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Purinergic P2X7 receptor involves in anti-retinal photodamage effects of berberine

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Abstract

Berberine (BBR) is a Chinese herb with antioxidant and anti-inflammatory properties. In a previous study, we found that BBR had a protective effect against light-induced retinal degeneration in BALB/c mice. The purinergic P2X7 receptor (P2X7R) plays a key role in retinal degeneration via inducing oxidative stress, inflammatory changes, and cell death. The aim of this study was to investigate whether BBR can induce protective effects in light damage experiments and whether P2X7R can get involved in these effects. C57BL/6 J mice and P2X7 knockout (KO) mice on the C57BL/6 J background were used. We found that BBR preserved the outer nuclear layer (ONL) thickness and retinal ganglion cells following light stimulation. Furthermore, BBR significantly suppressed photoreceptor apoptosis, pro-apoptotic c-fos expression, pro-inflammatory responses of Mϋller cells, and inflammatory factors (TNF-α, IL-1β). In addition, protein levels of P2X7R were downregulated in BBR-treated mice. Double immunofluorescence showed that BBR reduced overexpression of P2X7R in retinal ganglion cells and Mϋller cells. Furthermore, BBR combined with the P2X7R agonist BzATP blocked the effects of BBR on retinal morphology and photoreceptor apoptosis. However, in P2X7 KO mice, BBR had an additive effect resulting in thicker ONL and more photoreceptors. The data suggest that the P2X7 receptor is involved in retinal light damage, and BBR inhibits this process by reducing histological impairment, cell death, and inflammatory responses.

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References

  1. Wong WL, Su X, Li X, Cheung CMG, Klein R, Cheng CY, Wong TY (2014) Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health 2:E106. https://doi.org/10.1016/S2214-109X(13)70145-1

    Article  PubMed  Google Scholar 

  2. Falavarjani KG, Nguyen QD (2013) Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature. Eye 27:787. https://doi.org/10.1038/eye.2013.107

    Article  CAS  PubMed  Google Scholar 

  3. Fan H, Song JT (2022) Potential mechanisms of macular degeneration protection by fatty fish consumption. Curr Opin Pharmacol 63:102186. https://doi.org/10.1016/j.coph.2022.102186

    Article  CAS  PubMed  Google Scholar 

  4. Sliney DH (2016) What is light? The visible spectrum and beyond. Eye 30:222. https://doi.org/10.1038/eye.2015.252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Boulton ME, Rozanowska MB, Rozanowski B (2001) Retinal photodamage. J Photochem Photobiol B Biol 64:144. https://doi.org/10.1016/S1011-1344(01)00227-5

    Article  CAS  Google Scholar 

  6. Organisciak DT, Vaughan DK (2010) Retinal light damage: mechanisms and protection. Prog Retin Eye Res 29:113. https://doi.org/10.1016/j.preteyeres.2009.11.004

    Article  PubMed  Google Scholar 

  7. Zhou HJ, Zhang HN, Yu AQ, Xie JJ (2018) Association between sunlight exposure and risk of age-related macular degeneration: a meta-analysis. BMC Ophthalmol 18:331. https://doi.org/10.1186/s12886-018-1004-y

    Article  PubMed  PubMed Central  Google Scholar 

  8. Lambert NG, Singh MK, Elshelmani H, Mansergh FC, Wride MA, Padilla M, Keegan D, Hogg RE, Ambati BK (2016) Risk factors and biomarkers of age-related macular degeneration. Prog Retin Eye Res 54:64. https://doi.org/10.1016/j.preteyeres.2016.04.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mishra A, Behura A, Kumar A, Naik L, Swain A, Das M, Sarangi SS, Dokania P, Dirisala VR, Bhutia SK, Mishra A, Singh R, Dhiman R (2021) P2X7 receptor in multifaceted cellular signalling and its relevance as a potential therapeutic target in different diseases. Eur J Pharmacol 906:174235. https://doi.org/10.1016/j.ejphar.2021.174235

