Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Melatonin: Implications for Ocular Disease and Therapeutic Potential

Author(s): ">Luca Scuderi, ">Sergio Davinelli*, ">Clemente Maria Iodice, ">Silvia Bartollino, ">Giovanni Scapagnini, ">Ciro Costagliola and ">Gianluca Scuderi

Volume 25 , Issue 39 , 2019

Page: [4185 - 4191] Pages: 7

DOI: 10.2174/1381612825666191113110225

Price: $65


Melatonin, an indoleamine secreted mainly by the pineal gland, is known to modulate a wide range of circadian functions. However, this neurohormone is also synthesized within the eye and acts directly on ocular structures to mediate a variety of physiological processes. This review is focused on the role and therapeutic potential of melatonin in ocular diseases. We summarize data indicating that melatonin may represent a powerful tool to counteract ocular dysfunctions such as uveitis, glaucoma, age-related macular degeneration, and diabetic retinopathy. A search strategy was conducted to identify studies in PubMed (January 1990 to September 2017). In particular, we included experimental studies, clinical trials, and reviews to provide suitable insights and elucidations regarding the action of melatonin on age-related ocular disorders. Literature data suggest that melatonin could potentially protect ocular tissues by decreasing the production of free radicals and pro-inflammatory mediators. Additionally, melatonin appears to be safe and well-tolerated, even at high doses, and no adverse/side effects were reported. Although this topic remains under intense investigation, we can conclude that melatonin, as a single agent or in combination with other drugs, is an attractive pharmacological candidate for age-related ocular diseases.

Keywords: Melatonin, aging, aged-related ocular diseases, uveitis, cataract, glaucoma, age-related macular degeneration, diabetic retinopathy.

Zhdanova IV, Wang SY, Leclair OU, Danilova NP. Melatonin promotes sleep-like state in zebrafish. Brain Res 2001; 903(1-2): 263-8.
[] [PMID: 11382414]
Hardeland R, Reiter RJ, Poeggeler B, Tan DX. The significance of the metabolism of the neurohormone melatonin: antioxidative protection and formation of bioactive substances. Neurosci Biobehav Rev 1993; 17(3): 347-57.
[] [PMID: 8272286]
Acuña-Castroviejo D, Escames G, Venegas C, et al. Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol Life Sci 2014; 71(16): 2997-3025.
[] [PMID: 24554058]
Tosini G, Iuvone M, Boatright JH. Is the melatonin receptor type 1 involved in the pathogenesis of glaucoma? J Glaucoma 2013; 22(Suppl. 5): S49-50.
[] [PMID: 23733129]
Cahill GM, Besharse JC. Circadian clock functions localized in xenopus retinal photoreceptors. Neuron 1993; 10(4): 573-7.
[] [PMID: 8476609]
Tosini G, Baba K, Hwang CK, Iuvone PM. Melatonin: an underappreciated player in retinal physiology and pathophysiology. Exp Eye Res 2012; 103: 82-9.
[] [PMID: 22960156]
Fukuhara C, Dirden JC, Tosini G. Photic regulation of melatonin in rat retina and the role of proteasomal proteolysis. Neuroreport 2001; 12(17): 3833-7.
[] [PMID: 11726804]
Fukuhara C, Liu C, Ivanova TN, et al. Gating of the cAMP signaling cascade and melatonin synthesis by the circadian clock in mammalian retina. J Neurosci 2004; 24(8): 1803-11.
[] [PMID: 14985420]
Baba K, Benleulmi-Chaachoua A, Journé AS, et al. Heteromeric MT1/MT2 melatonin receptors modulate photoreceptor function. Sci Signal 2013; 6(296): ra89.
[] [PMID: 24106342]
Ayoub MA, Levoye A, Delagrange P, Jockers R. Preferential formation of MT1/MT2 melatonin receptor heterodimers with distinct ligand interaction properties compared with MT2 homodimers. Mol Pharmacol 2004; 66(2): 312-21.
