Skip to main content

Advertisement

SpringerLink
Log in

Fisetin rescues retinal functions by suppressing inflammatory response in a DBA/2J mouse model of glaucoma

  • Original Research Article
  • Published:
Documenta Ophthalmologica Aims and scope Submit manuscript

A Correction to this article was published on 15 November 2019

This article has been updated

Abstract

Purpose

Glaucoma is a common chronic neurodegenerative disease, which could lead to visual loss. In this study, we aimed to investigate whether fisetin, a natural flavone with anti-inflammatory and antioxidant properties, is able to alleviate glaucoma.

Methods

We employed a DBA/2J mouse model which was treated with or without fisetin. Pattern electroretinogram (P-ERG), visual evoked potentials (VEPs) and intraocular pressure (IOP) were evaluated. Quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) were used to measure the expression levels of TNF-α, IL-1β and IL-6. Western blotting was performed to assess the activation of nuclear factor kappa-B (NF-κB).

Results

We found that DBA/2J mice treated with fisetin (10-30 mg/kg) showed improved P-ERG and VEP amplitudes and reduced IOP compared to untreated DBA/2J mice. In addition, there were more survived retinal ganglion cells (RGCs) and less activated microglia in fisetin-treated DBA/2J mice than those in untreated mice. Furthermore, secreted protein levels and mRNA levels of TNF-α, IL-1β and IL-6 were significantly repressed by fisetin. The phosphorylated p65 level in the nucleus was dramatically reduced in fisetin-treated mice compared to it in untreated mice. Our results demonstrate that fisetin may exert its function through regulating cytokine productions and inhibiting NF-κB activation in the retina.

Conclusion

In conclusion, fisetin is able to promote the visual functions of DBA/2J mice by inhibiting NF-κB activation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Change history

  • 15 November 2019

    The Editor-in-Chief of Documenta Ophthalmologica is publishing an editorial expression of concern for the manuscript "Fisetin rescues retinal functions by suppressing inflammatory response in a DBA/2J mouse model of glaucoma” by Li et al. (2019) [1].

References

  1. Quigley HA, Broman AT (2006) The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90:262–267. https://doi.org/10.1136/bjo.2005.081224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Nuschke AC, Farrell SR, Levesque JM, Chauhan BC (2015) Assessment of retinal ganglion cell damage in glaucomatous optic neuropathy: axon transport, injury and soma loss. Exp Eye Res 141:111–124. https://doi.org/10.1016/j.exer.2015.06.006

    Article  CAS  PubMed  Google Scholar 

  3. Howell GR, Macalinao DG, Sousa GL, Walden M, Soto I, Kneeland SC, Barbay JM, King BL, Marchant JK, Hibbs M, Stevens B, Barres BA, Clark AF, Libby RT, John SWM (2011) Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J Clin Investig 121:1429–1444. https://doi.org/10.1172/Jci44646

    Article  CAS  PubMed  Google Scholar 

  4. Nickells RW, Howell GR, Soto I, John SWM (2012) Under pressure: cellular and molecular responses during glaucoma, a common neurodegeneration with axonopathy. Annu Rev Neurosci 35(35):153–179. https://doi.org/10.1146/annurev.neuro.051508.135728

    Article  CAS  PubMed  Google Scholar 

  5. Foster PJ, Buhrmann R, Quigley HA, Johnson GJ (2002) The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol 86:238–242. https://doi.org/10.1136/bjo.86.2.238

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wax MB, Tezel G, Yang J, Peng G, Patil RV, Agarwal N, Sappington RM, Calkins DJ (2008) Induced autoimmunity to heat shock proteins elicits glaucomatous loss of retinal ganglion cell neurons via activated T-cell-derived fas-ligand. J Neurosci 28:12085–12096. https://doi.org/10.1523/Jneurosci.3200-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tezel G, Thornton IL, Tong MG, Luo C, Yang XJ, Cai J, Powell DW, Soltau JB, Liebmann JM, Ritch R (2012) Immunoproteomic analysis of potential serum biomarker candidates in human glaucoma. Invest Ophthalmol Vis Sci 53:8222–8231. https://doi.org/10.1167/iovs.12-10076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tatton W, Chen D, Chalmers-Redman R, Wheeler L, Nixon R, Tatton N (2003) Hypothesis for a common basis for neuroprotection in glaucoma and Alzheimer’s disease: anti-apoptosis by alpha-2-adrenergic receptor activation. Surv Ophthalmol 48:S25–S37. https://doi.org/10.1016/S0039-6257(03)00005-5

    Article  PubMed  Google Scholar 

  9. Crish SD, Sappington RM, Inman DM, Horner PJ, Calkins DJ (2010) Distal axonopathy with structural persistence in glaucomatous neurodegeneration. Proc Natl Acad Sci USA 107:5196–5201. https://doi.org/10.1073/pnas.0913141107