    Article  CAS  PubMed  Google Scholar 

  10. Drysdale C, Park K, Vessey KA, Huang X, Caruso E, Li Y, Wong J, Wiley JS, Fletcher E, Guymer RH, Gu B (2022) P2X7-mediated alteration of membrane fluidity is associated with the late stages of age-related macular degeneration. Purinergic Signal 18:469. https://doi.org/10.1007/s11302-022-09894-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Platania CBM, Drago F, Bucolo C (2022) The P2X7 receptor as a new pharmacological target for retinal diseases. Biochem Pharmacol 198:114942. https://doi.org/10.1016/j.bcp.2022.114942

    Article  CAS  PubMed  Google Scholar 

  12. Notomi S, Hisatomi T, Murakami Y, Terasaki H, Sonoda S, Asato R, Takeda A, Ikeda Y, Enaida H, Sakamoto T, Ishibashi T (2013) Dynamic increase in extracellular ATP accelerates photoreceptor cell apoptosis via ligation of P2RX7 in subretinal hemorrhage. PLoS One 8:e53338. https://doi.org/10.1371/journal.pone.0053338

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Notomi S, Hisatomi T, Kanemaru T, Takeda A, Ikeda Y, Enaida H, Kroemer G, Ishibashi T (2011) Critical involvement of extracellular ATP acting on P2RX7 purinergic receptors in photoreceptor cell death. Am J Pathol 179:2798. https://doi.org/10.1016/j.ajpath.2011.08.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Habtemariam S (2016) Berberine and inflammatory bowel disease: a concise review. Pharmacol Res 113:592. https://doi.org/10.1016/j.phrs.2016.09.041

    Article  CAS  PubMed  Google Scholar 

  15. Wang LH, Li XL, Li Q, Fu Y, Yu HJ, Sun YQ, Zhang L, Shan HL (2012) Berberine alleviates ischemic arrhythmias via recovering depressed Ito and ICa currents in diabetic rats. Phytomedicine 19:206. https://doi.org/10.1016/j.phymed.2011.11.002

    Article  CAS  PubMed  Google Scholar 

  16. Lu QK, Fu YF, Li H (2022) Berberine and its derivatives represent as the promising therapeutic agents for inflammatory disorders. Pharmacol Rep 74:297. https://doi.org/10.1007/s43440-021-00348-7

    Article  CAS  PubMed  Google Scholar 

  17. Wang K, Feng XC, Chai LW, Cao SJ, Qiu F (2017) The metabolism of berberine and its contribution to the pharmacological effects. Drug Metab Rev 49:139. https://doi.org/10.1080/03602532.2017.1306544

    Article  CAS  PubMed  Google Scholar 

  18. Datta S, Cano M, Ebrahimi K, Wang L, Handa JT (2017) The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD. Prog Retin Eye Res 60:201–218. https://doi.org/10.1016/j.preteyeres.2017.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kang Q, Yang C (2020) Oxidative stress and diabetic retinopathy: molecular mechanisms, pathogenetic role and therapeutic implications. Redox Biol 37:101799. https://doi.org/10.1016/j.redox.2020.101799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fu DX, Yu JY, Connell AR, Yang SH, Hookham MB, McLeese R, Lyons TJ (2016) Beneficial effects of berberine on oxidized LDL-induced cytotoxicity to human retinal Mϋller cells. Invest Ophth Vis Sci 57:3369. https://doi.org/10.1167/iovs.16-19291

    Article  CAS  Google Scholar 

  21. Song DL, Song JT, Wang CG, Li YF, Dunaief JL (2016) Berberine protects against light-induced photoreceptor degeneration in the mouse retina. Exp Eye Res 145:1. https://doi.org/10.1016/j.exer.2015.10.005