[] [PMID: 15266022]
Sande PH, Dorfman D, Fernandez DC, et al. Treatment with melatonin after onset of experimental uveitis attenuates ocular inflammation. Br J Pharmacol 2014; 171(24): 5696-707.
[] [PMID: 25131343]
Doğanlar ZB, Güçlü H, Öztopuz Ö, et al. The role of melatonin in oxidative stress, DNA damage, apoptosis and angiogenesis in fetal eye under preeclampsia and melatonin deficiency stress. Curr Eye Res 2019; 44(10): 1157-69.
[] [PMID: 31090463]
Jiang T, Chang Q, Cai J, Fan J, Zhang X, Xu G. Protective effects of melatonin on retinal inflammation and oxidative stress in experimental diabetic retinopathy. Oxid Med Cell Longev 2016; 20163528274
[] [PMID: 27143993]
Srinivasan V, Pandi-Perumal SR, Maestroni GJ, Esquifino AI, Hardeland R, Cardinali DP. Role of melatonin in neurodegenerative diseases. Neurotox Res 2005; 7(4): 293-318.
[] [PMID: 16179266]
de Vos AF, Klaren VN, Kijlstra A. Expression of multiple cytokines and IL-1RA in the uvea and retina during endotoxin-induced uveitis in the rat. Invest Ophthalmol Vis Sci 1994; 35(11): 3873-83.
[PMID: 7928184]
Bellot JL, Palmero M, García-Cabanes C, Espí R, Hariton C, Orts A. Additive effect of nitric oxide and prostaglandin-E2 synthesis inhibitors in endotoxin-induced uveitis in the rabbit. Inflamm Res 1996; 45(4): 203-8.
[] [PMID: 8741011]
Sande PH, Fernandez DC, Aldana Marcos HJ, et al. Therapeutic effect of melatonin in experimental uveitis. Am J Pathol 2008; 173(6): 1702-13.
[] [PMID: 19008374]
Osborne NN, Block F, Sontag KH. Reduction of ocular blood flow results in glial fibrillary acidic protein (GFAP) expression in rat retinal Müller cells. Vis Neurosci 1991; 7(6): 637-9.
[] [PMID: 1772810]
Sáenz DA, Turjanski AG, Sacca GB, et al. Physiological concentrations of melatonin inhibit the nitridergic pathway in the Syrian hamster retina. J Pineal Res 2002; 33(1): 31-6.
[] [PMID: 12121483]
Shi D, Xiao X, Wang J, et al. Melatonin suppresses proinflammatory mediators in lipopolysaccharide-stimulated CRL1999 cells via targeting MAPK, NF-κB, c/EBPβ, and p300 signaling. J Pineal Res 2012; 53(2): 154-65.
[] [PMID: 22348531]
Nguyen QD, Callanan D, Dugel P, Godfrey DG, Goldstein DA, Wilensky JT. Treating chronic noninfectious posterior segment uveitis: the impact of cumulative damage. Proceedings of an expert panel roundtable discussion. Retina 2006; 1-16.
Scuderi G, Khaw PT, Medeiros FA, Manni G. Challenging glaucomas: update on diagnosis and management. J Ophthalmol 2016; 20166935086
[] [PMID: 26989501]
Lambiase A, Abdolrahimzadeh S, Recupero SM. An update on intravitreal implants in use for eye disorders. Drugs Today (Barc) 2014; 50(3): 239-49.
[] [PMID: 24696869]
Del Sole MJ, Sande PH, Fernandez DC, Sarmiento MI, Aba MA, Rosenstein RE. Therapeutic benefit of melatonin in experimental feline uveitis. J Pineal Res 2012; 52(1): 29-37.
[] [PMID: 21762209]
Rosenstein RE, Pandi-Perumal SR, Srinivasan V, Spence DW, Brown GM, Cardinali DP. Melatonin as a therapeutic tool in ophthalmology: implications for glaucoma and uveitis. J Pineal Res 2010; 49(1): 1-13.
