in Lumbar Disc Herniation via the CCL2/CCR2 Signaling Pathway

Drug Des Devel Ther. 2023 Jul 28:17:2239-2257. doi: 10.2147/DDDT.S415127. eCollection 2023.

Abstract

Purpose: The aim of this study was to investigate the effect of Zhiqiao Gancao decoction (ZQGCD) on hyperalgesia in lumbar disc herniation (LDH) and its mechanism.

Methods: The potential mechanism of ZQGCD's therapeutic effect on LDH was investigated through network pharmacology, which involved screening the targets of eight components that were absorbed into the bloodstream. The effects of CCR2 inhibitors and ZQGCD-containing serum on the excitability of the CCL2/CCR2 signaling pathway and dorsal root ganglion neurons (DRGn) were investigated in vitro. The effects of CCR2 inhibitors and ZQGCD on the expression of the CCL2/CCR2 signaling pathway and ASIC3 in the rat intervertebral disc and dorsal root ganglion (DRG), the degree of disc degeneration, the threshold of foot retreat, and the latency of foot retreat in LDH rats were examined in vivo. The binding affinities and interaction modes between CCR2 and the components absorbed into the blood were analyzed using the AutodockVina 1.2.2 software.

Results: Network pharmacology revealed that ZQGCD could treat LDH through a mechanism involving the chemokine signaling pathway. It was observed that the CCR2 inhibitor and ZQGCD-containing serum downregulated CCR2 and ASIC3 expression and decreased cell excitability in DRGn. The CCL2/CCR2 signaling pathway was activated in the degenerated intervertebral disc and DRG of LDH rats, increased the expression of ASIC3, and decreased the mechanical allodynia domain and thermal hyperalgesia domain. However, a CCR2 inhibitor or ZQGCD could ameliorate the above changes in LDH rats. The target proteins, CCL2 and CCR2, exhibited a robust affinity for the eight components that were absorbed into the bloodstream.

Conclusion: The CCL2/CCR2 pathway was activated in the intervertebral disc and DRG of LDH rats. This was accompanied by upregulation of ASIC3 expression, increased excitability of DRGn, and the occurrence of hyperalgesia. ZQGCD improves hyperalgesia in LDH rats by inhibiting the CCL2/CCR2 pathway and downregulating ASIC3 expression.

Keywords: dorsal root ganglion neurons; hyperalgesia; lumbar disc herniation; molecular docking; traditional Chinese medicine.

MeSH terms

  • Animals
  • Hyperalgesia* / drug therapy
  • Hyperalgesia* / metabolism
  • Intervertebral Disc Displacement* / drug therapy
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction

Substances

  • glycyrrhizae radix et rhizoma

Grants and funding

This work was supported by the National Natural Science Foundation of China (82174399), the Natural Science Foundation of Jiangsu province (BK20211084), Science and technology development plan project of Suzhou (SYS2020183), TCM Science and Technology Development Program of Jiangsu Province (QN202007), and Construction project of Key Laboratory of Bone Injury Science of Traditional Chinese Medicine (JSDW202253, SZS2022019). Jiangsu Province Capability Improvement Project through Science, Technology and Education: Jiangsu Provincial Medical Key Discipline(Laboratory) Cultivation Unit.