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P2X7 receptor antagonist BBG inhibits endoplasmic reticulum stress and pyroptosis to alleviate postherpetic neuralgia

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Abstract

Postherpetic neuralgia (PHN) is the most common complication of acute herpes zoster. The treatment of PHN remains a challenge for clinical pain management. The present study investigated the P2X7 receptor antagonist brilliant blue G (BBG) whether inhibits endoplasmic reticulum stress and pyroptosis (a necrotic form of cell death) and alleviates PHN. Varicella zoster virus (VZV)-infected CV-1 cells were used to induce PHN model. Mechanical paw withdrawal thresholds were measured using an ascending series of von Frey filaments. Immunohistochemistry was used to detect the expression of P2X7R in nerve tissues. Western blot was used to determine the expression of endoplasmic reticulum (ER) stress and pyroptosis-related molecules. The expression of IL-1β and IL-18 in tissue homogenate was detected by ELISA. The PHN rat has the lower paw withdrawal threshold, but higher expression of P2X7 in nerve tissues. And, endoplasmic reticulum stress was activated and pyroptosis was increased in PHN rats. BBG can decrease pain thresholds and reduce ER stress and pyroptosis in PHN rats. In addition, ER stress activator tunicamycin (TM) can reverse the effect of BBG on the paw withdrawal thresholds, endoplasmic reticulum stress, and pyroptosis. Therefore, P2X7 receptor antagonist BBG alleviates PHN by activating ER stress and reducing pyroptosis.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Johnson RW, Rice AS (2014) Clinical practice. Postherpetic neuralgia. N Engl J Med 371:1526–1533

    Article  CAS  Google Scholar 

  2. Guedon J, Yee M, Zhang M, Harvey S, Goins W, Kinchington P (2015) Neuronal changes induced by varicella zoster virus in a rat model of postherpetic neuralgia. Virology 482:167–180. https://doi.org/10.1016/j.virol.2015.03.046

    Article  CAS  PubMed  Google Scholar 

  3. Guedon JMG, Zhang M, Glorioso JC, Goins WF, Kinchington PR (2014) Relief of pain induced by varicella-zoster virus in a rat model of post-herpetic neuralgia using a herpes simplex virus vector expressing enkephalin. Gene Ther 21:694–702

    Article  CAS  Google Scholar 

  4. Chang M, Park D (2020) Effectiveness of intravenous immunoglobulin for management of neuropathic pain: a narrative review. J Pain Res 13:2879–2884. https://doi.org/10.2147/jpr.s273475

    Article  PubMed  PubMed Central  Google Scholar 

  5. Liu X, Wei L, Zeng Q, Lin K, Zhang J (2020) The treatment of topical drugs for postherpetic neuralgia: a network meta-analysis. Pain Physician 23:541–551

    PubMed  Google Scholar 

  6. Makharita M, Amr Y (2020) Effect of repeated paravertebral injections with local anesthetics and steroids on prevention of post-herpetic neuralgia. Pain Physician 23:565–572

    PubMed  Google Scholar 

  7. Lee W, Jeong J, Lee E, Choi Y, Kim J, Kim H, Yoo W (2018) Tacrolimus regulates endoplasmic reticulum stress-mediated osteoclastogenesis and inflammation: In vitro and collagen-induced arthritis mouse model. Cell Biol Int 42:393–402. https://doi.org/10.1002/cbin.10861

    Article  CAS  PubMed  Google Scholar 

  8. Negroni A, Prete E, Vitali R, Cesi V, Aloi M, Civitelli F, Cucchiara S, Stronati L (2014) Endoplasmic reticulum stress and unfolded protein response are involved in paediatric inflammatory bowel disease. Dig Liver Dis 46:788–794. https://doi.org/10.1016/j.dld.2014.05.013