[] [PMID: 20492443]
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 Opin Drug Discov 2012; 7(10): 989-1001.
[] [PMID: 22860991]
Jan JE, Hamilton D, Seward N, Fast DK, Freeman RD, Laudon M. Clinical trials of controlled-release melatonin in children with sleep-wake cycle disorders. J Pineal Res 2000; 29(1): 34-9.
[] [PMID: 10949538]
van Lookeren Campagne M, LeCouter J, Yaspan BL, Ye W. Mechanisms of age-related macular degeneration and therapeutic opportunities. J Pathol 2014; 232(2): 151-64.
[] [PMID: 24105633]
Sparrow JR, Boulton M. RPE lipofuscin and its role in retinal pathobiology. Exp Eye Res 2005; 80(5): 595-606.
[] [PMID: 15862166]
Shamsi FA, Boulton M. Inhibition of RPE lysosomal and antioxidant activity by the age pigment lipofuscin. Invest Ophthalmol Vis Sci 2001; 42(12): 3041-6.
[PMID: 11687553]
Sundelin S, Wihlmark U, Nilsson SE, Brunk UT. Lipofuscin accumulation in cultured retinal pigment epithelial cells reduces their phagocytic capacity. Curr Eye Res 1998; 17(8): 851-7.
[] [PMID: 9724002]
Gianesini C, Hiragaki S, Laurent V, Hicks D, Tosini G. Cone viability is affected by disruption of melatonin receptors signaling. Invest Ophthalmol Vis Sci 2016; 57(1): 94-104.
[] [PMID: 26780313]
Baba K, Pozdeyev N, Mazzoni F, et al. Melatonin modulates visual function and cell viability in the mouse retina via the MT1 melatonin receptor. Proc Natl Acad Sci USA 2009; 106(35): 15043-8.
[] [PMID: 19706469]
Curcio CA, Millican CL, Allen KA, Kalina RE. Aging of the human photoreceptor mosaic: evidence for selective vulnerability of rods in central retina. Invest Ophthalmol Vis Sci 1993; 34(12): 3278-96.
[PMID: 8225863]
Cunea A, Jeffery G. The ageing photoreceptor. Vis Neurosci 2007; 24(2): 151-5.
[] [PMID: 17640405]
Yi C, Pan X, Yan H, Guo M, Pierpaoli W. Effects of melatonin in age-related macular degeneration. Ann N Y Acad Sci 2005; 1057: 384-92.
[] [PMID: 16399908]
Schmid-Kubista KE, Glittenberg CG, Cezanne M, Holzmann K, Neumaier-Ammerer B, Binder S. Daytime levels of melatonin in patients with age-related macular degeneration. Acta Ophthalmol 2009; 87(1): 89-93.
[] [PMID: 18494741]
Wang M, Munch IC, Hasler PW, Prünte C, Larsen M. Central serous chorioretinopathy. Acta Ophthalmol 2008; 86(2): 126-45.
[] [PMID: 17662099]
Cheung CMG, Lee WK, Koizumi H, Dansingani K, Lai TYY, Freund KB. Pachychoroid disease. Eye (Lond) 2019; 33(1): 14-33.
[] [PMID: 29995841]
Yap EY, Robertson DM. The long-term outcome of central serous chorioretinopathy. Arch Ophthalmol 1996; 114(6): 689-92.
[] [PMID: 8639079]
Gramajo AL, Marquez GE, Torres VE, Juárez CP, Rosenstein RE, Luna JD. Therapeutic benefit of melatonin in refractory central serous chorioretinopathy. Eye (Lond) 2015; 29(8): 1036-45.
[] [PMID: 26160525]
Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012; 35(3): 556-64.
[] [PMID: 22301125]
Cai J, Boulton M. The pathogenesis of diabetic retinopathy: old concepts and new questions. Eye (Lond) 2002; 16(3): 242-60.
[] [PMID: 12032713]
Wilkinson CP, Ferris FL III, Klein RE, et al. Global Diabetic Retinopathy Project Group. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 2003; 110(9): 1677-82.