    Article  CAS  PubMed  Google Scholar 

  22. Lu L, Huang JJ, Xue X, Wang T, Huang ZQ, Li JM (2021) Berberine regulated miR150-5p to inhibit P2X7 receptor, EMMPRIN and MMP-9 expression in oxLDL induced macrophages. Front Pharmacol 12:639558. https://doi.org/10.3389/fphar.2021.639558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Guo Y, Pope C, Cheng X, Zhou H, Klaassen CD (2011) Dose-response of berberine on hepatic cytochromes P450 mRNA expression and activities in mice. J Ethnopharmacol 138(1):111–118. https://doi.org/10.1016/j.jep.2011.08.058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Guan C, Qiao S, Lv Q, Cao N, Wang K, Dai Y, Wei Z (2018) Orally administered berberine ameliorates bleomycin-induced pulmonary fibrosis in mice through promoting activation of PPAR-γ and subsequent expression of HGF in colons. Toxicol Appl Pharmacol 343:1–15. https://doi.org/10.1016/j.taap.2018.02.001

    Article  CAS  PubMed  Google Scholar 

  25. Hu H, Lu WN, Zhang M, Zhang XL, Argall AJ, Patel S, Lee GE, Kim YC, Jacobson KA, Laties AM, Mitchell CH (2010) Stimulation of the P2X7 receptor kills rat retinal ganglion cells in vivo. Exp Eye Res 91:425. https://doi.org/10.1016/j.exer.2010.06.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Puthussery T, Fletcher E (2009) Extracellular ATP induces retinal photoreceptor apoptosis through activation of purinoceptors in rodents. J Comp Neurol 513:430. https://doi.org/10.1002/cne.21964

    Article  CAS  PubMed  Google Scholar 

  27. Newman EA (2015) Glial cell regulation of neuronal activity and blood flow in the retina by release of gliotransmitters. Philos T R Soc B 370:20140195. https://doi.org/10.1098/rstb.2014.0195

    Article  CAS  Google Scholar 

  28. Harada T, Harada C, Nakayama N, Okuyama S, Yoshida K, Kohsaka S, Matsuda H, Wada K (2000) Modification of glial-neuronal cell interactions prevents photoreceptor apoptosis during light-induced retinal degeneration. Neuron 26:533. https://doi.org/10.1016/S0896-6273(00)81185-X

    Article  CAS  PubMed  Google Scholar 

  29. Xue B, Xie YT, Xue Y, Hu N, Zhang GW, Guan HJ, Ji M (2016) Involvement of P2X7 receptors in retinal ganglion cell apoptosis induced by activated Muller cells. Exp Eye Res 153:42. https://doi.org/10.1016/j.exer.2016.10.005

    Article  CAS  PubMed  Google Scholar 

  30. Bhansali P, Rayport I, Rebsam A, Mason C (2014) Delayed neurogenesis leads to altered specification of ventrotemporal retinal ganglion cells in albino mice. Neural Dev 9:11. https://doi.org/10.1186/1749-8104-9-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. García-Ayuso D, Di Pierdomenico J, Vidal-Sanz M, Villegas-Pérez MP (2019) Retinal ganglion cell death as a late remodeling effect of photoreceptor degeneration. Int J Mol Sci 20:4649. https://doi.org/10.3390/ijms20184649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. del Olmo-Aguado S, Manso AG, Osborne NN (2012) Light might directly affect retinal ganglion cell mitochondria to potentially influence function. Photochem Photobiol 88:1346. https://doi.org/10.1111/j.1751-1097.2012.01120.x

    Article  CAS  PubMed  Google Scholar 

  33. Iandiev I, Wurm A, Hollborn M, Wiedemann P, Grimm C, Remé CE, Reichenbach A, Pannicke T, Bringmann A (2008) Muller cell response to blue light injury of the rat retina. Invest Ophthalmol Vis Sci 49:3559. https://doi.org/10.1167/iovs.08-1723

