Melatonin
Melatonin appears to be a real powerhouse for adding all sorts of health conditions. Melatonin is a power antioxidant that crosses the brain barrier that may help in certain types of cancer, in viral infections, in sleeping aids, and more. Please scan through the latest findings in melatonin research.
  • : J Pineal Res. 2004 Mar;36(2):73-9. : Melatonin and viral infections.
    Bonilla E, Valero N, Chacin-Bonilla L, Medina-Leendertz S.
    Instituto de Investigaciones Clinicas 'Dr. Americo Negrette', Facultad de Medicina, Universidad del Zulia, Maracaibo Instituto de Investigaciones Biomedicas, FUNDACITE-Zulia, Maracaibo, Venezuela.

    The therapeutic effects of melatonin against viral infections, with emphasis on the Venezuelan equine encephalomyelitis (VEE), are reviewed. Melatonin has been shown to prevent paralysis and death in mice infected with the encephalomyocarditis virus and to decrease viremia. Melatonin also postpones the onset of the disease produced by Semliki Forest virus inoculation and reduces the mortality of West Nile virus-infected mice stressed by either isolation or dexamethasone injection. An increase in the host resistance to the virus via a peripheral immunostimulatory activity is considered responsible for these effects. It has also been demonstrated that melatonin protects some strains of mink against Aleutian disease, and prevents the reduction of B- and T-cells as well as Th1 cytokine secretion in mice infected with leukemia retrovirus. In VEE-infected mice, melatonin postpones the onset of the disease and death for several days and reduces the mortality rate. This protective effect seems to be due to the increase in the production of interleukin-1beta (IL-1beta), as 100% of the infected mice treated with melatonin die when IL-1beta is blocked with antimurine IL-1beta antibodies. Although melatonin administration raises serum levels of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), the mortality observed in neutralization experiments with the corresponding anticytokine antibodies, suggests that neither TNF-alpha nor IFN-gamma are essential for the protective effect of melatonin on murine VEE virus infection. Melatonin treatment also enhances the efficiency of immunization against the VEE virus. Reactive oxygen species have been implicated in the dissemination of this virus, and their deleterious effects may be diminished by melatonin. This indole inhibits nitric oxide synthetase activity and it is a potent scavenger of nitric oxide, which also plays an important role in the spread of the VEE virus. In conclusion, the immunomodulatory, antioxidant, and neuroprotective effects of melatonin suggest that this indole must be considered as an additional therapeutic alternative to fight viral diseases. J Urol. 2004 Mar;171(3):1199-202. : Melatonin pharmacotherapy for nocturia in men with benign prostatic enlargement.
    Drake MJ, Mills IW, Noble JG.
    SUMMARY: PURPOSE Nocturia is a common condition often attributed in aging men to benign prostatic enlargement. Older adults are prone to nocturnal sleep disturbance, of which disturbed circadian rhythm may be a component since it improves with nighttime administration of melatonin. This study was designed to investigate melatonin as a potential treatment for nocturia associated with bladder outflow obstruction in older men.MATERIALS AND METHODS A total of 20 men with urodynamically confirmed bladder outflow obstruction and nocturia were entered into a randomized, double blind, placebo controlled crossover study assessing the effect of 2 mg controlled release melatonin at night on nocturia. Symptoms were assessed at baseline and after each 4-week treatment period using a frequency volume chart, the International Prostate Symptom Score and symptom problem index. Maximum urinary flow rate and post-void residual urine volume were also assessed.RESULTS Baseline frequency of nocturia was 3.1 episodes per night. There were 7 men (35%) with detrusor overactivity and 10 (50%) had nocturnal polyuria. Melatonin and placebo caused a decrease in nocturia of 0.32 and 0.05 episodes per night (p = 0.07) and a decrease in the nocturia bother score of 0.51 and 0.05, respectively (p = 0.008). Nocturia responder rates (a reduction from baseline of at least -0.5 episodes per night) differed between the active medication and placebo groups (p = 0.04). Daytime urinary frequency, International Prostate Symptom Score, relative nocturnal urine volume, maximum urinary flow rate and post-void residual were unaffected by melatonin treatment.CONCLUSIONS Melatonin treatment is associated with a significant nocturia response rate, improvement in nocturia related bother and a good adverse effect profile. However, it is uncertain whether the observed changes in this study are clinically significant. Headache. 2004 Feb;44(2):198-199. : CLUSTER HEADACHE.