[] [PMID: 13129861]
Bandello F, Battaglia Parodi M, Lanzetta P, et al. Diabetic macular edema. Dev Ophthalmol 2010; 47: 73-110.
[] [PMID: 20703045]
Fehér J, Taurone S, Spoletini M, et al. Ultrastructure of neurovascular changes in human diabetic retinopathy. Int J Immunopathol Pharmacol 2018; 31394632017748841
[] [PMID: 29251013]
Kowluru RA, Tang J, Kern TS. Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII. Effect of long-term administration of antioxidants on the development of retinopathy. Diabetes 2001; 50(8): 1938-42.
[] [PMID: 11473058]
Murphy MP. How mitochondria produce reactive oxygen species. Biochem J 2009; 417(1): 1-13.
[] [PMID: 19061483]
Bek T. Mitochondrial dysfunction and diabetic retinopathy. Mitochondrion 2017; 36: 4-6.
[] [PMID: 27456429]
Scarpulla RC. Nucleus-encoded regulators of mitochondrial function: integration of respiratory chain expression, nutrient sensing and metabolic stress. Biochim Biophys Acta 2012; 1819(9-10): 1088-97.
[] [PMID: 22080153]
Reiter RJ, Tan DX, Osuna C, Gitto E. Actions of melatonin in the reduction of oxidative stress. A review. J Biomed Sci 2000; 7(6): 444-58.
[] [PMID: 11060493]
Rodriguez C, Mayo JC, Sainz RM, et al. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 2004; 36(1): 1-9.
[] [PMID: 14675124]
Fischer TW, Kleszczyński K, Hardkop LH, Kruse N, Zillikens D. Melatonin enhances antioxidative enzyme gene expression (CAT, GPx, SOD), prevents their UVR-induced depletion, and protects against the formation of DNA damage (8-hydroxy-2′-deoxyguanosine) in ex vivo human skin. J Pineal Res 2013; 54(3): 303-12.
[] [PMID: 23110400]
Hardeland R. Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine 2005; 27(2): 119-30.
[] [PMID: 16217125]
Salido EM, Bordone M, De Laurentiis A, et al. Therapeutic efficacy of melatonin in reducing retinal damage in an experimental model of early type 2 diabetes in rats. J Pineal Res 2013; 54(2): 179-89.
[] [PMID: 22946773]
Kaur C, Sivakumar V, Yong Z, Lu J, Foulds WS, Ling EA. Blood-retinal barrier disruption and ultrastructural changes in the hypoxic retina in adult rats: the beneficial effect of melatonin administration. J Pathol 2007; 212(4): 429-39.
[] [PMID: 17582234]
Ozdemir G, Ergün Y, Bakariş S, Kılınç M, Durdu H, Ganiyusufoğlu E. Melatonin prevents retinal oxidative stress and vascular changes in diabetic rats. Eye (Lond) 2014; 28(8): 1020-7.
[] [PMID: 24924441]
Djordjevic B, Cvetkovic T, Stoimenov TJ, et al. Oral supplementation with melatonin reduces oxidative damage and concentrations of inducible nitric oxide synthase, VEGF and matrix metalloproteinase 9 in the retina of rats with streptozotocin/nicotinamide induced pre-diabetes. Eur J Pharmacol 2018; 833: 290-7.
[] [PMID: 29890158]
Mauriz JL, Collado PS, Veneroso C, Reiter RJ, González-Gallego J. A review of the molecular aspects of melatonin’s anti-inflammatory actions: recent insights and new perspectives. J Pineal Res 2013; 54(1): 1-14.
[] [PMID: 22725668]
Jahanban-Esfahlan R, Mehrzadi S, Reiter RJ, et al. Melatonin in regulation of inflammatory pathways in rheumatoid arthritis and osteoarthritis: involvement of circadian clock genes. Br J Pharmacol 2018; 175(16): 3230-8.
