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SIRT1 is required for the neuroprotection of resveratrol on retinal ganglion cells after retinal ischemia-reperfusion injury in mice

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Abstract

Purpose

Retinal ganglion cells (RGCs) loss is closely related to visual impairment in glaucoma, so the neuroprotection on RGCs is important and novel for glaucoma research. SIRT1, a family member of sirtuins, is implicated in many crucial processes of eye diseases. The purpose of this study is to determine the neuroprotection of SIRT1 on RGCs and to investigate the underlying mechanisms of these effects in an experimental model for acute glaucoma.

Methods

Retinal ischemia-reperfusion (IR) injury was induced in C57BL/6J mice. Resveratrol (RSV, activator of SIRT1) and sirtinol (inhibitor of SIRT1) were injected intravitreally 1 day before IR injury. RGCs survival rate was quantified by immunofluorescence staining. RGCs apoptosis was evaluated by the staining of TUNEL and cleaved caspase-3, and SIRT1 level was detected by western blot. Expressions of phospho-Akt, Akt, Bax, and Bcl-2 were further determined by western blot to investigate the neuroprotective mechanisms of SIRT1.

Results

RGCs survival rates and SIRT1 levels were decreased over time after IR injury. Intravitreal injection of RSV remarkably attenuated RGCs loss in a dose-dependent manner, and the most effective concentration of RSV was 100 μM. Up-regulation of SIRT1 by RSV significantly inhibited RGCs apoptosis, increased p-Akt level, decreased Bax and cleaved caspase-3 expressions, and all these effects were diminished by 100 μM sirtinol. Moreover, there were no significant changes in total Akt and Bcl-2 levels.

Conclusion

SIRT1 activation by RSV confers neuroprotection on RGCs in retinal IR injury through the activation of Akt pathway and subsequent suppression of mitochondrial apoptotic pathway. Determination of the effective concentration of intravitreal injection of RSV also provides a theoretical basis for the clinical application of RSV.

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References

  1. Quigley HA, Broman AT (2006) The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90(3):262–267. https://doi.org/10.1136/bjo.2005.081224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kingman S (2004) Glaucoma is second leading cause of blindness globally. Bulletin of the World Health Organization 82 (11):887-888. doi:/S0042-96862004001100019

  3. Kim SH, Park JH, Kim YJ, Park KH (2013) The neuroprotective effect of resveratrol on retinal ganglion cells after optic nerve transection. Mol Vis 19:1667–1676

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Luo H, Zhuang J, Hu P, Ye W, Chen S, Pang Y, Li N, Deng C, Zhang X (2018) Resveratrol delays retinal ganglion cell loss and attenuates gliosis-related inflammation from ischemia-reperfusion injury. Invest Ophthalmol Vis Sci 59(10):3879–3888. https://doi.org/10.1167/iovs.18-23806

    Article  CAS  PubMed  Google Scholar 

  5. Chang EE, Goldberg JL (2012) Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement. Ophthalmology 119(5):979–986. https://doi.org/10.1016/j.ophtha.2011.11.003

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sauve AA, Wolberger C, Schramm VL, Boeke JD (2006) The biochemistry of sirtuins. Annu Rev Biochem 75:435–465. https://doi.org/10.1146/annurev.biochem.74.082803.133500

    Article  CAS  PubMed  Google Scholar 

  7. Balaiya S, Abu-Amero KK, Kondkar AA, Chalam KV (2017) Sirtuins expression and their role in retinal diseases. Oxidative Med Cell Longev 2017:3187594. https://doi.org/10.1155/2017/3187594

    Article  CAS  Google Scholar 

  8. Jaliffa C, Ameqrane I, Dansault A, Leemput J, Vieira V, Lacassagne E, Provost A, Bigot K, Masson C, Menasche M, Abitbol M (2009) Sirt1 involvement in rd10 mouse retinal degeneration. Invest Ophthalmol Vis Sci 50(8):3562–3572. https://doi.org/10.1167/iovs.08-2817

    Article  PubMed  Google Scholar 

  9. Mimura T, Kaji Y, Noma H, Funatsu H, Okamoto S (2013) The role of SIRT1 in ocular aging. Exp Eye Res 116:17–26. https://doi.org/10.1016/j.exer.2013.07.017