    May A, Leone M. Update on cluster headache. Curr Opin Neurol. 2003;16:333-340. Purpose of Review: Although cluster headache has traditionally been thought of as a vascular headache disorder, its periodicity suggests an involvement of central areas such as the hypothalamus. This review covers the past 3 years, which have seen remarkable progress in understanding the pathophysiology of circadian headache syndromes and have brought exciting news. Recent Findings: As more cluster headache patients are seen by headache specialists, new forms of this well-defined primary headache syndrome are being identified. In addition, we discuss recent findings with regard to abnormalities in the secretion of hormones, genetic influences, neuroimaging of cluster headache attacks, and the use of newer substances as preventive therapy in cluster headache. Summary: We have entered a new diagnostic and therapeutic era in primary headache disorders. In recent reports, the use of deep brain stimulation of the hypothalamus has enabled intractable chronic cluster headache patients to be successfully operated upon. Further research in this field is urgently needed and the recent possibility of combining deep brain stimulation with positron emission tomography will certainly help to unravel the brain circuitry implicated in stimulation-produced analgesia. The time has come to use the evidence for a disorder of circadian rhythm in cluster headache to further the development of chronobiotics in the treatment of this disorder. Comments: Is there a role for melatonin or "natural light" stimulation to control circadian rhythms and prevent the seasonal onset and peaks of acute cluster headache activity? DSM The melatonin story so far is mixed. Melatonin 10 mg was effective preventively in 5 of 10 patients (compared to no placebo response) for episodic cluster headache (ECH) in one study (Leone M, D'Amico D, Moschiano F, Fraschini F, Bussone G. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia. 1996;16:494-496). A case report of 2 patients with chronic cluster headache (CCH) who responded to melatonin 9 mg preventively was published in 2001 (Peres MF, Rozen TD. Melatonin in the preventive treatment of chronic cluster headache. Cephalalgia. 2001;21:993-994). A small randomized pilot trial from the Montreal Neurologic Institute was published in 2002 of 9 patients, 6 with CCH, 3 with ECH (Pringshem T, Magnoux E, Dobson CF, Hamel E, Aube M. Melatonin as adjunctive therapy in the prophylaxis of cluster headache: a pilot study. Headache. 2002;42:787-792). Patients were crossed over, with the patients with CCH receiving a month of melatonin 2 mg controlled release, then a month of placebo, and the patients with ECH receiving a month of placebo, then a month of melatonin. Patients continued their regular prophylaxis and acute treatments, and no treatment effect from the melatonin was demonstrated in any primary or secondary end point. Therefore, with these small numbers, we do not even have properly powered studies with which to make a clinical therapeutic decision. As far as light therapy is concerned, Dr. Lee Kudrow attempted it for patients with CH in the early 1990s, after noting increased frequency of the onset of ECH periods at the time shifts of daylight savings in the spring and fall. While he thought light therapy showed promise, the technical problems of doing the research finally caused him to abandon the project. SJT 1: Maturitas. 2004 Jan 20;47(1):11-20. : Soy isoflavones and melatonin for the relief of climacteric symptoms: a multicenter, double-blind, randomized study.
    Secreto G, Chiechi LM, Amadori A, Miceli R, Venturelli E, Valerio T, Marubini E.
    Endocrinology Unit, Hormone Research Laboratory, National Cancer Institute, Via Venezian 1, 20133, Milan, Italy