[] [PMID: 28585236]
Jung KH, Hong SW, Zheng HM, Lee DH, Hong SS. Melatonin downregulates nuclear erythroid 2-related factor 2 and nuclear factor-kappaB during prevention of oxidative liver injury in a dimethylnitrosamine model. J Pineal Res 2009; 47(2): 173-83.
[] [PMID: 19627459]
Jenwitheesuk A, Nopparat C, Mukda S, Wongchitrat P, Govitrapong P. Melatonin regulates aging and neurodegeneration through energy metabolism, epigenetics, autophagy and circadian rhythm pathways. Int J Mol Sci 2014; 15(9): 16848-84.
[] [PMID: 25247581]
Cohen LP, Pasquale LR. Clinical characteristics and current treatment of glaucoma. Cold Spring Harb Perspect Med 2014; 4(6)pii: a017236
[] [PMID: 24890835]
Alkozi H, Sánchez-Naves J, de Lara MJ, et al. Elevated intraocular pressure increases melatonin levels in the aqueous humour. Acta Ophthalmol 2017; 95(3): e185-9.
[] [PMID: 27595784]
Blasiak J, Reiter RJ, Kaarniranta K. Melatonin in retinal physiology and pathology: the case of age-related macular degeneration. Oxid Med Cell Longev 2016; 20166819736
[] [PMID: 27688828]
Ismail SA, Mowafi HA. Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia. Anesth Analg 2009; 108(4): 1146-51.
[] [PMID: 19299777]
Huete-Toral F, Crooke A, Martínez-Águila A, Pintor J. Melatonin receptors trigger cAMP production and inhibit chloride movements in nonpigmented ciliary epithelial cells. J Pharmacol Exp Ther 2015; 352(1): 119-28.
[] [PMID: 25344385]
Civan MM. Transport components of net secretion of the aqueous humor and their integrated regulation. Curr Top Membr 1998; 45: 1-24.
Civan MM, Macknight AD. The ins and outs of aqueous humour secretion. Exp Eye Res 2004; 78(3): 625-31.
[] [PMID: 15106942]
Alcantara-Contreras S, Baba K, Tosini G. Removal of melatonin receptor type 1 increases intraocular pressure and retinal ganglion cells death in the mouse. Neurosci Lett 2011; 494(1): 61-4.
[] [PMID: 21362461]
Alkozi HA, Pintor J. TRPV4 activation triggers the release of melatonin from human non-pigmented ciliary epithelial cells. Exp Eye Res 2015; 136: 34-7.
[] [PMID: 25933715]
Crooke A, Colligris B, Pintor J. Update in glaucoma medicinal chemistry: emerging evidence for the importance of melatonin analogues. Curr Med Chem 2012; 19(21): 3508-22.
[] [PMID: 22709004]
Meyer P, Pache M, Loeffler KU, et al. Melatonin MT-1-receptor immunoreactivity in the human eye. Br J Ophthalmol 2002; 86(9): 1053-7.
[] [PMID: 12185137]
Rada JA, Wiechmann AF. Melatonin receptors in chick ocular tissues: implications for a role of melatonin in ocular growth regulation. Invest Ophthalmol Vis Sci 2006; 47(1): 25-33.
[] [PMID: 16384940]
Wiechmann AF, Rada JA. Melatonin receptor expression in the cornea and sclera. Exp Eye Res 2003; 77(2): 219-25.
[] [PMID: 12873453]
Crooke A, Guzman-Aranguez A, Mediero A, et al. Effect of melatonin and analogues on corneal wound healing: involvement of Mt2 melatonin receptor. Curr Eye Res 2015; 40(1): 56-65.
[] [PMID: 24892818]
Wahl C, Li T, Takagi Y, Howland H. The effects of light regimes and hormones on corneal growth in vivo and in organ culture. J Anat 2011; 219(6): 766-75.
[] [PMID: 21951233]
Ciuffi M, Pisanello M, Pagliai G, et al. Antioxidant protection in cultured corneal cells and whole corneas submitted to UV-B exposure. J Photochem Photobiol B 2003; 71(1-3): 59-68.
