Role of Melatonin in Human Eye Physiology and Its Implications for Ophthalmic Diseases Treatment (Review)

Melatonin is a hormone of the epiphysis and a regulator of circadian rhythms of living organisms, which affects a number of important physiological processes. Melatonin synthesis has also been found in other organs, in particular in various structural systems of the eyeball. A number of studies demonstrate that melatonin plays an important role in a variety of biochemical and physiological processes that ensure functioning of visual analyzer. This review provides information on the synthesis of melatonin, its secretion and metabolism, considers key information about melatonin receptors (MT1, MT2 and MT3), their localization in various eye’s structures, and their affinity to melatonin. Over the last years, researchers’ attention has been drawn to the therapeutic properties of melatonin, relevant for treatment of age-related diseases. The aggressive effects of solar radiation and environmental toxicants expose the organ of vision to oxidative attacks. A large amount of evidence has been accumulated of the participation of oxidative stress in the development of many eye diseases, resulting in an imbalance between the generation of reactive oxygen species and the expression of antioxidant enzymes. Melatonin, which has antioxidant and anti-inflammatory properties and regulates mitochondrial functions, can be a powerful tool to counter age-related changes. Globally, the number of people of all ages with visual impairment is estimated at 285 million. Cataract and age-related macular degeneration (AMD) are the leading causes of vision loss around the world. AMD and cataracts often coexist in patients, so there is a concern that age-related cataract surgery increases the risk of morbidity and progression of AMD. The pathogenesis of both cataracts and AMD is still unclear, although a number of theories have been put forward, including oxidative stress, age-related changes, inflammatory processes, etc. Analysis of modern domestic and foreign literature shows good perspectives of using melatonin as preventive and therapeutic agent in the treatment of ophthalmic diseases of various origins. 

1. Tök L., Nazıroğlu M., Doğan S., Kahya MC., Tök O. Effects of melatonin on WiFi-induced oxidative stress in lens of rats. Indian Journal of Ophthalmology. 2014;62(1):12–15. DOI: 10.4103/0301-4738.126166

2. Itoh M.T., Takahashi N., Abe M., Shimizu K. Expression and cellular localization of melatonin-synthesizing enzymes in the rat lens. Journal of Pineal Research. 2007;42(1):92–96. DOI: 10.1111/j.1600-079X.2006.00389.x

3. Lo Sardo F., Muti P., Blandino G., Strano S. Melatonin and Hippo Pathway: Is There Existing Cross-Talk? International Journal of Molecular Sciences. 2017;18(9):1–26. DOI: 10.3390/ijms18091913

4. Farajnia S., Michel S., Deboer T., vanderLeest HT., Houben T., Rohling JH., Ramkisoensing A., Yasenkov R., Meijer JH. Evidence for neuronal desynchrony in the aged suprachiasmatic nucleus clock. Journal of Neuroscience. 2012. 32(17):5891– 5899. DOI: 10.1523/JNEUROSCI.0469-12.2012

5. Schernhammer E.S., Rosner B., Willett W.C., Laden F., Colditz G.A., Hankinson S.E. Epidemiology of urinary melatonin in women and its relation to other hormones and night work. Cancer Epidemiology Biomarkers & Prevention. 2004;13(6):936–943.

6. Baba K., Mazzoni F., Owino S., Contreras-Alcantara S., Strettoi E., Tosini G. AgeRelated Changes in the Daily Rhythm of Photoreceptor Functioning and Circuitry in a Melatonin-Proficient Mouse Strain. Public Library of Science. 2012;7(5):1–7. DOI: 10.1371/journal.pone.0037799

7. Pandi-Perumal S.R., Trakht I., Srinivasan V., Spence D.W., Maestroni G.J., Zisapel N., Cardinali D.P. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Progress in Neurobiology. 2008;85(3):335–353. DOI: 10.1016/j.pneurobio.2008.04.001

8. Slominski R.M., Reiter R.J., Schlabritz-Loutsevitch N., Ostrom R.S., Slominski A.T. Melatonin membrane receptors in peripheral tissues: Distribution and functions. Molecular and Cellular Endocrinology. 2012;351(2):152–166. DOI: 10.1016/j.mce.2012.01.004