    Article  CAS  Google Scholar 

  9. Cai Z, Shen L, Ma H, Yang J, Yang D, Chen H, Wei J, Lu Q, Wang D, Xiang M, Wang J (2015) Involvement of endoplasmic reticulum stress-mediated c/ebp homologous protein activation in coxsackievirus B3-induced acute viral myocarditis. Circ Heart Fail 8:809–818. https://doi.org/10.1161/circheartfailure.114.001244

    Article  CAS  PubMed  Google Scholar 

  10. Xue H, Gan F, Qian G, Hu J, Hao S, Xu J, Chen X, Huang K (2017) Astragalus polysaccharides attenuate PCV2 infection by inhibiting endoplasmic reticulum stress in vivo and in vitro. Sci Rep 7:40440

    Article  CAS  Google Scholar 

  11. Chen X, Guo X, Ge Q, Zhao Y, Mu H, Zhang J (2019) ER stress activates the nlrp3 inflammasome: a novel mechanism of atherosclerosis. Oxid Med Cell Longev 2019:3462530. https://doi.org/10.1155/2019/3462530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Xing X, Bai Y, Sun K, Chen Q, Huang H, Qiu W, Yan M (2020) Identification of candidate genes associated with postherpetic neuralgia susceptibility. Pain Physician 23:E281–E288

    PubMed  Google Scholar 

  13. Kayagaki N, Stowe I, Lee B, O’Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung Q, Liu P, Lill J, Li H, Wu J, Kummerfeld S, Zhang J, Lee W, Snipas S, Salvesen G, Morris L, Fitzgerald L, Zhang Y, Bertram E, Goodnow C, Dixit V (2015) Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526:666–671. https://doi.org/10.1038/nature15541

    Article  CAS  PubMed  Google Scholar 

  14. Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F (2015) Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526:660–665

    Article  CAS  Google Scholar 

  15. Chao CC, Huang CC, Lu DY, Wong KL, Chen YR, Cheng TH, Leung YM (2012) Ca2+ store depletion and endoplasmic reticulum stress are involved in P2X7 receptor-mediated neurotoxicity in differentiated NG108-15 cells. J Cell Biochem 113:1377–1385

    Article  CAS  Google Scholar 

  16. Carpenter J, Jackson W, Benetti L, Grose C (2011) Autophagosome formation during varicella-zoster virus infection following endoplasmic reticulum stress and the unfolded protein response. J Virol 85:9414–9424. https://doi.org/10.1128/jvi.00281-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Carpenter J, Grose C (2014) Varicella-zoster virus glycoprotein expression differentially induces the unfolded protein response in infected cells. Front Microbiol 5:322. https://doi.org/10.3389/fmicb.2014.00322

    Article  PubMed  PubMed Central  Google Scholar 

  18. Turtle J, Strain M, Reynolds J, Huang Y, Lee K, Henwood M, Garraway S, Grau J (2018) Pain input after spinal cord injury (SCI) undermines long-term recovery and engages signal pathways that promote cell death. Front Syst Neurosci 12:27. https://doi.org/10.3389/fnsys.2018.00027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jiang L, Zhang Y, Jing F, Long T, Qin G, Zhang D, Chen L, Zhou J (2021) P2X7R-mediated autophagic impairment contributes to central sensitization in a chronic migraine model with recurrent nitroglycerin stimulation in mice. J Neuroinflammation 18:5. https://doi.org/10.1186/s12974-020-02056-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. da Silva C, Calió M, Mosini A, Pires J, Rêgo D, Mello L, Leslie A (2019) LPS-induced systemic neonatal inflammation: blockage of P2X7R by BBG decreases mortality on rat pups and oxidative stress in hippocampus of adult rats. Front Behav Neurosci 13:240. https://doi.org/10.3389/fnbeh.2019.00240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gilden D, Mahalingam R, Nagel M, Pugazhenthi S, Cohrs R (2011) Review: The neurobiology of varicella zoster virus infection. Neuropathol Appl Neurobiol 37:441–463. https://doi.org/10.1111/j.1365-2990.2011.01167.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dalziel RG, Bingham S, Sutton D, Grant D, Champion JM, Dennis SA, Quinn JP, Bountra C, Mark MA (2004) Allodynia in rats infected with varicella zoster virus–a small animal model for post-herpetic neuralgia. Brain Res Rev 46:234–242

