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Geniposide Alleviates Neuropathic Pain in CCI Rats by Inhibiting the EGFR/PI3K/AKT Pathway And Ca2+ Channels

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Abstract

Neuropathic pain (NP) is a common disorder among individuals worldwide, but there is still no effective treatment for NP. The EGFR pathway promotes NP nociceptive sensitization and represents a potential therapeutic target. Geniposide is abundant in natural plants and has various pharmacological activities, such as analgesia and anti-inflammation properties, which can improve NP, but the specific mechanisms have not been elucidated. The present study first predicted and molecularly docked geniposide targets, suggesting that geniposide may play a role in improving NP by targeting EGFR. This study further clarified that geniposide alleviates NP and improves the inflammatory response using a chronic constriction injury (CCI) model, whereas the administration of an EGFR agonist weakens the above effects of geniposide. Analysis of transcriptome data further suggests that geniposide not only improves CCI symptoms by reducing EGFR/PI3K/AKT pathway activity but also may exert anti-inflammatory effects by inhibiting the Ca2+ signaling pathway. The above results affirm the potential value of geniposide in the treatment of NP and lay the foundation for further clinical application.

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References

  • Borges JP, Mekhail K, Fairn GD, Antonescu CN, Steinberg BE (2021) Modulation of Pathological Pain by Epidermal Growth Factor Receptor. Front Pharmacol 12:642820

    Article  CAS  Google Scholar 

  • Buteau J, Foisy S, Joly E, Prentki M (2003) Glucagon-like peptide 1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor. Diabetes 52:124–132

    Article  CAS  Google Scholar 

  • Cai L, Mu YR, Liu MM, Tang WJ, Li R (2020) Antidepressant-like effects of penta-acetyl geniposide in chronic unpredictable mild stress-induced depression rat model: Involvement of inhibiting neuroinflammation in prefrontal cortex and regulating hypothalamic-pituitaryadrenal axis. Int Immunopharmacol 80:106182

    Article  CAS  Google Scholar 

  • Cavalli E, Mammana S, Nicoletti F, Bramanti P, Mazzon E (2019) The neuropathic pain: An overview of the current treatment and future therapeutic approaches. Int J Immunopathol Pharmacol 33:2058738419838383

    Article  Google Scholar 

  • Chang DS, Hsu E, Hottinger DG, Cohen SP (2016) Anti-nerve growth factor in pain management: current evidence. J Pain Res 9:373–383

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen P, Lin D, Wang C, Song C, Wang W, Qu J, Wu Z (2021) Proteomic Analysis of Emodin Treatment in Neuropathic Pain Reveals Dysfunction of the Calcium Signaling Pathway. J Pain Res 14:613–622

    Article  CAS  Google Scholar 

  • Chen Y, Shou K, Gong C, Yang H, Yang Y, Bao T (2018) Anti-Inflammatory Effect of Geniposide on Osteoarthritis by Suppressing the Activation of p38 MAPK Signaling Pathway. Biomed Res Int 2018:8384576

    PubMed  PubMed Central  Google Scholar 

  • Dan XU, Yu-Xiang D, Feng W, Hong-Yan GE, You-Tian LI, Jiang Y, Li-Jie W (2013) Extraction of Geniposide and Its Application in Anesthesiology. Chem Res Chin Univ 29:724–729

  • Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C, Trneny M, Offner F, Caballero D, Joao C, Witzens-Harig M et al (2016) Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet 387:770–778

    Article  CAS  Google Scholar 

  • Esposito MF, Malayil R, Hanes M, Deer T (2019) Unique Characteristics of the Dorsal Root Ganglion as a Target for Neuromodulation. Pain Med 20:S23–S30

    Article  Google Scholar 

  • Finnerup NB, Kuner R, Jensen TS (2021) Neuropathic Pain: From Mechanisms to Treatment. Physiol Rev 101:259–301

    Article  CAS  Google Scholar 

  • Gao Y, Sun N, Wang L, Wu Y, Ma L, Hong J, Ren J, Zhu B, Yu L, Yan M (2018) Bioinformatics Analysis Identifies p53 as a Candidate Prognostic Biomarker for Neuropathic Pain. Front Genet 9:320

    Article  Google Scholar 

  • Ghaly RF, Plesca A, Rana S, Candido KD, Knezevic NN (2018) Gabapentin-related suicide: Myth or fact. Surg Neurol Int 9:210

    Article  Google Scholar 

  • Gong N, Fan H, Ma AN, Xiao Q, Wang YX (2014) Geniposide and its iridoid analogs exhibit antinociception by acting at the spinal GLP-1 receptors. Neuropharmacology 84:31–45

    Article  CAS  Google Scholar 

  • Jackson NM, Ceresa BP (2017) EGFR-mediated apoptosis via STAT3. Exp Cell Res 356:93–103

    Article  CAS  Google Scholar 

  • Kersten C, Cameron MG, Laird B, Mjåland S (2015) Epidermal growth factor receptor-inhibition (EGFR-I) in the treatment of neuropathic pain. Br J Anaesth 115:761–767

    Article  CAS  Google Scholar 

  • Lacagnina MJ, Watkins LR, Grace PM (2018) Toll-like receptors and their role in persistent pain. Pharmacol Ther 184:145–158