9. Vincent L., Cohen W., Delagrange P., Boutin J.A., Nosjean O. Molecular and cellular pharmacological properties of 5-methoxycarbonylamino-N-acetyltryptamine (MCA-NAT): a nonspecific MT3 ligand. Journal of Pineal Research. 2010;48(3):222– 229. DOI: 10.1111/j.1600-079X

10. Ebisawa T., Karne S., Lerner M.R., Reppert S.M. Expression cloning of a high-affinity melatonin receptor from Xenopus dermal melanophores. Proceedings of the National Academy of Sciences of the United States of America. 1994;91(13):6133–6137. DOI: 10.1073/pnas.91.13.6133

11. Reppert S.M., Weaver D.R., Ebisawa T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron. 1994;13(5):1177–1185. DOI: 10.1016/0896-6273(94)90055-8

12. Reppert S.M., Godson C., Mahle C.D., Weaver D.R., Slaugenhaupt S.A., Gusella J.F. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proceedings of the National Academy of Sciences of the United States of America. 1995;92(19):8734–8738. DOI: 10.1073/ pnas.92.19.8734

13. Nosjean O., Nicolas J.P., Klupsch F., Delagrange P., Canet E., Boutin J.A. Comparative pharmacological studies of melatonin receptors: MT1, MT2 and MT3/QR2. Tissue distribution of MT3/QR2. Biochemical Pharmacology. 2001;61(11):1369– 1379. DOI: 10.1016/S0006-2952(01)00615-3

14. Mailliet F., Ferry G., Vella F. Organs from mice deleted for NRH:quinone oxid reductase 2 are deprived of the melatonin binding site MT3. FEBS Lett. 2004;578:116– 120. DOI: 10.1016/j.febslet.2004.10.083

15. Legros C., Devavry S., Caignard S., Tessier C., Delagrange P., Ouvry C., Boutin J.A., Nosjean O. Melatonin MT1 and MT2 receptors display different molecular pharmacologies only in the G-protein coupled state. British Journal of Pharmacology. 2014;171(1):186–201. DOI: 10.1111/bph.12457

16. Alkozi H.A., Wang X., Perez de Lara M.J., Pintor J. Presence of melanopsin in human crystalline lens epithelial cells and its role in melatonin synthesis. Experimental Eye Research. 2017;154:168–176. DOI: 10.1016/j.exer.2016.11.019

17. Sengupta A., Baba K., Mazzoni F., Pozdeyev N.V., Strettoi E., Iuvone P.M., Tosini G. Localization of melatonin receptor 1 in mouse retina and its role in the circadian regulation of the electroretinogram and dopamine levels. Public Library of Science. 2011;6(9):1–7. DOI: 10.1371/journal.pone.0024483

18. Gianesini С., Hiragaki S., Laurent V., Hicks D., Tosini G. Cone Viability Is Affected by Disruption of Melatonin Receptors Signaling. Investigative Ophthalmology & Visual Science. 2016;57(1):94–104. DOI: 10.1167/iovs.15-18235

19. Galano A., Tan D.X., Reiter R.J. Melatonin as a natural ally against oxidative stress: a physicochemical examination. Journal of Pineal Research. 2011;51(1):1–16. DOI: 10.1111/j.1600-079X.2011.00916.x

20. Rodriguez C., Mayo J.C., Sainz R.M., Antolín I., Herrera F., Martín V., Reiter R.J. Regulation of antioxidant enzymes: a significant role for melatonin. Journal of Pineal Research. 2004;36(1):1–9. DOI: 10.1046/j.1600-079x.2003.00092.x

21. Crooke A., Huete-Toral F., Colligris B., Pintor J. The role and therapeutic potential of melatonin in age-related ocular diseases. Journal of Pineal Research. 2017;63(2):1–25. DOI: 10.1111/jpi.12430