    OBJECTIVE: To evaluate the effect of soy isoflavones and melatonin in relieving menopausal symptoms. METHODS: Double-blind, multicenter, randomized trial performed according to a 2x2 factorial design. Treatment groups: (1) soy isoflavones+melatonin; (2) soy isoflavones alone; (3) melatonin alone; (4) placebo. 80 mg of soy isoflavones, 3 mg of pure melatonin or placebo were supplemented to participants for 3 months. Severity of menopausal symptoms was recorded at baseline and after 3 months using the Greene Climacteric Scale. RESULTS: 388 consecutive women were screened: not eligible 98, refused informed consent 28. Randomized 262 and analyzed 232; twelve women withdrew because of adverse events. Median percent differences between basal and final scores were 39% in the isoflavones+melatonin group, 38% in the isoflavones alone group, 26% in the melatonin alone group and 38% in the placebo group. Placebo response was much higher than planned, making it meaningless to perform any statistical test. With regard to somatic and vasomotor symptoms, outcome was similar among the four groups, whereas improvement of psychological symptoms was higher in the isoflavones+melatonin group than in the other three. CONCLUSIONS: Present data do not show any advantage of isoflavones or melatonin over placebo for the relief of menopausal symptoms. However, the effect in psychological symptoms in the isoflavones+melatonin group should be further investigated Am J Med. 2004 Jan 15;116(2):91-5. : Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy.
    Leger D, Laudon M, Zisapel N.
    Centre du Sommeil, Hotel-Dieu de Paris, Paris, France.
    PURPOSE: Melatonin, which is produced by the pineal gland at night, is an endogenous sleep regulator. Both sleep disorders and impaired melatonin production are common among the elderly. We examined the excretion of the major melatonin metabolite 6-sulfatoxymelatonin in insomnia patients aged >or=55 years and its relation with the subsequent response to melatonin therapy. METHODS: We studied 517 insomnia patients, along with 29 age-matched and 30 younger healthy volunteers. Nocturnal urinary 6-sulfatoxymelatonin excretion was assessed between 10 pm and 10 am. Three hundred and ninety-six of the insomnia patients were treated for 2 weeks with placebo and for 3 weeks with 2 mg per night of controlled-release melatonin, of which 372 provided complete datasets. Clinical response, assessed with the Leeds Sleep Evaluation Questionnaire, was defined as an improvement of 10 mm or more on the visual analog scales. RESULTS: Mean (+/- SD) 6-sulfatoxymelatonin excretion was lower in the insomnia patients (9.0 +/- 8.3 microg per night) than in volunteers of the same age (18.1 +/- 12.7 microg per night, P <0.05) and in younger volunteers (24.2 +/- 11.9 microg per night, P <0.05). About 30% of patients (112/372) excreted J Pineal Res. 2003 Sep;35(2):71-4. : Melatonin binding sites in estrogen receptor-positive cells derived from human endometrial cancer.
    Kobayashi Y, Itoh MT, Kondo H, Okuma Y, Sato S, Kanishi Y, Hamada N, Kiguchi K, Ishizuka B.
    Department of Obstetrics and Gynecology; Department of Chemistry, St Marianna University School of Medicine, Miyamae-ku, Kawasaki-city, Kanagawa, Japan.

    Our previous work showed that melatonin (N-acetyl-5-methoxytryptamine) inhibits proliferation of the human endometrial cancer cell line, Ishikawa, which is estrogen receptor-positive. The aim of the present study was to determine whether Ishikawa cells possess membrane melatonin receptors. Binding of the radioligand 2-[125I]-iodomelatonin to membrane preparations obtained from Ishikawa cells was detectable, saturable and stable. Scatchard analysis revealed that the dissociation constant (Kd) of the binding sites was 179.0 pm (similar to that of the MT2 [Mel1b] melatonin receptor subtype), and that the concentration (Bmax) of the binding sites was 12.9 fmol/mg protein. Luzindole, a selective MT2 melatonin receptor antagonist, significantly suppressed binding of 2-[125I]-iodomelatonin at all concentrations tested (10-8 to 10-4 m). These results suggest that the MT2 melatonin receptor subtype is present in the membranes of Ishikawa cells, and that the antiproliferative effect of melatonin on Ishikawa cells is mediated via the MT2 receptor. This may have implications for the use of melatonin in endometrial cancer therapy.
  • J Pineal Res. 2003 Aug;35(1):12-5. : Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial.
    Lissoni P, Chilelli M, Villa S, Cerizza L, Tancini G.
    Divisione di Radioterapia Oncologica, Ospedale San Gerardo, Monza, Milan, Italy.
    p.lissoni@hsgerardo.org

    Numerous experimental data have documented the oncostatic properties of melatonin. In addition to its potential direct antitumor activity, melatonin has proved to modulate the effects of cancer chemotherapy, by enhancing its therapeutic efficacy and reducing its toxicity. The increase in chemotherapeutic efficacy by melatonin may depend on two main mechanisms, namely prevention of chemotherapy-induced lymphocyte damage and its antioxidant effect, which has been proved to amplify cytotoxic actions of the chemotherapeutic agents against cancer cells. However, the clinical results available at present with melatonin and chemotherapy in the treatment of human neoplasms are generally limited to the evaluation of 1-year survival in patients with very advanced disease. Thus, the present study was performed to assess the 5-year survival results in metastatic non-small cell lung cancer patients obtained with a chemotherapeutic regimen consisting of cisplatin and etoposide, with or without the concomitant administration of melatonin (20 mg/day orally in the evening). The study included 100 consecutive patients who were randomized to receive chemotherapy alone or chemotherapy and melatonin. Both the overall tumor regression rate and the 5-year survival results were significantly higher in patients concomitantly treated with melatonin. In particular, no patient treated with chemotherapy alone was alive after 2 years, whereas a 5-year survival was achieved in three of 49 (6%) patients treated with chemotherapy and melatonin. Moreover, chemotherapy was better tolerated in patients treated with melatonin. This study confirms, in a considerable number of patients and for a long follow-up period, the possibility to improve the efficacy of chemotherapy in terms of both survival and quality of life by a concomitant administration of melatonin. This suggests a new biochemotherapeutic strategy in the treatment of human neoplasms
  • J Physiol. 2003 Jul 17 [Epub ahead of print]. : Melatonin Attenuates Sympathetic Nerve Responses to Orthostatic Stress in Humans.
    Ray CA.
    Pennsylvania State University.