    Article  PubMed  Google Scholar 

  34. Reichenbach A, Wurm A, Pannicke T, Iandiev I, Wiedemann P, Bringmann A (2007) Mϋller cells as players in retinal degeneration and edema. Graef Arch Clin Exp 245:627. https://doi.org/10.1007/s00417-006-0516-y

    Article  Google Scholar 

  35. Ventura ALM, dos Santos-Rodrigues A, Mitchell CH, Faillace MP (2019) Purinergic signaling in the retina: from development to disease. Brain Res Bull 151:92. https://doi.org/10.1016/j.brainresbull.2018.10.016

    Article  CAS  PubMed  Google Scholar 

  36. Kerur N, Hirano Y, Tarallo V, Fowler BJ, Bastos-Carvalho A, Yasuma T, Yasuma R, Kim Y, Hinton DR, Kirschninget CJ (2013) TLR-independent and P2X7-dependent signaling mediateAluRNA-induced NLRP3 inflammasome activation in geographic atrophy. Invest Ophthalmol Vis Sci 54:7395. https://doi.org/10.1167/iovs.13-12500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Vivoli E, Cappon A, Milani S, Piombanti B, Provenzano A, Novo E, Masi A, Navari N, Narducci R, Mannaioni G, Moneti G, Oliveira CP, Parola M, Marra F (2016) NLRP3 inflammasome as a target of berberine in experimental murine liver injury: interference with P2X7 signaling. Clin Sci 130:1793. https://doi.org/10.1042/CS20160400

    Article  CAS  Google Scholar 

  38. Yao MJ, Fan XD, Yuan B, Takagi N, Liu S, Han X, Ren JG, Liu JX (2019) Berberine inhibits NLRP3 inflammasome pathway in human triple-negative breast cancer MDA-MB-231 cell. BMC Complem Altern M 19:216. https://doi.org/10.1186/s12906-019-2615-4

    Article  CAS  Google Scholar 

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Funding

This work was supported by grants from Eye Hospital of China Academy of Chinese Medical Sciences Scientific Research fund (202001), and China Academy of Chinese Medical Sciences Innovation Fund (CI2021A02608).

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  1. Shan-Shan Ye and Jia-Ning Wang equally contributed to the work.

Authors and Affiliations

  1. Eye Hospital, China Academy of Chinese Medical Sciences, Beijing, 100040, China

    Shan-Shan Ye, Jia-Ning Wang, Le-Shu Dai & Jian-Tao Song

  2. School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China

    Ya-Fei Zhao, Ji-Zhou Zhang & Yan-Qin Zuo

  3. China Academy of Chinese Medical Sciences, Beijing, 100700, China

    Le-Shu Dai

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Contributions

Shan-Shan Ye and Jian-Tao Song contributed to the conception and design of the study. Shan-Shan Ye drafted the manuscript and performed most of the experiments. Jia-Ning Wang, Ya-Fei Zhao, Le-Shu Dai, Ji-Zhou Zhang, Yan-Qin Zuo participated in some of the experiments. Shan-Shan Ye and Jia-Ning Wang analyzed the data. All authors contributed to manuscript revision, and have read and given final approval of the submission.

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Correspondence to Jian-Tao Song.

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The animal study was reviewed and approved by the Institutional Review Board of Chengdu University of Traditional Chinese Medicine (Chengdu, China).

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Shan-Shan Ye declares that he/she has no conflict of interest.

Jia-Ning Wang declares that he/she has no conflict of interest.

Ya-Fei Zhao declares that he/she has no conflict of interest.

Le-Shu Dai declares that he/she has no conflict of interest.

Ji-Zhou Zhang declares that he/she has no conflict of interest.

Yan-Qin Zuo declares that he/she has no conflict of interest.

Jian-Tao Song declares that he/she has no conflict of interest.

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Ye, SS., Wang, JN., Zhao, YF. et al. Purinergic P2X7 receptor involves in anti-retinal photodamage effects of berberine. Purinergic Signalling (2024). https://doi.org/10.1007/s11302-024-09999-6

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