    Article  PubMed  Google Scholar 

  10. Murphy JA, Clarke DB (2006) Target-derived neurotrophins may influence the survival of adult retinal ganglion cells when local neurotrophic support is disrupted: implications for glaucoma. Med Hypotheses 67:1208–1212. https://doi.org/10.1016/j.mehy.2006.04.049

    Article  CAS  PubMed  Google Scholar 

  11. Zhang HF, Lin Y, Li JH, Pober JS, Min W (2007) RIP1-mediated AIP1 phosphorylation at a 14-3-3-binding site is critical for tumor necrosis factor-induced ASK1-JNK/p38 activation. J Biol Chem 282:14788–14796

    Article  CAS  Google Scholar 

  12. Wax MB, Tezel G (2009) Immunoregulation of retinal ganglion cell fate in glaucoma. Exp Eye Res 88:825–830. https://doi.org/10.1016/j.exer.2009.02.005

    Article  CAS  PubMed  Google Scholar 

  13. Nakazawa T, Nakazawa C, Matsubara A, Noda K, Hisatomi T, She HC, Michaud N, Hafezi-Moghadam A, Miller JW, Benowitz LI (2006) Tumor necrosis factor-alpha mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma. J Neurosci 26:12633–12641. https://doi.org/10.1523/Jneurosci.2801-06.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lebrun-Julien F, Bertrand MJ, De Backer O, Stellwagen D, Morales CR, Di Polo A, Barker PA (2010) ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway. Proc Natl Acad Sci 107:3817–3822

    Article  CAS  Google Scholar 

  15. Funayama T, Ishikawa K, Ohtake Y, Tanino T, Kurosaka D, Kimura I, Suzuki K, Ideta H, Nakamoto K, Yasuda N, Fujimaki T, Murakami A, Asaoka R, Hotta Y, Tanihara H, Kanamoto T, Mishima H, Fukuchi T, Abe H, Iwata T, Shimada N, Kudoh J, Shimizu N, Mashima Y (2004) Variants in optineurin gene and their association with tumor necrosis factor-alpha polymorphisms in Japanese patients with glaucoma. Invest Ophthalmol Vis Sci 45:4359–4367. https://doi.org/10.1167/iovs.03-1403

    Article  PubMed  Google Scholar 

  16. Pal HC, Athar M, Elmets CA, Afaq F (2015) Fisetin inhibits UVB-induced cutaneous inflammation and activation of PI3 K/AKT/NFκB signaling pathways in SKH-1 hairless mice. Photochem Photobiol 91:225–234

    Article  CAS  Google Scholar 

  17. Kim SC, Kang SH, Jeong SJ, Kim SH, Ko HS, Kim SH (2012) Inhibition of c-Jun N-terminal kinase and nuclear factor kappa B pathways mediates fisetin-exerted anti-inflammatory activity in lipopolysaccharide-treated RAW264.7 cells. Immunopharmacol Immunotoxicol 34:645–650. https://doi.org/10.3109/08923973.2011.648270

    Article  CAS  PubMed  Google Scholar 

  18. Chuang JY, Chang PC, Shen YC, Lin CJ, Tsai CF, Chen JH, Yeh WL, Wu LH, Lin HY, Liu YS, Lu DY (2014) Regulatory effects of fisetin on microglial activation. Molecules 19:8820–8839. https://doi.org/10.3390/molecules19078820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lee JD, Huh JE, Jeon G, Yang HR, Woo HS, Choi DY, Park DS (2009) Flavonol-rich RVHxR from Rhus verniciflua Stokes and its major compound fisetin inhibits inflammation-related cytokines and angiogenic factor in rheumatoid arthritic fibroblast-like synovial cells and in vivo models. Int Immunopharmacol 9:268–276. https://doi.org/10.1016/j.intimp.2008.11.005

    Article  CAS  PubMed  Google Scholar 

  20. Goh FY, Upton N, Guan S, Cheng C, Shanmugam MK, Sethi G, Leung BP, Wong WF (2012) Fisetin, a bioactive flavonol, attenuates allergic airway inflammation through negative regulation of NF-κB. Eur J Pharmacol 679:109–116

    Article  CAS  Google Scholar 

  21. Porciatti V, Saleh M, Nagaraju M (2007) The pattern electroretinogram as a tool to monitor progressive retinal ganglion cell dysfunction in the DBA/2J mouse model of glaucoma. Invest Ophthalmol Vis Sci 48:745–751. https://doi.org/10.1167/iovs.06-0733