    Article  CAS  PubMed  Google Scholar 

  10. Buhrmann C, Shayan P, Popper B, Goel A, Shakibaei M (2016) Sirt1 is required for resveratrol-mediated chemopreventive effects in colorectal cancer cells. Nutrients 8(3):145. https://doi.org/10.3390/nu8030145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Seong H, Ryu J, Yoo WS, Kim SJ, Han YS, Park JM, Kang SS, Seo SW (2017) Resveratrol ameliorates retinal ischemia/reperfusion injury in C57BL/6J mice via downregulation of caspase-3. Curr Eye Res 42(12):1650–1658. https://doi.org/10.1080/02713683.2017.1344713

    Article  CAS  PubMed  Google Scholar 

  12. Pirhan D, Yuksel N, Emre E, Cengiz A, Kursat Yildiz D (2016) Riluzole- and resveratrol-induced delay of retinal ganglion cell death in an experimental model of glaucoma. Curr Eye Res 41(1):59–69. https://doi.org/10.3109/02713683.2015.1004719

    Article  CAS  PubMed  Google Scholar 

  13. Xiong S, Xu Y, Ma M, Wang H, Wei F, Gu Q, Xu X (2017) Neuroprotective effects of a novel peptide, FK18, under oxygen-glucose deprivation in SH-SY5Y cells and retinal ischemia in rats via the Akt pathway. Neurochem Int 108:78–90. https://doi.org/10.1016/j.neuint.2017.02.015

    Article  CAS  PubMed  Google Scholar 

  14. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425(6954):191–196. https://doi.org/10.1038/nature01960

    Article  CAS  PubMed  Google Scholar 

  15. Porcu M, Chiarugi A (2005) The emerging therapeutic potential of sirtuin-interacting drugs: from cell death to lifespan extension. Trends Pharmacol Sci 26(2):94–103. https://doi.org/10.1016/j.tips.2004.12.009

    Article  CAS  PubMed  Google Scholar 

  16. Shindler KS, Ventura E, Rex TS, Elliott P, Rostami A (2007) SIRT1 activation confers neuroprotection in experimental optic neuritis. Invest Ophthalmol Vis Sci 48(8):3602–3609. https://doi.org/10.1167/iovs.07-0131

    Article  PubMed  PubMed Central  Google Scholar 

  17. Manning BD, Toker A (2017) AKT/PKB signaling: navigating the network. Cell 169(3):381–405

    Article  CAS  Google Scholar 

  18. Martinou JC, Desagher S, ., Antonsson B, . (2000) Cytochrome c release from mitochondria: all or nothing. Nat Cell Biol 2 (3):41–43

    Article  Google Scholar 

  19. Osborne NN, Casson RJ, Wood JP, Chidlow G, Graham M, Melena J (2004) Retinal ischemia: mechanisms of damage and potential therapeutic strategies. Prog Retin Eye Res 23(1):91–147. https://doi.org/10.1016/j.preteyeres.2003.12.001

    Article  CAS  PubMed  Google Scholar 

  20. Minhas G, Sharma J, Khan N (2016) Cellular stress response and immune signaling in retinal ischemia-reperfusion injury. Front Immunol 7:444. https://doi.org/10.3389/fimmu.2016.00444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zuo L, Khan RS, Lee V, Dine K, Wu W, Shindler KS (2013) SIRT1 promotes RGC survival and delays loss of function following optic nerve crush. Invest Ophthalmol Vis Sci 54(7):5097–5102. https://doi.org/10.1167/iovs.13-12157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim SJ, Sung MS, Heo H, Lee JH, Park SW (2016) Mangiferin protects retinal ganglion cells in ischemic mouse retina via SIRT1. Curr Eye Res 41(6):844–855. https://doi.org/10.3109/02713683.2015.1050736

    Article  CAS  PubMed  Google Scholar 

  23. Abu-Amero KK, Kondkar AA, Chalam KV (2016) Resveratrol and Ophthalmic Diseases. Nutrients 8(4):200. https://doi.org/10.3390/nu8040200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kokona D, Thermos K (2015) Synthetic and endogenous cannabinoids protect retinal neurons from AMPA excitotoxicity in vivo, via activation of CB1 receptors: involvement of PI3K/Akt and MEK/ERK signaling pathways. Exp Eye Res 136:45–58. https://doi.org/10.1016/j.exer.2015.05.007

    Article  CAS  PubMed  Google Scholar 

  25. Liu C, Wu J, Xu K, Cai F, Gu J, Ma L, Chen J (2010) Neuroprotection by baicalein in ischemic brain injury involves PTEN/AKT pathway. J Neurochem 112(6):1500–1512. https://doi.org/10.1111/j.1471-4159.2009.06561.x