    Previous studies have suggested that melatonin may alter sympathetic outflow in humans. The purpose of the present study was to determine the effect of melatonin on sympathetic nerve activity and arterial blood pressure during orthostatic stress in humans. Fifty minutes after receiving a 3-mg tablet of melatonin or placebo (different day), muscle sympathetic nerve activity (MSNA), arterial blood pressure, heart rate, forearm blood flow, and thoracic impedance were measured for 10 min at rest and during 5 min of lower body negative pressure (LBNP) at -10 and -40 mmHg (n=11). During LBNP, MSNA responses were attenuated after melatonin during both the -10 and -40 mmHg levels (P < 0.03). Specifically, during the placebo trial MSNA increased 33+/-8% and 251+/-70% during -10 and -40 mmHg, respectively, but increased only 8+/-7% and 111+/-35% during -10 and -40 mmHg with melatonin. However, arterial blood pressure and forearm vascular resistance responses were unchanged by melatonin during LBNP. MSNA responses were not affected by melatonin during isometric handgrip (30% maximum voluntary contraction) and a cold pressor test. In 6 subjects, plasma melatonin concentration was measured at 25-min intervals for 125 min. Melatonin concentration was 14+/-11 pg/ml before ingestion and was significantly increased at each time point (peaked at 75 min; 1830+/-848 pg/ml). These findings indicate that high concentration of melatonin can attenuate reflex sympathetic increases to orthostatic stress in humans. These alterations appear to be mediated by melatonin-induced changes to the baroreflexes.
  • Toxicology. 2003 Jul 15;189(1-2):1-20. : Protection against ionizing radiation by antioxidant nutrients and phytochemicals.
    Weiss JF, Landauer MR.
    Office of Health Studies, US Department of Energy, EH-6/270 Corporate Square, 1000 Independence Avenue, SW, Washington, DC 20585-0270, USA.
    joseph.weiss@eh.doe.gov

    The potential of antioxidants to reduce the cellular damage induced by ionizing radiation has been studied in animal models for more than 50 years. The application of antioxidant radioprotectors to various human exposure situations has not been extensive although it is generally accepted that endogenous antioxidants, such as cellular non-protein thiols and antioxidant enzymes, provide some degree of protection. This review focuses on the radioprotective efficacy of naturally occurring antioxidants, specifically antioxidant nutrients and phytochemicals, and how they might influence various endpoints of radiation damage. Results from animal experiments indicate that antioxidant nutrients, such as vitamin E and selenium compounds, are protective against lethality and other radiation effects but to a lesser degree than most synthetic protectors. Some antioxidant nutrients and phytochemicals have the advantage of low toxicity although they are generally protective when administered at pharmacological doses. Naturally occurring antioxidants also may provide an extended window of protection against low-dose, low-dose-rate irradiation, including therapeutic potential when administered after irradiation. A number of phytochemicals, including caffeine, genistein, and melatonin, have multiple physiological effects, as well as antioxidant activity, which result in radioprotection in vivo. Many antioxidant nutrients and phytochemicals have antimutagenic properties, and their modulation of long-term radiation effects, such as cancer, needs further examination. In addition, further studies are required to determine the potential value of specific antioxidant nutrients and phytochemicals during radiotherapy for cancer.
  • Ann Pharmacother. 2003 Jul-Aug;37(7-8):1128-31. : Melatonin for the treatment of tardive dyskinesia.
    Nelson LA, McGuire JM, Hausafus SN.
    St. Louis College of Pharmacy/St. Louis University School of Medicine, St. Louis, MO, USA.