    Article  PubMed  PubMed Central  Google Scholar 

  22. Gustafson E, Silberschmidt A, Esguerra M, Miller R (2013) Recording and manipulation of the pattern electroretinogram in a mouse eyecup preparation. Investig Ophthalmol Vis Sci 54:6132

    Google Scholar 

  23. Nadal-Nicolas FM, Jimenez-Lopez M, Salinas-Navarro M, Sobrado-Calvo P, Alburquerque-Bejar JJ, Vidal-Sanz M, Agudo-Barriuso M (2012) Whole number, distribution and co-expression of Brn3 transcription factors in retinal ganglion cells of adult albino and pigmented rats. PLoS ONE 7:e49830. https://doi.org/10.1371/journal.pone.0049830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Libby RT, Gould DB, Anderson MG, John SWM (2005) Complex genetics of glaucoma susceptibility. Annu Rev Genom Hum Genet 6:15–44. https://doi.org/10.1146/annurev.genom.6.080604.162209

    Article  CAS  Google Scholar 

  25. Anderson MG, Libby RT, Mao M, Cosma IM, Wilson LA, Smith RS, John SWM (2006) Genetic context determines susceptibility to intraocular pressure elevation in a mouse pigmentary glaucoma. BMC Biol 4:20. https://doi.org/10.1186/1741-7007-4-20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Libby RT, Li Y, Savinova OV, Barter J, Smith RS, Nickells RW, John SWM (2005) Susceptibility to neurodegeneration in a glaucoma is modified by Bax gene dosage. PLoS Genet 1:17–26. https://doi.org/10.1371/journal.pgen.0010004

    Article  CAS  PubMed  Google Scholar 

  27. Reichstein D, Ren LZ, Filippopoulos T, Mittag T, Danias J (2007) Apoptotic retinal ganglion cell death in the DBA/2 mouse model of glaucoma. Exp Eye Res 84:13–21. https://doi.org/10.1016/j.exer.2006.08.009

    Article  CAS  PubMed  Google Scholar 

  28. Bosco A, Inman DM, Steele MR, Wu GM, Soto I, Marsh-Armstrong N, Hubbard WC, Calkins DJ, Horner PJ, Vetter ML (2008) Reduced retina microglial activation and improved optic nerve integrity with minocycline treatment in the DBA/2J mouse model of glaucoma. Invest Ophthalmol Vis Sci 49:1437–1446. https://doi.org/10.1167/iovs.07-1337

    Article  PubMed  Google Scholar 

  29. Neufeld AH (1999) Microglia in the optic nerve head and the region of parapapillary chorioretinal atrophy in glaucoma. Arch Ophthalmol 117:1050–1056

    Article  CAS  Google Scholar 

  30. Son JL, Soto I, Oglesby E, Lopez-Roca T, Pease ME, Quigley HA, Marsh-Armstrong N (2010) Glaucomatous optic nerve injury involves early astrocyte reactivity and late oligodendrocyte loss. Glia 58:780–789. https://doi.org/10.1002/glia.20962

    Article  PubMed  Google Scholar 

  31. Neufeld AH, Liu B (2003) Glaucomatous optic neuropathy: when glia misbehave. Neurosci 9:485–495

    CAS  Google Scholar 

  32. Sobrado-Calvo P, Vidal-Sanz M, Villegas-Pérez MP (2007) Rat retinal microglial cells under normal conditions, after optic nerve section, and after optic nerve section and intravitreal injection of trophic factors or macrophage inhibitory factor. J Comp Neurol 501:866–878

    Article  CAS  Google Scholar 

  33. Karlstetter M, Ebert S, Langmann T (2010) Microglia in the healthy and degenerating retina: insights from novel mouse models. Immunobiology 215:685–691. https://doi.org/10.1016/j.imbio.2010.05.010

    Article  CAS  PubMed  Google Scholar 

  34. Tezel G, Yang XJ, Yang JJ, Wax MB (2004) Role of tumor necrosis factor receptor-1 in the death of retinal ganglion cells following optic nerve crush injury in mice. Brain Res 996:202–212. https://doi.org/10.1016/j.brainres.2003.10.029

    Article  CAS  PubMed  Google Scholar 

  35. Al-Gayyar M, Elsherbiny N (2013) Contribution of TNF-α to the development of retinal neurodegenerative disorders. Eur Cytokine Netw 24:27–36

    CAS  PubMed  Google Scholar 

  36. Balaiya S, Edwards J, Tillis T, Khetpal V, Chalam KV (2011) Tumor necrosis factor-alpha (TNF-α) levels in aqueous humor of primary open angle glaucoma. Clin Ophthalmol 5:553