[] [PMID: 14705640]
Sasaki M, Masuda A, Oishi T. Circadian rhythms of corneal mitotic rate, retinal melatonin and immunoreactive visual pigments, and the effects of melatonin on the rhythms in the Japanese quail. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 1995; 176(4): 465-71.
[] [PMID: 7722956]
Doughty MJ. Morphometric analysis of the surface cells of rabbit corneal epithelium by scanning electron microscopy. Am J Anat 1990; 189(4): 316-28.
[] [PMID: 2285040]
Buffa A, Rizzi E, Falconi M, et al. Bromodeoxyuridine incorporation in corneal epithelium: an immunocytochemical study in rats. Boll Soc Ital Biol Sper 1993; 69(12): 767-73.
[PMID: 8003292]
Sandvig KU, Haaskjold E, Refsum SB. Time dependency in the regenerative response to injury of the rat corneal epithelium. Chronobiol Int 1994; 11(3): 173-9.
[] [PMID: 8082226]
Davinelli S, Calabrese V, Zella D, Scapagnini G. Epigenetic nutraceutical diets in Alzheimer’s disease. J Nutr Health Aging 2014; 18(9): 800-5.
[] [PMID: 25389957]
Davinelli S, Maes M, Corbi G, Zarrelli A, Willcox DC, Scapagnini G. Dietary phytochemicals and neuro-inflammaging: from mechanistic insights to translational challenges. Immun Ageing 2016; 13: 16.
[] [PMID: 27081392]
Davinelli S, Scapagnini G. Polyphenols: a promising nutritional approach to prevent or reduce the progression of prehypertension. High Blood Press Cardiovasc Prev 2016; 23(3): 197-202.
[] [PMID: 27115149]
Davinelli S, Bertoglio JC, Zarrelli A, Pina R, Scapagnini G. A randomized clinical trial evaluating the efficacy of an anthocyanin-maqui berry extract (delphinol®) on oxidative stress biomarkers. J Am Coll Nutr 2015; 34(Suppl. 1): 28-33.
[] [PMID: 26400431]
Davinelli S, Corbi G, Zarrelli A, et al. Short-term supplementation with flavanol-rich cocoa improves lipid profile, antioxidant status and positively influences the AA/EPA ratio in healthy subjects. J Nutr Biochem 2018; 61: 33-9.
[] [PMID: 30179727]
Davinelli S, Chiosi F, Di Marco R, Costagliola C, Scapagnini G. Cytoprotective effects of citicoline and homotaurine against glutamate and high glucose neurotoxicity in primary cultured retinal cells. Oxid Med Cell Longev 2017; 20172825703
[] [PMID: 29163753]
Ratay ML, Bellotti E, Gottardi R, Little SR. Modern therapeutic approaches for noninfectious ocular diseases involving inflammation. Adv Healthc Mater 2017; 6(23): 6.
[] [PMID: 29034584]
Semeraro F, Morescalchi F, Cancarini A, et al. Diabetic retinopathy, a vascular and inflammatory disease: therapeutic implications. Diabetes Metab 2019; 45(6): 517-27.
Hesselink JM, Chiosi F, Costagliola C. Resolvins and aliamides: lipid autacoids in ophthalmology - what promise do they hold? Drug Des Devel Ther 2016; 10: 3133-41.
[] [PMID: 27729772]
Bondy SC, Sharman EH. Melatonin and the aging brain. Neurochem Int 2007; 50(4): 571-80.
[] [PMID: 17276551]
Ostrin LA. Ocular and systemic melatonin and the influence of light exposure. Clin Exp Optom 2019; 102(2): 99-108.
[] [PMID: 30074278]
Aranda ML, Fleitas MFG, Dieguez H, et al. Melatonin as a therapeutic resource for inflammatory visual diseases. Curr Neuropharmacol 2017; 15(7): 951-62.
[] [PMID: 28088912]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy