Eriocalyxin B inhibits inflammation induced by CCI-induced microglia activation to relieve neuropathic pain through inhibition of JAK2/STAT3 and NF-κB pathways

Main Article Content

Zhifeng Sheng
Xiaoyan Pan


EriB, inflammation, microglia activation, neuropathic pain, JAK2/STAT3 and NF-κB pathways


Neuropathic pain is a very troublesome disease that seriously affects human life. Eriocalyxin B (EriB) has been revealed to attenuate various diseases through its anti-inflammatory effects, but its regulatory effects on neuropathic pain remains unclear. The paw withdrawal threshold and paw withdrawal thermal latency were detected through mechanical allodynia and thermal hyperalgesia tests. The spinal injury was assessed through hematoxylin and eosin staining. The cell apoptosis was measured through terminal deoxynucleotide transferase-mediated dUTP nick end-labeling assay. The protein expressions were examined through Western blot analysis. The mRNA expression was examined through reverse transcription-quantitative polymerase chain reaction. The ionized calcium-binding adaptor molecule 1 level in the spinal cord was evaluated through immunofluorescence assay. The levels of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 were measured through enzyme-linked-immunosorbent serologic assay. The chronic constriction injury (CCI) rat model was constructed for the study. Our results demonstrated that EriB relieved CCI-stimulated neuropathic pain and nerve damage. In addition, the enhanced neural apoptosis mediated by CCI induction was reduced after EriB treatment. In addition, EriB inhibited CCI-induced microglia activity and inflammation. At last, the Janus kinase 2–signal transducer and activator of transcription 3 (JAK2/STAT3) and nuclear factor kappa B (NF-κB) pathways were activated in CCI rat model, which were attenuated following EriB treatment. Importantly, EriB (10 mg/kg) had a strong effect that was similar to the positive control (1-μg/kg dexmedetomidine), suggesting that EriB may be an effective drug for neuropathic pain. This study demonstrated that EriB inhibited inflammation caused by CCI-induced microglia activation to relieve neuropathic pain through inhibition of JAK2/STAT3 and NF-κB pathways. This study may highlight the regulatory functions of EriB in the treatment of neuropathic pain.


Download data is not yet available.
Abstract 76 | PDF Downloads 111 HTML Downloads 45 XML Downloads 2


Baron, R., Binder, A. and Wasner, G., 2010. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurology 9: 807–819. 10.1016/s1474-4422(10)70143-5

Bostani, M., Rahmati, M. and Mard, S.A., 2020. The effect of endurance training on levels of LINC complex proteins in skeletal muscle fibers of STZ-induced diabetic rats. Scientific Reports 10: 8738. 10.1038/s41598-020-65793-5

Bouhassira, D., 2019. Neuropathic pain: definition, assessment and epidemiology. Revue Neurologique (Paris) 175: 16–25. 10.1016/j.neurol.2018.09.016

Choi, D.C., Lee, J.Y., Lim, E.J., Baik, H.H., Oh, T.H. and Yune, T.Y., 2012. Inhibition of ROS-induced p38MAPK and ERK activation in microglia by acupuncture relieves neuropathic pain after spinal cord injury in rats. Experimental Neurology 236: 268–282. 10.1016/j.expneurol.2012.05.014

Cohen, S.P. and Mao, J., 2014. Neuropathic pain: mechanisms and their clinical implications. British Medical Journal 348: f7656. 10.1136/bmj.f7656

Devor, M., 1991. Neuropathic pain and injured nerve: peripheral mechanisms. British Medical Bulletin 47: 619–630. 10.1093/oxfordjournals.bmb.a072496

Ding, C.P., Guo, Y.J., Li, H.N., Wang, J.Y. and Zeng, X.Y., 2018. Red nucleus interleukin-6 participates in the maintenance of neuropathic pain through JAK/STAT3 and ERK signaling pathways. Experimental Neurology 300: 212–221. 10.1016/j.expneurol.2017.11.012

Dou, F., Chu, X., Zhang, B., Liang, L., Lu, G., Ding, J., et al. 2018. EriB-targeted inhibition of microglia activity attenuates MPP(+)-induced DA neuron injury through the NF-κB signaling pathway. Molecular Brain 11: 75. 10.1186/s13041-018-0418-z

Duan, D., Wang, Y., Jin, X., Li, M., Wang, L., Yan, Y., et al. 2021. Natural diterpenoid eriocalyxin B covalently modifies glutathione and selectively inhibits thioredoxin reductase inducing potent oxidative stress-mediated apoptosis in colorectal carcinoma RKO cells. Free Radical Biology and Medicine 177: 15–23. 10.1016/j.freeradbiomed.2021.10.013

Fei, R., Zhang, Y., Wang, S., Xiang, T. and Chen, W., 2017. α7 Nicotinic acetylcholine receptor in tumor-associated macrophages inhibits colorectal cancer metastasis through the JAK2/STAT3 signaling pathway. Oncology Reports 38: 2619–2628. 10.3892/or.2017.5935

Feng, L., Liu, W.K., Deng, L., Tian, J.X. and Tong, X.L., 2014. Clinical efficacy of aconitum-containing traditional Chinese medicine for diabetic peripheral neuropathic pain. American Journal of Chinese Medicine 42: 109–117. 10.1142/s0192415x14500074

Fujita, Y. and Yamashita, T., 2019. The effects of leptin on glial cells in neurological diseases. Frontiers in Neuroscience 13: 828. 10.3389/fnins.2019.00828

Gierthmühlen, J. and Baron, R., 2016. Neuropathic pain. Seminars in Neurology 36: 462–468. 10.1055/s-0036-1584950

Guo, C., Fan, Y., Kong, X. and Zhao, C., 2022. The effect of different water immersion strategies on delayed onset muscle soreness and inflammation in elite race walker. American Journal of Men’s Health 18(3): 64. 10.31083/j.jomh1803064

Guo, A., Li, J., Luo, L., Chen, C., Lu, Q., Ke, J., et al. 2021. Valproic acid mitigates spinal nerve ligation-induced neuropathic pain in rats by modulating microglial function and inhibiting neuroinflammatory response. International Immunopharmacology 92: 107332. 10.1016/j.intimp.2020.107332

Huang, X., Deng, R., Tu, W. and Hu, Z., 2017. Dexmedetomidine reduces neuropathic pain in a rat model of skin/muscle incision and retraction. Asian Journal of Surgery 40: 35–40. 10.1016/j.asjsur.2015.10.009

Inoue, N., Ito, S., Tajima, K., Nogawa, M., Takahashi, Y., Sasagawa, T., et al. 2009. Etodolac attenuates mechanical allodynia in a mouse model of neuropathic pain. Journal of Pharmacological Sciences 109: 600–605. 10.1254/jphs.08287fp

Leung, C.H., Grill, S.P., Lam, W., Gao, W., Sun, H.D., and Cheng, Y.C., 2006. Eriocalyxin B inhibits nuclear factor-kappaB activation by interfering with the binding of both p65 and p50 to the response element in a noncompetitive manner. Molecular Pharmacology 70: 1946–1955. 10.1124/mol.106.028480

Li, S.H., Li, L., Yang, R.N. and Liang, S.D., 2020. Compounds of traditional Chinese medicine and neuropathic pain. Chinese Journal of Natural Medicines (CJNM) 18: 28–35. 10.1016/s1875-5364(20)30002-9

Li, L., Yue, G.G., Lau, C.B., Sun, H., Fung, K.P., Leung, P.C., et al. 2012. Eriocalyxin B induces apoptosis and cell cycle arrest in pancreatic adenocarcinoma cells through caspase-and p53-dependent pathways. Toxicology and Applied Pharmacology 262: 80–90. 10.1016/j.taap.2012.04.021

Lu, Y., Chen, B., Song, J.H., Zhen, T., Wang, B.Y., Li, X., et al. 2013. Eriocalyxin B ameliorates experimental autoimmune encephalomyelitis by suppressing Th1 and Th17 cells. Proceedings of Natlional Academy of Sciences, USA 110: 2258–2263. 10.1073/pnas.1222426110

Luo, Y., Wang, C.Z., Sawadogo, R., Tan, T. and Yuan, C.S., 2020. Effects of herbal medicines on pain management. American Journal of Chinese Medicine 48: 1–16. 10.1142/s0192415x20500019

Mücke, M., Phillips, T., Radbruch, L., Petzke, F. and Häuser, W., 2018. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane database of systematic reviews 3: Cd012182. 10.1002/14651858.CD012182.pub2

Niu, X.M., Li, S.H., Mei, S.X., Na, Z., Zhao, Q.S., Lin, Z.W., et al. 2002. Cytotoxic 3,20-epoxy-ent-kaurane diterpenoids from Isodon eriocalyx var. laxiflora. Journal of Natural Products 65: 1892–1896. 10.1021/np020059e

