Melatonin: Helping cells cope with oxidative disaster

Year 2010, Volume: 2 Issue: 3, 99 - 111, 14.08.2013

Sergio Paredes Royano , Russel Reiter

Abstract

Melatonin possesses the capability of donating electrons, consequently reducing the reactivity of molecules with an unpaired electron in their valence orbital, i.e. free radicals. A plethora of studies support the role of this indoleamine in diminishing molecular damage associated with massive free radical generation both in vitro and in vivo. Melatonin protects against neurodegenerative disorders, ischemia/reperfusion injury, acts as a radio protector, and counteracts herbicide and metal toxicity due to its essential role in antioxidant protection. At the intracellular level, it reduces electron leakage from the mitochondrial respiratory chain complexes as well as scavenging radicals generated in the cytosol (exclusive of its actions in mitochondria) and nucleus. Comparative studies with other well-known naturally occurring antioxidants show that melatonin's efficacy is equal to or better in neutralizing highly toxic oxygen and nitrogen-reactants. However, not only melatonin but a series of its metabolites are also capable of detoxifying free radicals and related species in what is referred to as the antioxidative cascade. Thus, melatonin may be actually seen as a prodrug for a family of other molecules that also have the capability of reducing oxidative/nitrosative stress. Taken together, the results reviewed here indicate that melatonin is a key element in antioxidative medicine in the context of the antioxidative defense system.