22. Jung K.H., Hong S.W., Zheng H.M., Lee D.H., Hong S.S. Melatonin downregulates nuclear erythroid 2-related factor 2 and nuclear factor-kappaB during prevention of oxidative liver injury in a dimethylnitrosamine model. Journal of Pineal Research. 2009;47(2):173–183. DOI: 10.1111/j.1600-079X.2009.00698.x

23. Brennan L.A., Kantorow M. Mitochondrial function and redox control in the aging eye: role of MsrA and other repair systems in cataract and macular degenerations. Experimental Eye Research. 2009;88(2):195–203. DOI: 10.1016/j.exer.2008.05.018

24. Tan D.X., Manchester L.C., Qin L., Reiter R.J. Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics. International Journal of Molecular Sciences. 2016;17(12):2124. DOI: 10.3390/ijms17122124

25. Korkmaz A., Topal T., Tan D.X., Reiter R.J. Role of melatonin in metabolic regulation. Reviews in Endocrine and Metabolic Disorders. 2009;10(4):261–270. DOI: 10.1007/s11154-009-9117-5

26. Galano A., Tan D.X., Reiter R.J. On the freeradical scavenging activities of melatonin’s metabolites, AFMK and AMK. Journal of Pineal Research. 2013;54(3):245–557. DOI: 10.1111/jpi.12010

27. Stefanova N.A., Zhdankina A.A., Fursova A.Zh., Kolosova N.G. Potential of melatonin for prevention of age-related macular degeneration: experimental study. Advances in Gerontology. 2013;26(1):122–129. DOI: 10.1134/S2079057013040073

28. Khorsand M., Akmali M., Sharzad S., Beheshtitabar M. Melatonin Reduces Cataract Formation and Aldose Reductase Activity in Lenses of Streptozotocin-induced Diabetic Rat. Iranian Journal of Medical Sciences. 2016;41(4):305–313.

29. Liang F.Q., Aleman T.S., Yang Z., Cideciyan A.V., Jacobson S.G., Bennett J. Melatonin delays photoreceptor degeneration in the rds/rds mouse. Neuroreport. 200;12:1011–1014. DOI: 10.1097/00001756-200104170-00029

30. Crooke A., Huete-Toral F., Martínez-Águila A., Colligris B., Pintor J. Ocular disorders and the utility of animal models in the discovery of melatoninergic drugs with therapeutic potential. Expert Opinion on Drug Discovery. 2012;7(10):989–1001. DOI: 10.1517/17460441.2012.714769

31. Tosini G., Baba K., Hwang C.K., Iuvone P.M. Melatonin: An Underappreciated Player in Retinal Physiology and Pathophysiology. Experimental Eye Research. 2012;103:82–89. DOI: 10.1016/j.exer.2012.08.009

32. Hollyfield J.G., Bonilha V.L., Rayborn M.E., Yang X., Shadrach K.G., Lu L., Ufret R.L., Salomon R.G., Perez V.L. Oxidative damage-induced inflammation initiates age-related macular degeneration. Nature Medicine. 2008;14(2):194–198. DOI: 10.1038/nm1709

33. Pulliero A., Seydel A., Camoirano A., Saccà S.C, Sandri M., Izzotti A. Oxidative damage and autophagy in the human trabecular meshwork as related with ageing. PLoS ONE 9(6): e98106. DOI: 10.1371/journal.pone.0098106

34. Frost L.S., Mitchell C.H., Boesze-Battaglia K. Autophagy in the eye: implications for ocular cell health. Experimental Eye Research. 2014;124:56–66. DOI: 10.1016/j.exer.2014.04.010

35. Pascolini D., Mariotti S.P. Global estimates of visual impairment: 2010. British Journal of Ophthalmology. 2012;96(5):614–618. DOI: 10.1136/bjophthalmol-2011-300539

36. Simpanya M.F., Ansari R.R., Suh K., Leverenz V.R., Giblin F.J. Aggregation of lens crystallins in an in vivo hyperbaric oxygen guinea pig model of nuclear cataract: dynamic light-scattering and HPLC analysis. Investigative Ophthalmology & Visual Science. 2005;46(12):4641–4651. DOI: 10.1167/iovs.05-0843