    OBJECTIVE: To review the available literature regarding the use of melatonin in the treatment of tardive dyskinesia (TD). DATA SOURCES: Literature was identified through MEDLINE (1966-September 2002), PsycINFO (1967-September 2002), and references of relevant articles. Review articles, case reports/series, and animal and human studies were reviewed. DATA SYNTHESIS: Melatonin has been investigated in TD based on its antioxidant properties. Animal studies and several human case series describe an association between melatonin and TD. Two recent, controlled studies evaluated the role of melatonin in the treatment of TD. CONCLUSIONS: There is a paucity of data evaluating the use of melatonin in TD. Both of the controlled studies evaluating its use are limited by methodologic issues. Although the most recent trial did report a statistically significant improvement in TD with melatonin, these results are not considered to be clinically significant. There are inadequate data at the present time to support the use of melatonin in patients with TD.
  • J Natl Cancer Inst. 2003 Jun 4;95(11):825-8. : Night-shift work and risk of colorectal cancer in the nurses' health study.
    Schernhammer ES, Laden F, Speizer FE, Willett WC, Hunter DJ, Kawachi I, Fuchs CS, Colditz GA.
    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
    schernhammer@channing.harvard.edu

    Exposure to light at night suppresses the physiologic production of melatonin, a hormone that has antiproliferative effects on intestinal cancers. Although observational studies have associated night-shift work with an increased risk of breast cancer, the effect of night-shift work on the risk of other cancers is not known. We prospectively examined the relationship between working rotating night shifts and the risk of colorectal cancers among female participants in the Nurses' Health Study. We documented 602 incident cases of colorectal cancer among 78 586 women who were followed up from 1988 through 1998. Compared with women who never worked rotating night shifts, women who worked 1-14 years or 15 years or more on rotating night shifts had multivariate relative risks of colorectal cancer of 1.00 (95% confidence interval [CI] = 0.84 to 1.19) and 1.35 (95% CI = 1.03 to 1.77), respectively (P(trend) =.04). These data suggest that working a rotating night shift at least three nights per month for 15 or more years may increase the risk of colorectal cancer in women.
  • J Pineal Res 2003 May;34(4):269-77 : Melatonin, xanthurenic acid, resveratrol, EGCG, vitamin C and alpha-lipoic acid differentially reduce oxidative DNA damage induced by Fenton reagents: a study of their individual and synergistic actions.
    Lopez-Burillo S, Tan DX, Mayo JC, Sainz RM, Manchester LC, Reiter RJ
    . Department of Biochemistry, Molecular Biology and Physiology, School of Medicine, University of Valladolid, Valladolid, Spain.
    DNA damage generated by oxygen-derived free radicals is related to mutagenesis, carcinogenesis and aging. In the last several years, hundreds of publications have confirmed that melatonin is a potent endogenous free radical scavenger. In the present in vitro study, we have examined the efficacy of three polyphenolic antioxidants, i.e. xanthurenic acid, resveratrol (3,4',5-trihydroxy-trans-stilbene) and (-)-epigallocatechin-3-gallate (EGCG) and two classical non-polyphenolic antioxidants, i.e. vitamin C (ascorbic acid) and alpha-lipoic acid (LA, 1,2-dithiolane-3-pentanoic acid) in inhibiting *OH-induced oxidative DNA damage. We compared the efficacy of these five antioxidants with the effectiveness of melatonin (N-acetyl-5-methoxytryptamine) and we also investigated the possible synergistic effects of melatonin with the other five molecules. Using high performance liquid chromatography (HPLC), the formation of 8-hydroxy-2-deoxyguanosine (8-OH-dG) in purified calf thymus DNA treated with the Fenton reagents, chromium(III) (as CrCl3) plus hydrogen peroxide (H2O2) (Cr(III)/H2O2), was measured in the presence or absence of the antioxidants alone or in combination with melatonin. 8-OH-dG is considered a biomarker of oxidative DNA damage. Among the antioxidants tested, melatonin was the most effective of these with an IC50 = 3.6 +/- 0.1 micro m. For the other antioxidants the IC50 values were as follows: xanthurenic acid (IC50 = 7.9 +/- 0.3), resveratrol (IC50 = 10.9 +/- 0.3), EGCG (IC50 = 5.7 +/- 0.3), vitamin C (IC50 = 16.9 +/- 0.5) and LA (IC50 = 38.8 +/- 0.7). These values differ from that of melatonin with a P < 0.01. Melatonin (1 micro M) reversed the pro-oxidant effect of resveratrol (0.5 micro M) and vitamin C (0.5 micro M), had an antagonistic effect when used in combination with EGCG (1 micro M) and it exhibited synergism in combination with vitamin C (0.5 micro M) and with LA (5 micro M).
  • J Pineal Res 2003 May;34(4):249-59 : Mechanistic and comparative studies of melatonin and classic antioxidants in terms of their interactions with the ABTS cation radical.
    Tan DX, Hardeland R, Manchester LC, Poeggeler B, Lopez-Burillo S, Mayo JC, Sainz RM, Reiter RJ.
    Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.