Keywords

Antioxidant, free radical, lipid peroxidation, melatonin, oxidative stress

References

• Acuna-Castroviejo D, Coto-Montes A, Gaia Monti M, Ortiz GG, Reiter RJ. 1997. Melatonin is protective against MPTP-induced striatal and hippocampal lesions. Life Sci 60: PL23-29.
• Acuna-Castroviejo D, Escames G, Leon J, Carazo A, Khaldy H. 2003. Mitochondrial regulation by melatonin and its metabolites. Adv Exp Med Biol 527: 549-557.
• Alonso-Gonzalez C, Gonzalez A, Mazarrasa O, Guezmes A, Sanchez-Mateos S, Martinez-Campa C, Cos S, Sanchez-Barcelo EJ, Mediavilla MD. 2007. Melatonin prevents the estrogenic effects of sub-chronic administration of cadmium on mice mammary glands and uterus. J Pineal Res 42: 403-410.
• Antolin I, Mayo JC, Sainz RM, del Brio M de L, Herrera F, Martin V, Rodriguez C. 2002. Protective effect of melatonin in a chronic experimental model of Parkinson’s disease. Brain Res 943: 163-173.
• Barlow-Walden LR, Reiter RJ, Abe M, Pablos M, Menendez-Pelaez A, Chen LD, Poeggeler B. 1995. Melatonin stimulates brain glutathione peroxidase activity. Neurochem Int 26: 497-502.
• Baydas G, Canatan H, Turkoglu A. 2002a. Comparative analysis of the protective effects of melatonin and vitamin E on streptozocin-induced diabetes mellitus. J Pineal Res 32: 225-230.
• Baydas G, Gursu MF, Yilmaz S, Canpolat S, Yasar A, Cikim G, Canatan H. 2002b. Daily rhythm of glutathione peroxidase activity, lipid peroxidation and glutathione levels in tissues of pinealectomized rats. Neurosci Lett 323: 195-198.
• Behrends A, Riediger S, Grube S, Poeggeler B, Haldar C, Hardeland R. 2007. Photocatalytic mechanisms of indoleamine destruction by the quinalphos metabolite 2-hydroxyquinoxaline: A study on melatonin and its precursors serotonin and N-acetylserotonin. J Environ Sci Health B 42: 599-606.
• Belles M, Linares V, Luisa Albina M, Sirvent J, Sanchez DJ, Domingo JL. 2007. Melatonin reduces uranium-induced nephrotoxicity in rats. J Pineal Res 43: 87-95.
• Blanchard B, Pompon D, Ducrocq C. 2000. Nitrosation of melatonin by nitric oxide and peroxynitrite. J Pineal Res 29: 184-192.
• Bromme HJ, Morke W, Peschke D, Ebelt H, Peschke D. 2000. Scavenging effect of melatonin on hydroxyl radicals generated by alloxan. J Pineal Res 29: 201-208.
• Budu A, Peres R, Bueno VB, Catalani LH, Garcia CR. 2007. N1-acetyl-N2-formyl- 5-methoxykynuramine modulates the cell cycle of malaria parasites. J Pineal Res 42: 261-266.
• Burkhardt S, Poeggeler B, Tan DX, Rosner C, Gruetzner T, Nitzki F, Schoenke M, Thuermann S, Reiter RJ, Hardeland R. 2001. Oxidation products formed from melatonin in various radical-generating systems. In: Hardeland R, editor. Actions and Redox Properties of Melatonin and Other Aromatic Amino Acid Metabolites, Cuvillier: Göttingen, Germany. pp 9-22.
• Cadenas S, Barja G. 1999. Resveratrol, melatonin, vitamin E, and PBN protect against renal oxidative DNA damage induced by the kidney carcinogen KBrO3. Free Radic Biol Med 26: 1531-1537.
• Ceraulo L, Ferrugia M, Tesoriere L, Segreto S, Livrea MA, Turco Liveri V. 1999. Interactions of melatonin with membrane models: Portioning of melatonin in AOT and lecithin reversed micelles. J Pineal Res 26: 108-112.
• Chen LD, Tan DX, Reiter RJ, Yaga K, Poeggeler B, Kumar P, Manchester LC, Chambers JP. 1993. In vivo and in vitro effects of the pineal gland and melatonin on [ca(2+) + Mg2+]-dependent ATPase in cardiac sarcolemma. J Pineal Res 14: 178-183.
• Chen LJ, Gao YQ, Li XJ, Shen DH, Sun FY. 2005. Melatonin protects against MPTP/MPP+ -induced mitochondrial DNA oxidative damage in vivo and in vitro. J Pineal Res 39: 34-42.
• Chen ST, Chuang JI, Hong MH, Li EI. 2002. Melatonin attenuates MPP+-induced neurodegeneration and glutathione impairment in the nigrostriatal dopaminergic pathway. J Pineal Res 32: 262-269.
• Cheng S, Ma C, Qu H, Fan W, Pang J, He H. 2008. Differential effects of melatonin on hippocampal neurodegeneration in different aged accelerated senescence prone mouse-8. Neuro Endocrinol Lett 29: 91-99.
• Citron M. 2010. Alzheimer’s disease: Strategies for disease modification. Nat Rev Drug Discov 9: 387-398.
• Clark IA, Chaudhri G, Cowden WB. 1989. Some roles of free radicals in malaria. Free Radic Biol Med 6: 315-321.
• Coulom H, Birman S. 2004. Chronic exposure to rotenone models sporadic Parkinson’s disease in Drosophila melanogaster. J Neurosci 24: 10993- 10998.
• Deng YQ, Xu GG, Duan P, Zhang Q, Wang JZ. 2005. Effects of melatonin on wortmannin-induced tau hyperphosphorylation. Acta Pharmacol Sin 26: 519-526.
• mechanisms from radical detoxification to radical avoidance. Endocrine 27: 119-130.
• Leon J, Escames G, Rodriguez MI, Lopez LC, Tapias V, Entrena A, Camacho E, Carrion MD, Gallo MA, Espinosa A, Tan DX, Reiter RJ, Acuna-Castroviejo D. 2006. Inhibition of neuronal nitric oxide synthase activity by N1-acetyl-5- methoxykynuramine, a brain metabolite of melatonin. J Neurochem 98: 2023-2033.
• Li XJ, Gu J, Lu SD, Sun FY. 2002. Melatonin attenuates MPTP-induced dopaminergic neuronal injury associated with scavenging hydroxyl radical. J Pineal Res 32: 47-52.
• Limson J, Nyokong T, Daya S. 1998. The interaction of melatonin and its precursors with aluminium, cadmium, copper, iron, lead, and zinc: An adsorptive voltammetric study. J Pineal Res 24: 15-21.
• Lin AM, Fang SF, Chao PL, Yang CH. 2007. Melatonin attenuates arsenite- induced apoptosis in rat brain: Involvement of mitochondrial and endoplasmic reticulum pathways and aggregation of alpha-synuclein. J Pineal Res 43: 163-171.
• Manda K, Reiter RJ. 2010. Melatonin maintains adult hippocampal neurogenesis and cognitive functions after irradiation. Prog Neurobiol 90: 60-68.
• Manda K, Ueno M, Anzai K. 2007. AFMK, a melatonin metabolite, attenuates X-ray-induced oxidative damage to DNA, proteins and lipids in mice. J Pineal Res 42: 386-393.
• Mansouri A, Demeilliers C, Amsellem S, Pessayre D, Fromenty B. 2001. Acute ethanol administration oxidatively damages and depletes mitochondrial dna in mouse liver, brain, heart, and skeletal muscles: Protective effects of antioxidants. J Pharmacol Exp Ther 298: 737-743.
• Martinez-Cruz F, Osuna C, Guerrero JM. 2006. Mitochondrial damage induced by fetal hyperphenylalaninemia in the rat brain and liver: Its prevention by melatonin, vitamin E, and vitamin C. Neurosci Lett 392: 1-4.
• Martinez-Cruz F, Pozo D, Osuna C, Espinar A, Marchante C, Guerrero JM. 2002. Oxidative stress induced by phenylketonuria in the rat: Prevention by melatonin, vitamin E, and vitamin C. J Neurosci Res 69: 550-558.
• Matsubara E, Bryant-Thomas T, Pacheco Quinto J, Henry TL, Poeggeler B, Herbert D, Cruz-Sanchez F, Chyan YJ, Smith MA, Perry G, Shoji M, Abe K, Leone A, Grundke-Ikbal I, Wilson GL, Ghiso J, Williams C, Refolo LM, Pappolla MA, Chain DG, Neria E. 2003. Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of alzheimer’s disease. J Neurochem 85: 1101-1108.
• Matsura T, Nishida T, Togawa A, Horie S, Kusumoto C, Ohata S, Nakada J, Ishibe Y, Yamada K, Ohta Y. 2006. Mechanisms of protection by melatonin against acetaminophen-induced liver injury in mice. J Pineal Res 41: 211-219.
• Matuszak Z, Reszka K, Chignell CF. 1997. Reaction of melatonin and related indoles with hydroxyl radicals: EPR and spin trapping investigations. Free Radic Biol Med 23: 367-372.
• Mayo JC, Sainz RM, Uria H, Antolin I, Esteban MM, Rodriguez C. 1998. Melatonin prevents apoptosis induced by 6-hydroxydopamine in neuronal cells: Implications for Parkinson’s disease. J Pineal Res 24: 179-192.
• Mayo JC, Sainz RM, Tan DX, Antolin I, Rodriguez C, Reiter RJ. 2005a. Melatonin and Parkinson’s disease. Endocrine 27: 169-178.
• Mayo JC, Sainz RM, Tan DX, Hardeland R, Leon J, Rodriguez C, Reiter RJ. 2005b. Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5- methoxykynuramine (AMK), in macrophages. J Neuroimmunol 165: 139- 149.
• Melchiorri D, Reiter RJ, Attia AM, Hara M, Burgos A, Nistico G. 1995. Potent protective effect of melatonin on in vivo paraquat-induced oxidative damage in rats. Life Sci 56: 83-89.
• Melchiorri D, Reiter RJ, Sewerynek E, Hara M, Chen L, Nistico G. 1996. Paraquat toxicity and oxidative damage: reduction by melatonin. Biochem Pharmacol 51: 1095-1099.
• Monobe M, Hino M, Sumi M, Uzawa A, Hirayama R, Ando K, Kojima S. 2005. Protective effects of melatonin on gamma-ray induced intestinal damage. Int J Radiat Biol 81: 855-860.
• Montilla P, Cruz A, Padillo FJ, Tunez I, Gascon F, Munoz MC, Gomez M, Pera C. 2001. Melatonin versus vitamin E as protective treatment against oxidative stress after extra-hepatic bile duct ligation in rats. J Pineal Res 31: 138-144.
• Nesic O, Lee J, Unabia GC, Johnson K, Ye Z, Vergara L, Hulsebosch CE, Perez- Polo JR. 2008. Aquaporin 1 - a novel player in spinal cord injury. J Neurochem 105: 628-640.
• Noda Y, Mori A, Liburdy R, Packer L. 1999. Melatonin and its precursors scavenge nitric oxide. J Pineal Res 27: 159-163.
• Pablos MI, Agapito MT, Gutierrez R, Recio JM, Reiter RJ, Barlow-Walden L, Acuna-Castroviejo D, Menendez-Pelaez A. 1995. Melatonin stimulates the activity of the detoxifying enzyme glutathione peroxidase in several tissues of chicks. J Pineal Res 19: 111-115.
• Pappolla MA, Chyan YJ, Poeggeler B, Frangione B, Wilson G, Ghiso J, Reiter RJ. 2000. An assessment of the antioxidant and the antiamyloidogenic properties of melatonin: Implications for alzheimer’s disease. J Neural Transm 107: 203-231.
• Pappolla MA, Reiter RJ, Bryant-Thomas TK, Poeggeler B. 2003. Oxidative mediated neurodegeneration in Alzheimer’s disease: Melatonin and related antioxidants as neuroprotective agents. Curr Med Chem 3: 233- 243.
• Paradies G, Petrosillo G, Paradies V, Reiter RJ, Ruggiero FM. 2010. Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease. J Pineal Res 48: 297-310.
• Paredes SD, Korkmaz A, Manchester LC, Tan DX, Reiter RJ. 2009. Phytomelatonin: A review. J Exp Bot 60: 57-69.
• Petrosillo G, Di Venosa N, Pistolese M, Casanova G, Tiravanti E, Colantuono G, Federici A, Paradies G, Ruggiero FM. 2006. Protective effect of melatonin against mitochondrial dysfunction associated with cardiac ischemia- reperfusion: Role of cardiolipin. FASEB J 20: 269-276.
• Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, Fiore T, Paradies G. 2009. Melatonin protects against heart ischemia- reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol 297: H1487-493.
• Regulation of antioxidant enzymes: A significant role for melatonin. J
• Tan DX, Poeggeler B, Reiter RJ, Chen LD, Chen S, Manchester LC, Barlow-Walden LR. 1993b. The pineal hormone melatonin inhibits DNA-adduct formation induced by the chemical carcinogen safrole in vivo. Cancer Lett 70: 65-71.
• Tan DX, Manchester LC, Reiter RJ, Plummer BF, Limson J, Weintraub ST, Qi W. 2000. Melatonin directly scavenges hydrogen peroxide: A potentially new metabolic pathway of melatonin biotransformation. Free Radic Biol Med 29: 1177-1185.
• Tan DX, Manchester LC, Burkhardt S, Sainz RM, Mayo JC, Kohen R, Shohami E, Huo YS, Hardeland R, Reiter RJ. 2001. N1-acetyl-N2-formyl-5- methoxykynuramine, a biogenic amine and melatonin metabolite, Zhang H, Squadrito GL, Pryor WA. 1998. The reaction of melatonin with functions as a potent antioxidant. FASEB J 15: 2294-2296.
• Tan DX, Reiter RJ, Manchester LC, Yan MT, El-Sawi M, Sainz RM, Mayo JC, Kohen R, Allegra M, Hardeland R. 2002. Chemical and physical properties and potential mechanisms: Melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2: 181-197.
• Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ. 2007. One molecule, many derivatives: A never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 42: 28-42.
• Tengattini S, Reiter RJ, Tan DX, Terron MP, Rodella LF, Rezzani R. 2008. Cardiovascular diseases: Protective effects of melatonin. J Pineal Res 44: 16-25.
• Thomas B, Mohanakumar KP. 2004. Melatonin protects against oxidative stress caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the mouse nigrostriatum. J Pineal Res 36: 25-32.
• Tomas-Zapico C, Coto-Montes A. 2005. A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes. J Pineal Res 39: 99-104.
• Tunez I, Munoz MC, Medina FJ, Salcedo M, Feijoo M, Montilla P. 2007. Comparison of melatonin, vitamin E and L-carnitine in the treatment of neuro- and hepatotoxicity induced by thioacetamide. Cell Biochem Funct 25: 119-127.
• Turjanski AG, Saenz DA, Doctorovich F, Estrin DA, Rosenstein RE. 2001. Nitrosation of melatonin by nitric oxide: A computational study. J Pineal Res 31: 97-101.
• Valko M, Morris H, Cronin MT. 2005. Metals, toxicity and oxidative stress. Curr Med Chem 12: 1161-1208.
• Vijayalaxmi, Reiter RJ, Meltz ML. 1995a. Melatonin protects human blood lymphocytes from radiation-induced chromosome damage. Mutat Res 346: 23-31.
• Vijayalaxmi, Reiter RJ, Sewerynek E, Poeggeler B, Leal BZ, Meltz ML. 1995b. Marked reduction of radiation-induced micronuclei in human blood lymphocytes pretreated with melatonin. Radiat Res 143: 102-106.
• Vijayalaxmi, Reiter RJ, Tan DX, Herman TS, Thomas CR Jr. 2004. Melatonin as a radioprotective agent: A review. Int J Radiat Oncol Biol Phys 59: 639-653.
• Wahab MH, Akoul ES, Abdel-Aziz AA. 2000. Modulatory effects of melatonin and vitamin E on doxorubicin-induced cardiotoxicity in ehrlich ascites carcinoma-bearing mice. Tumori 86: 157-162.
• Xu J, Sun S, Wei W, Fu J, Qi W, Manchester LC, Tan DX, Reiter RJ. 2007. Melatonin reduces mortality and oxidatively mediated hepatic and renal damage due to diquat treatment. J Pineal Res 42: 166-171.
• Yilmaz S, Yilmaz E. 2006. Effects of melatonin and vitamin E on oxidative- antioxidative status in rats exposed to irradiation. Toxicology 222: 1-7.
• Yilmaz T, Celebi S, Kukner AS. 2002. The protective effects of melatonin, vitamin E and octreotide on retinal edema during ischemia-reperfusion in the guinea pig retina. Eur J Ophthalmol 12: 443-449.
• Yin J, Liu YH, Xu YF, Zhang YJ, Chen JG, Shu BH, Wang JZ. 2006. Melatonin arrests peroxynitrite-induced tau hyperphosphorylation and the overactivation of protein kinases in rat brain. J Pineal Res 41: 124-129. peroxynitrite: Formation of melatonin radical cation and absence of stable nitrated products. Biochem Biophys Res Commun 251: 83-87.