37. Ganea E., Harding J.J. Glutathione-related enzymes and the eye. Current Eye Research. 2006;31(1):1–11. DOI: 10.1080/02713680500477347

38. Costello M.J., Brennan L.A., Basu S., Chauss D., Mohamed A., Gilliland K.O., Johnsen S., Menko S., Kantorow M. Autophagy and mitophagy participate in ocular lens organelle degradation. Experimental Eye Research. 2013;116:141–150. DOI: 10.1016/j.exer.2013.08.017

39. Bardak Y., Ozertürk Y., Ozgüner F., Durmus M., Delibaş N. Effect of melatonin against oxidative stress in ultraviolet-B exposed ratlens. Current Eye Research. 2000;20(3):225–230. DOI: 10.1076/0271-3683(200003)20319FT225

40. Anwar M.M., Moustafa M.A. The effect of melatonin oneye lens of rats exposed toultraviolet radiation. Comp Biochem Physiol C Toxicol Pharmacol. 2001;129(1):57–63. DOI: 10.1016/s1532-0456(01)00180-6

41. Kiliç A., Selek S., Erel O., Aksoy N. Protective effects of melatonin onoxidativeantioxidative balance and cataractformation inrats. Ann Ophthalmol (Skokie). 2008;40(1):22–27.

42. Bai J., Dong L., Song Z., Ge H., Cai X., Wang G., Liu P. The role of melatonin as an antioxidant in human lens epithelial cells. Free Radical Research. 2013;47(8):635– 642. DOI: 10.3109/10715762.2013.808743

43. McCubrey J.A., Steelman L.S., Chappell W.H., Abrams S., Montalto G., Cervello M., Nicoletti F., Fagone P., Malaponte G., Mazzarino M.C., Candido S., Libra M., Bäsecke J., Mijatovic S.A., Maksimovic-Ivanic D., Milella M., Tafuri A., Chiarini F., Evangelisti C., Cocco L., Martelli A.M. Mutations and deregulation of Ras/Raf/ MEK/ERK and PI3K/PTEN/Akt/mTOR cascades which alter therapy response. Oncotarget. 2012;3(9):954–987. DOI: 10.18632/oncotarget.652

44. Shakespeare T.I., Sellitto C., Li L., Rubinos C., Gong X., Srinivas M., White T.W. Interaction between Connexin50 and mitogen-activated proteinkinasesignaling in lenshomeostasis. Molecular and Cellular Biology. 2009;20(10):2582–2592. DOI: 10.1091/mbc.e08-12-1257

45. Richter T., Zglinicki T. A continuous correlation between oxidative stress and telomere shortening in fibroblasts. Experimental Gerontology. 2007;42(11):1039–1042. DOI: 10.1016/j.exger.2007.08.005

46. Babizhayev M.A., Vishnyakova K.S., Yegorov Y.E. Telomere-dependent senescent phenotype of lens epithelial cells as a biological marker of aging and cataractogenesis: the role of oxidative stress intensity and specific mechanism of phospholipid hydroperoxide toxicity in lens and aqueous. Fundamental & Clinical Pharmacology. 2011;25(2):139–162. DOI: 10.1111/j.1472-8206.2010.00829.x

47. Hardeland R. Melatonin and the theories of aging: a critical appraisal of melatonin’srole in antiaging mechanisms. Journal of Pineal Research. 2013;55(4):325–356. DOI: 10.1111/jpi.12090

48. Bandello F., Sacconi R., Querques L., Corbelli E., Cicinelli M.V., Querques G. Recent advances in the management of dry age-related macular degeneration: A review. F1000Research. 2017;6:245. DOI: 10.12688/f1000research.10664.1

49. Hogg R., Chakravarthy U. AMD and micronutrient antioxidants. Current Eye Research. 2004;29(6):387–401. DOI: 10.1080/02713680490517890

50. Yi C., Pan X., Yan H., Guo M., Pierpaoli W. Effects of melatonin in age-related macular degeneration. Annals of the New York Academy of Sciences. 2005;1057:384–392. DOI: 10.1196/annals.1356.029