    Melatonin and classic antioxidants possess the capacity to scavenge ABTSb+ with IC50s of 4, 11, 15.5, 15.5, 17 and 21 microm for melatonin, glutathione, vitamin C, trolox, NADH and NADPH, respectively. In terms of scavenging ABTSb+, melatonin exhibits a different profile than that of the classic antioxidants. Classic antioxidants scavenge one or less ABTSb+, while each melatonin molecule can scavenge more than one ABTSb+, probably with a maximum of four. Classic antioxidants do not synergize when combined in terms of scavenging ABTSb+. However, a synergistic action is observed when melatonin is combined with any of the classic antioxidants. Cyclic voltammetry indicates that melatonin donates an electron at the potential of 715 mV. The scavenging mechanism of melatonin on ABTSb+ may involve multiple-electron donations via intermediates through a stepwise process. Intermediates including the melatoninyl cation radical, the melatoninyl neutral radical and cyclic 3-hydroxymelatonin (cyclic 3-OHM) and N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) seem to participate in these reactions. More interestingly, the pH of the solution dramatically modifies the ABTSb+ scavenging capacity of melatonin while pH changes have no measurable influence on the scavenging activity of classic antioxidants. An acidic pH markedly reduces the ABTSb+ scavenging capacity of melatonin while an increased pH promotes the interaction of melatonin and ABTSb+. The major melatonin metabolites that develop when melatonin interacts with ABTSb+ are cyclic 3-OHM and AFMK. Cyclic 3-OHM is the intermediate between melatonin and AFMK, and cyclic 3-OHM also has the ability to scavenge ABTSb+. Melatonin and the metabolites which are generated via the interaction of melatonin with ABTSb+, i.e. the melatoninyl cation radical, melatoninyl neutral radical and cyclic 3-OHM, all scavenge ABTSb+. This unique cascade action of melatonin, in terms of scavenging, increases its efficiency to neutralized ABTSb+; this contrasts with the effects of the classic antioxidants.
  • J Pineal Res 2003 Apr;34(3):178-84: Melatonin and its derivatives cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine and 6-methoxymelatonin reduce oxidative DNA damage induced by Fenton reagents.
    Lopez-Burillo S, Tan DX, Rodriguez-Gallego V, Manchester LC, Mayo JC, Sainz RM, Reiter RJ.
    Department of Biochemistry, Molecular Biology and Physiology, School of Medicine, University of Valladolid, Spain.

    Free radicals are generated in vivo and they oxidatively damage DNA because of their high reactivities. In the last several years, hundreds of publications have confirmed that melatonin is a potent endogenous free radical scavenger. Some of the metabolites produced as a result of these scavenging actions have been identified using pure chemical systems. This is the case with both N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), identified as a product of the scavenging reaction of H2O2 by melatonin, and cyclic 3-hydroxymelatonin (C-3-OHM) which results when melatonin detoxifies two hydroxyl radicals (bOH). In the present in vitro study, we investigated the potential of two different derivatives of melatonin to scavenger free radicals. One of these derivatives is C-3-OHM, while the other is 6-methoxymelatonin (6-MthM). We also examined the effect of two solvents, i.e., methanol and acetonitrile, in this model system. As an endpoint, using high-performance liquid chromatography we measured the formation of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) in purified calf thymus DNA treated with the Fenton reagents, chromium(III) [Cr(III)] plus H2O2, in the presence and in the absence of these molecules. The 8-OH-dG is considered a biomarker of oxidative DNA damage. Increasing concentrations of Cr(III) (as CrCl3) and H2O2 was earlier found to induce progressively greater levels of 8-OH-dG in isolated calf thymus DNA because of the generation of bOH via the Fenton-type reaction. We found that C-3-OHM reduces bOH-mediated damage in a dose-dependent manner, with an IC50 = 5.0 +/- 0.2 microm; melatonin has an IC50 = 3.6 +/- 0.1 microm. These values differ statistically significantly with P < 0.05. In these studies, AFMK had an IC50 = 17.8 +/- 0.7 microm (P < 0.01). The 6-MthM also reduced DNA damage in a dose-dependent manner, with an IC50 = 4.2 +/- 0.2 microm; this value does not differ from the ICs for melatonin and C-3-OHM. We propose a hypothetical reaction pathway in which a mole of C-3-OHM scavenges 2 mol of bOH yielding AFMK as a final product. As AFMK is also a free radical scavenger, the action of melatonin as a free radical scavenger is a sequence of scavenging reactions in which the products are themselves scavengers, resulting in a cascade of protective reactions
  • J Pineal Res 2003 Jan;34(1):32-5 : Different responsiveness of central nervous system tissues to oxidative conditions and to the antioxidant effect of melatonin.
    Kaptanoglu E, Palaoglu S, Demirpence E, Akbiyik F, Solaroglu I, Kilinc A.
    Department of Neurosurgery, Hacettepe University Institute of Neurological Sciences and Psychiatry, Ankara Numune Education and Research Hospital, Ankara, Turkey.