    Article  CAS  PubMed  Google Scholar 

  26. Wang RH, Kim HS, Xiao C, Xu X, Gavrilova O, Deng CX (2011) Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J Clin Invest 121(11):4477–4490. https://doi.org/10.1172/jci46243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lee S, Van Bergen NJ, Kong GY, Chrysostomou V, Waugh HS, O'Neill EC, Crowston JG, Trounce IA (2011) Mitochondrial dysfunction in glaucoma and emerging bioenergetic therapies. Exp Eye Res 93(2):204–212. https://doi.org/10.1016/j.exer.2010.07.015

    Article  CAS  PubMed  Google Scholar 

  28. Maes ME, Schlamp CL, Nickells RW (2017) BAX to basics: how the BCL2 gene family controls the death of retinal ganglion cells. Prog Retin Eye Res 57:1–25. https://doi.org/10.1016/j.preteyeres.2017.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen ST, Garey LJ, Jen LS (1994) Bcl-2 proto-oncogene protein immunoreactivity in normally developing and axotomised rat retinas. Neurosci Lett 172(1):11–14. https://doi.org/10.1016/0304-3940(94)90650-5

    Article  CAS  Google Scholar 

  30. Vin AP, Hu H, Zhai Y, Von Zee CL, Logeman A, Stubbs EB Jr, Perlman JI, Bu P (2013) Neuroprotective effect of resveratrol prophylaxis on experimental retinal ischemic injury. Exp Eye Res 108:72–75. https://doi.org/10.1016/j.exer.2012.11.022

    Article  CAS  PubMed  Google Scholar 

  31. Lindsey JD, Duong-Polk KX, Hammond D, Leung CK, Weinreb RN (2015) Protection of injured retinal ganglion cell dendrites and unfolded protein response resolution after long-term dietary resveratrol. Neurobiol Aging 36(5):1969–1981. https://doi.org/10.1016/j.neurobiolaging.2014.12.021

    Article  CAS  PubMed  Google Scholar 

  32. Gambini J, Inglés M, Olaso G, Lopez-Grueso R, Bonet-Costa V, Gimeno-Mallench L, Mas-Bargues C, Abdelaziz KM, Gomez-Cabrera MC, Vina J, Borras C (2015) Properties of resveratrol: in vitro and in vivo studies about metabolism, bioavailability, and biological effects in animal models and humans. Oxidative Med Cell Longev 2015:837042. https://doi.org/10.1155/2015/837042

    Article  CAS  Google Scholar 

  33. Walle T (2011) Bioavailability of resveratrol. Ann N Y Acad Sci 1215:9–15. https://doi.org/10.1111/j.1749-6632.2010.05842.x

    Article  CAS  PubMed  Google Scholar 

  34. Weiskirchen S, Weiskirchen R (2016) Resveratrol: how much wine do you have to drink to stay healthy? Advances in nutrition (Bethesda, Md) 7(4):706–718. https://doi.org/10.3945/an.115.011627

    Article  CAS  Google Scholar 

  35. Cunha-Vaz J (1979) The blood-ocular barriers. Surv Ophthalmol 23(5):279–296

    Article  CAS  Google Scholar 

  36. Wang S, Wang Z, Yang S, Yin T, Zhang Y, Qin Y, Weinreb RN, Sun X (2017) Tissue distribution of trans-resveratrol and its metabolites after oral administration in human eyes. J Ophthalmol 2017:4052094. https://doi.org/10.1155/2017/4052094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Ying Li, Xinlan Lei, Qinqin Deng, and Xiao Zhang for their constructive scientific suggestions.

Funding

This work was funded by the National Natural Science Foundation of China (grant number 81271025).

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Author notes

  1. Jinyuan Luo and Tao He contributed equally to this work.

Authors and Affiliations

  1. Department of Ophthalmology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei Province, People’s Republic of China

    Jinyuan Luo, Tao He, Jiayi Yang, Ning Yang, Zongyuan Li & Yiqiao Xing

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  1. Jinyuan Luo
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Correspondence to Yiqiao Xing.

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Luo, J., He, T., Yang, J. et al. SIRT1 is required for the neuroprotection of resveratrol on retinal ganglion cells after retinal ischemia-reperfusion injury in mice. Graefes Arch Clin Exp Ophthalmol 258, 335–344 (2020). https://doi.org/10.1007/s00417-019-04580-z

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