    Article  CAS  Google Scholar 

  • Leinders M, Koehrn FJ, Bartok B, Boyle DL, Shubayev V, Kalcheva I, Yu NK, Park J, Kaang BK, Hefferan MP et al (2014) Differential distribution of PI3K isoforms in spinal cord and dorsal root ganglia: potential roles in acute inflammatory pain. Pain 155:1150–1160

    Article  CAS  Google Scholar 

  • Liu W, Lv Y, Ren F (2018) PI3K/Akt Pathway is Required for Spinal Central Sensitization in Neuropathic Pain. Cell Mol Neurobiol 38:747–755

    Article  CAS  Google Scholar 

  • Martin LJ, Smith SB, Khoutorsky A, Magnussen CA, Samoshkin A, Sorge RE, Cho C, Yosefpour N, Sivaselvachandran S, Tohyama S et al (2017) Epiregulin and EGFR interactions are involved in pain processing. J Clin Invest 127:3353–3366

    Article  Google Scholar 

  • Pan T, Shi X, Chen H, Chen R, Wu D, Lin Z, Zhang J, Pan J (2018) Geniposide Suppresses Interleukin-1β-Induced Inflammation and Apoptosis in Rat Chondrocytes via the PI3K/Akt/NF-κB Signaling Pathway. Inflammation 41:390–399

    Article  CAS  Google Scholar 

  • Ran D, Hong W, Yan W, Mengdie W (2021) Properties and molecular mechanisms underlying geniposide-mediated therapeutic effects in chronic inflammatory diseases. J Ethnopharmacol 273:113958

    Article  CAS  Google Scholar 

  • Rayiti RK, Munnangi SR, Bandarupalli R, Chakka V, Nimmagadda SL, Sk LS, Uppalapati S, Bolla R, Challa SR (2020) Effect of Chrysin on Mechanical Hyperalgesia in Chronic Constriction Injury-Induced Neuropathic Pain in Rat Model. Int J Appl Basic Med Res 10:189–193

    Article  CAS  Google Scholar 

  • Wang S, Liu S, Xu L, Zhu X, Liu W, Tian L, Chen Y, Wang Y, Nagendra B, Jia S et al (2019) The upregulation of EGFR in the dorsal root ganglion contributes to chronic compression of dorsal root ganglions-induced neuropathic pain in rats. Mol Pain 15:1744806919857297

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xiao H, Ma K, Huang D, Liu XG, Liu TH, Liu Q, Liu GZ, Song T, Tao W, Wu DS et al (2021) Expert consensus of the Chinese Association for the Study of Pain on ion channel drugs for neuropathic pain. World J Clin Cases 9:2100–2109

    Article  Google Scholar 

  • Xu D, Dong Y, Feng W, Ge H, Li Y, Jiang Y, Wang L, Song D (2013) Extraction of geniposide and its application in anesthesiology. Chemical Research in Chinese Universities 29

  • Zhang T, Zhang N, Zhang R, Zhao W, Chen Y, Wang Z, Xu B, Zhang M, Shi X, Zhang Q et al (2018) Preemptive intrathecal administration of endomorphins relieves inflammatory pain in male mice via inhibition of p38 MAPK signaling and regulation of inflammatory cytokines. J Neuroinflammation 15:320

    Article  CAS  Google Scholar 

  • Zhou L, Bao L, Wang Y, Chen M, Zhang Y, Geng Z, Zhao R, Sun J, Bao Y, Shi Y et al (2021) An Integrated Analysis Reveals Geniposide Extracted From Gardenia jasminoides J. Ellis Regulates Calcium Signaling Pathway Essential for Influenza A Virus Replication. Front Pharmacol 12:755796

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Funding

This study was supported by Zhejiang Provincial Traditional Chinese Medicine Research Fund Project (No.: 2017ZB082).

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Authors and Affiliations

  1. Institute of Pharmacology, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, 310053, China

    Dan-dan Zhang & Li Yao

  2. Department of Pharmacy, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, 315020, China

    Dan-dan Zhang

  3. Department of Clinical Laboratory, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, 315020, China

    Qiao-qiao Chen

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  1. Dan-dan Zhang
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  2. Qiao-qiao Chen
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  3. Li Yao
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Contributions

DD Z and L Y designed the study. DD Z was responsible for animal and pathology and immunohistochemical experiments. QQ C was responsible for western blotting and statistical analysis. L Y obtained the funding and drafted the original manuscript. All authors have read and approved the final manuscript.

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Correspondence to Li Yao.

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Ethics Approval

The animal study conformed to the regulations on the administration of experimental animals of the Animal Ethics Committee of Ningbo University (Authorization number: NBU20210055).

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The authors declare no competing interests.

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Zhang, Dd., Chen, Qq. & Yao, L. Geniposide Alleviates Neuropathic Pain in CCI Rats by Inhibiting the EGFR/PI3K/AKT Pathway And Ca2+ Channels. Neurotox Res 40, 1057–1069 (2022). https://doi.org/10.1007/s12640-022-00531-5

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  • DOI: https://doi.org/10.1007/s12640-022-00531-5

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