    Melatonin, a product of the pineal gland, is an effective free-radical scavenger both in vitro and in vivo. Free-radical-mediated lipid peroxidation has been increasingly considered as an important factor in post-traumatic neuronal degeneration. The aim of the present study was (i). to examine the responses of different regions of central nervous system (CNS) to free-radical generation induced in vitro and (ii). to test the efficacy of melatonin in reducing oxidative damage in different regions of the CNS. Rat brain, total spinal cord, spinal cord white matter and optic nerves were dissected with the rats under general anesthesia and immediately frozen at -20 degrees C. Thiobarbituric acid reactive substances were measured as an index of lipid peroxidation. Peroxidation was induced with ferrous iron (0.02 mm), ascorbate (1 mm), and hydrogen peroxide (H2O2) (0.5 mm). All tissue samples showed increased lipid peroxidation levels after treatment with free-radical generating agents. The highest amount of damage was observed in the presence of ferrous iron, ascorbate, and H2O2. Melatonin showed antioxidant effects in the brain, total spinal cord, optic nerve, and spinal cord white matter. The results show that melatonin has differential protective effects on CNS tissues in vitro and the most potent effect is observed in the spinal cord white matter.
  • Melatonin protects against gastric ulceration and increases the efficacy of ranitidine and omeprazole in reducing gastric damage
    The findings raise the possibility of melatonin being considered as an effective gastroprotective agent individually or as a cotreatment with either ranitidine and omeprazole.
    Protective effect of melatonin in a chronic experimental model of Parkinson's disease.
    Parkinson's disease is a chronic condition characterized by cell death of dopaminergic neurons mainly in the substantia nigra. Among the several experimental models used in mice for the study of Parkinson's disease 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) induced parkinsonism is perhaps the most commonly used. This neurotoxin has classically been applied acutely or sub-acutely to animals. In this paper we use a chronic experimental model for the study of Parkinson's disease where a low dose (15 mg/kg bw) of MPTP was administered during 35 days to mice to induce nigral cell death in a non-acute way thus emulating the chronic condition of the disease in humans. Free radical damage has been implicated in the origin of this degeneration. We found that the antioxidant melatonin (500 &mgr;g/kg bw) prevents cell death as well as the damage induced by chronic administration of MPTP measured as number of nigral cells, tyrosine hydroxylase levels, and several ultra-structural features. Melatonin, which easily passes the blood-brain barrier and lacks of any relevant side-effect, is proposed as a potential therapy agent to prevent the disease and/or its progression.
    Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation.
    In summary, these findings indicated for the first time that melatonin at pharmacologic doses in mice causes an inhibition of bone resorption and an increase in bone mass. These skeletal effects probably were caused by the melatonin-mediated down-regulation of the RANKL-mediated osteoclast formation and activation
  • Melatonin as an effective protector against doxorubicin-induced cardiotoxicity.
    Neither melatonin nor 6-hydroxymelatonin compromised the antitumor activity of doxorubicin in cultured PC-3 cells. These results suggest that melatonin protect against doxorubicin-induced cardiotoxicity without interfering with its antitumor effect.