    Article  CAS  Google Scholar 

  37. Tezel G (2008) TNF-α signaling in glaucomatous neurodegeneration. Prog Brain Res 173:409–421

    Article  CAS  Google Scholar 

  38. Wilson GN, Inman DM, Dengler-Crish CM, Smith MA, Crish SD (2015) Early pro-inflammatory cytokine elevations in the DBA/2J mouse model of glaucoma. J Neuroinflammation 12:176

    Article  Google Scholar 

  39. H-l Peng, Huang W-C, S-c Cheng, Liou C-J (2018) Fisetin inhibits the generation of inflammatory mediators in interleukin-1β–induced human lung epithelial cells by suppressing the Nf-κb and Erk1/2 pathways. Int Immunopharmacol 60:202–210

    Article  Google Scholar 

  40. Sahu BD, Kumar JM, Sistla R (2016) Fisetin, a dietary flavonoid, ameliorates experimental colitis in mice: relevance of NF-κB signaling. J Nutr Biochem 28:171–182

    Article  CAS  Google Scholar 

  41. Seo S-H, Jeong G-S (2015) Fisetin inhibits TNF-α-induced inflammatory action and hydrogen peroxide-induced oxidative damage in human keratinocyte HaCaT cells through PI3 K/AKT/Nrf-2-mediated heme oxygenase-1 expression. Int Immunopharmacol 29:246–253

    Article  CAS  Google Scholar 

  42. Mookherjee S, Banerjee D, Chakraborty S, Banerjee A, Mukhopadhyay I, Sen A, Ray K (2010) Association of IL1A and IL1B loci with primary open angle glaucoma. BMC Med Genet 11:99. https://doi.org/10.1186/1471-2350-11-99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chidlow G, Wood JPM, Ebneter A, Casson RJ (2012) Interleukin-6 is an efficacious marker of axonal transport disruption during experimental glaucoma and stimulates neuritogenesis in cultured retinal ganglion cells. Neurobiol Dis 48:568–581. https://doi.org/10.1016/j.nbd.2012.07.026

    Article  CAS  PubMed  Google Scholar 

  44. Li GR, Luna C, Liton PB, Navarro I, Epstein DL, Gonzalez P (2007) Sustained stress response after oxidative stress in trabecular meshwork cells. Mol Vis 13:2282–2288

    PubMed  PubMed Central  Google Scholar 

  45. Lebrun-Julien F, Duplan L, Pernet V, Osswald I, Sapieha P, Bourgeois P, Dickson K, Bowie D, Barker PA, Di Polo A (2009) Excitotoxic death of retinal neurons in vivo occurs via a non-cell-autonomous mechanism. J Neurosci 29:5536–5545. https://doi.org/10.1523/Jneurosci.0831-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chen C, Yao L, Cui J, Liu B (2018) Fisetin protects against intracerebral hemorrhage-induced neuroinflammation in aged mice. Cerebrovasc Dis 45:154–161. https://doi.org/10.1159/000488117

    Article  CAS  PubMed  Google Scholar 

  47. Sandireddy R, Yerra VG, Komirishetti P, Areti A, Kumar A (2016) Fisetin imparts neuroprotection in experimental diabetic neuropathy by modulating Nrf2 and NF-κB pathways. Cell Mol Neurobiol 36:883–892

    Article  CAS  Google Scholar 

  48. Feng G, Z-y Jiang, Sun B, Fu J, T-z Li (2016) Fisetin alleviates lipopolysaccharide-induced acute lung injury via TLR4-mediated NF-κB signaling pathway in rats. Inflammation 39:148–157

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Ophthalmology, People’s Hospital of Rizhao, No. 126 Tai’an Road, Donggang District, Rizhao, 276800, Shandong, China

    Linlin Li & Jiaxiang Shen

  2. Department of Ophthalmology, Rizhao Central Hospital of Shandong, No. 66 Wanghai Road, Donggang District, Rizhao, 276800, Shandong, China

    Jie Qin & Tingting Fu

Authors
  1. Linlin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tingting Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiaxiang Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jiaxiang Shen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving animal were in accordance with the ethical standards of the institutional and/or national research committee. Animal studies were approved by the People’s Hospital of Rizhao, and all efforts were made to minimize the number of animals used and their suffering.

Statements of human rights

There is no human participation in this study.

Statement on the welfare of animals

All animal experiments were conducted according to the guidelines in our institute and all efforts were made to minimize the nubmer of animals used and their suffering.

Informed consent

Not applicable. There is no human participation in this study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, L., Qin, J., Fu, T. et al. Fisetin rescues retinal functions by suppressing inflammatory response in a DBA/2J mouse model of glaucoma. Doc Ophthalmol 138, 125–135 (2019). https://doi.org/10.1007/s10633-019-09676-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10633-019-09676-9

Keywords

Search

Navigation