    Article  Google Scholar 

  23. Xie J, Liu S, Wu B, Li G, Rao S, Zou L, Yi Z, Zhang C, Jia T, Zhao S, Schmalzing G, Hausmann R, Nie H, Li G, Liang S (2017) The protective effect of resveratrol in the transmission of neuropathic pain mediated by the P2X receptor in the dorsal root ganglia. Neurochem Int 103:24–35. https://doi.org/10.1016/j.neuint.2016.12.006

    Article  CAS  PubMed  Google Scholar 

  24. Barragán-Iglesias P, Pineda-Farias J, Bravo-Hernández M, Cervantes-Durán C, Price T, Murbartián J, Granados-Soto V (2016) Predominant role of spinal P2Y1 receptors in the development of neuropathic pain in rats. Brain Res 1636:43–51. https://doi.org/10.1016/j.brainres.2016.01.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Luchting B, Heyn J, Woehrle T, Rachinger-Adam B, Kreth S, Hinske L, Azad S (2016) Differential expression of P2X7 receptor and IL-1β in nociceptive and neuropathic pain. J Neuroinflammation 13:100. https://doi.org/10.1186/s12974-016-0565-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang E, Yi M, Shin N, Baek H, Kim S, Kim E, Kwon K, Lee S, Kim H, Chul Bae Y, Kim Y, Kwon O, Lee W, Kim D (2015) Endoplasmic reticulum stress impairment in the spinal dorsal horn of a neuropathic pain model. Sci Rep 5:11555. https://doi.org/10.1038/srep11555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Khangura R, Sharma J, Bali A, Singh N, Jaggi A (2019) An integrated review on new targets in the treatment of neuropathic pain. Korean J Physiol Pharmacol 23:1–20. https://doi.org/10.4196/kjpp.2019.23.1.1

    Article  CAS  PubMed  Google Scholar 

  28. Zhou Y, Tong Z, Jiang S, Zheng W, Zhao J, Zhou X (2020) The roles of endoplasmic reticulum in nlrp3 inflammasome activation. Cells 9:1219 https://doi.org/10.3390/cells9051219

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This study was funded from the Natural Science Foundation of Anhui Province, China (No. 1808085MH260) and New Medicine of University of Science and Technology of China (No. WK9110000114).

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Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of USTC, 17 Lujiang Road, Hefei, 230001, Anhui Province, China

    Yuyou Zhu & Yuanbo Wu

  2. Department of Dermatology, The First Affiliated Hospital of USTC, 17 Lujiang Road, Hefei, 230001, Anhui Province, China

    Siping Zhang & Juan Wang

Authors
  1. Yuyou Zhu
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  2. Siping Zhang
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  3. Yuanbo Wu
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  4. Juan Wang
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Contributions

J. Wang, Y. Zhu designed the project and analyzed the data, J. Wang, Y. Zhu, S. Zhang, and Y. Wu performed the study; J. Wang drafted the paper; Y. Zhu revised the paper. All authors approved the paper.

Corresponding authors

Correspondence to Yuanbo Wu or Juan Wang.

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The authors declare no conflicts of interest.

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This study was ethically approved by First Affiliated Hospital of USTC.

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Zhu, Y., Zhang, S., Wu, Y. et al. P2X7 receptor antagonist BBG inhibits endoplasmic reticulum stress and pyroptosis to alleviate postherpetic neuralgia. Mol Cell Biochem 476, 3461–3468 (2021). https://doi.org/10.1007/s11010-021-04169-3

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  • DOI: https://doi.org/10.1007/s11010-021-04169-3

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