Orihuela, R., McPherson, C.A. and Harry, G.J., 2016. Microglial M1/M2 polarization and metabolic states. British Journal of Pharmacology 173: 649–665. 10.1111/bph.13139

Popiolek-Barczyk, K. and Mika, J., 2016. Targeting the microglial signaling pathways: new insights in the modulation of neuropathic pain. Current Medicinal Chemistry 23: 2908–2928. 10.2174/0929867323666160607120124

Prinz, M. and Priller, J., 2014. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nature Reviews Neuroscience 15: 300–312. 10.1038/nrn3722

Rahmati, M. and Rashno, A., 2021. Automated image segmentation method to analyse skeletal muscle cross section in exercise-induced regenerating myofibers. Scientific Reports 11: 21327. 10.1038/s41598-021-00886-3

Rahmati, M. and Taherabadi, S.J., 2021. The effects of exercise training on kinesin and GAP-43 expression in skeletal muscle fibers of STZ-induced diabetic rats. Scientific Reports 11: 9535. 10.1038/s41598-021-89106-6

Riaz, A., Rasul, A., Hussain, G., Zubair, M., Samiullah, K., Sarfraz, I., et al. 2019. Eriocalyxin B induces apoptosis in human triple negative breast cancer cells via inhibiting STAT3 activation and mitochondrial dysfunction. Pakistan Journal of Pharmaceutical Sciences 32: 2843–2848.

Shan, W., Liao, X., Tang, Y. and Liu, J., 2021. Dexmedetomidine alleviates inflammation in neuropathic pain by suppressing NLRP3 via Nrf2 activation. Experimental and Therapeutic Medicine 22: 1046. 10.3892/etm.2021.10479

Song, C., Adili, A., Kari, A. and Abuduhaer, A., 2021. FSTL1 aggravates sepsis-induced acute kidney injury through regulating TLR4/MyD88/NF-κB pathway in newborn rats. Signa Vitae 17: 167–173.

Streit, W.J., 1993. Microglial-neuronal interactions. Journal of Chemical Neuroanatomy 6: 261–266. 10.1016/0891-0618(93)90047-8

Wang, S., Li, A. and Guo, S., 2016. Ligustrazine attenuates neuropathic pain by inhibition of JAK/STAT3 pathway in a rat model of chronic constriction injury. Die Pharmazie 71: 408–412. 10.1691/ph.2016.6546

Wu, J., Wang, C. and Ding, H., 2020. LncRNA MALAT1 promotes neuropathic pain progression through the miR-154-5p/AQP9 axis in CCI rat models. Molecular Medicine Reports 21: 291–303. 10.3892/mmr.2019.10829

Xu, H.-l. and Xu, S.-y., 2021. Tacrine alleviates neuropathic pain in mice by mimicking the cell adhesion molecule L1. Signa Vitae 17: 140–150.

Xu, L., Zhang, Y. and Huang, Y., 2016. Advances in the treatment of neuropathic pain. Advances in Experimental Medicine and Biologyl 904: 117–129. 10.1007/978-94-017-7537-3_9

Yang, R., Li, Z., Zou, Y., Yang, J., Li, L., Xu, X., et al. 2021. Gallic acid alleviates neuropathic pain behaviors in rats by inhibiting P2X7 receptor-mediated NF-κB/STAT3 signaling pathway. Frontiers in Pharmacology 12: 680139. 10.3389/fphar.2021.680139

Zhang, W., Suo, M., Yu, G. and Zhang, M., 2019. Antinociceptive and anti-inflammatory effects of cryptotanshinone through PI3K/Akt signaling pathway in a rat model of neuropathic pain. Chemico-Biological Interactions 305: 127–133. 10.1016/j.cbi.2019.03.016

Zhao, L., Tao, X. and Song, T., 2021. Astaxanthin alleviates neuropathic pain by inhibiting the MAPKs and NF-κB pathways. European Journal of Pharmacology 912: 174575. 10.1016/j.ejphar.2021.174575

Zheng, Y., Hou, X. and Yang, S., 2019. Lidocaine potentiates SOCS3 to attenuate inflammation in microglia and suppress neuropathic pain. Cellular and Molecular Neurobiology 39: 1081–1092. 10.1007/s10571-019-00703-6