  • Effect of melatonin on two stage skin carcinogenesis in Swiss mice.
    SOURCE: Med Sci Monit; 6(3):471-5 2000 UI: 21123058
    ABSTRACT: Melatonin, a hormone secreted by the pineal gland, is known to have anti-mutagenic and oncostatic actions. This beneficial action of melatonin has been explained in terms of its ability to scavenge free radicals and augment the activities of anti-oxidant enzymes. In the present study, we evaluated the effect of melatonin on benzo(a)pyrene-induced two stage skin carcinogenesis in mice and observed that it can not only decrease the number of animals bearing papillomas but also the number of papillomas per animal both in the initiation and promotion stages of skin carcinogenesis. It was also found that melatonin treated animals have low levels of lipid peroxides and that it can also prevent the binding of BP or its metabolites to DNA. In view of these evidence, it can be suggested that melatonin may function as an endogenous anti-mutagenic and oncostatic agent
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    Mutat Res 2001 Mar 1;474(1-2):87-92
    Comparison of the protective effect of melatonin with other antioxidants in the hamster kidney model of estradiol-induced DNA damage.
    Karbownik M, Reiter RJ, Cabrera J, Garcia JJ.
    Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
    17beta-Estradiol (E(2)) is a known carcinogen. Estrogen induction of tumors in hamster kidney is a model of estrogen-related carcinogenesis. Melatonin is a well-known antioxidant, free radical scavenger and oncostatic agent. Changes in the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), an index of DNA damage, were measured in kidneys, liver and testes from hamsters treated with E(2) (75mg/kg b.w.) and collected 5h later. Potential protective effects of melatonin, N-acetylserotonin (NAS), indole-3-propionic acid (IPA) and ascorbic acid (AA) against E(2)-induced DNA damage were tested. The antioxidants were applied in equimolar doses of 64.5 micromol/kg b.w., 2 and 0.5h before and 2 and 4h after E(2) treatment. E(2) treatment caused a significant increase in 8-oxodGuo levels in kidneys, but did not influence significantly the oxidation of guanine bases in liver and testes. Melatonin, IPA and AA, but not NAS, completely prevented E(2)-induced DNA damage in hamster kidneys. It is concluded that melatonin, IPA and AA may be effective in protecting against E(2)-related DNA damage and, consequently, carcinogenesis.

    Melatonin reduces the oxidation of nuclear DNA and membrane lipids induced by the carcinogen delta-aminolevulinic acid.
    Karbownik M, Tan DX, Reiter RJ.
    Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.
    Well known are the anti-oxidant, free radical-scavenging and anti-tumorigenic properties of melatonin. delta-Aminolevulinic acid (ALA) is a precursor of heme synthesis. When over-produced and accumulated in tissues, ALA is a potential carcinogen, such as in the course of acute intermittent porphyria, hereditary tyrosinemia and lead poisoning. Our aim was to examine the potential protective effect of melatonin against oxidative damage to nuclear DNA and membrane lipids in rat lung and spleen caused by ALA. Changes in 8-hydroxy-2;-deoxyguanosine (8-OHdG) levels, an index of DNA damage, and the level of malondialdehyde + 4-hydroxyalkenals, an index of lipid peroxidation, were measured. Rats were injected with ALA (i.p., 40 mg/kg body weight, every other day) and/or with melatonin (i.p., 10 mg/kg body weight, 3 times daily) for 2 weeks. Both 8-OHdG and lipid peroxidation levels increased significantly in lung and spleen due to ALA treatment. Co-treatment with melatonin completely counteracted the effects of ALA. In conclusion, melatonin effectively protects nuclear DNA and lipids in rat lung and spleen against oxidative damage caused by the carcinogen ALA, and the indole may be of value as a supplement in patients suffering from molecular damage related to ALA accumulation.

    Zhongguo Yao Li Xue Bao 1998 Nov;19(6):575-81
    Suppression of oxygen toxicity by melatonin.
    Reiter RJ, Tan DX, Qi WB.
    Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio 78284-7762, USA. Reiter@uthscsa.edu
    Melatonin, the chief secretory product of the pineal gland, was recently found to be a free radical scavenger and antioxidant. While most studies to date have used pharmacological quantities of melatonin to limit oxidative damage, physiologic concentrations of the indole which are present in aerobic organisms have also been shown to resist molecular damage inflicted by free radicals. Melatonin has several functions in terms of its antioxidative ability. It readily scavenges the most highly toxic free radical, the hydroxyl radical, and it directly detoxifies the peroxynitrite anion, nitric oxide, singlet oxygen, and the peroxyl radical. Precisely how efficient melatonin is in neutralizing each of these toxic agents remains to be determined. Melatonin also may stimulate several antioxidative enzymes including superoxide dismutase, glutathione peroxidase, and glutathione reductase as well as inhibiting the pro-oxidative enzyme, nitric-oxide synthase. Finally, melatonin chelates transition metal ions and prevents the deterioration of cellular membranes. This combination of actions may all contribute to melatonin's ability to reduce oxidative damage. Melatonin is highly effective in reducing nuclear DNA damage and membrane lipid destruction due to toxic free radicals in vivo. These findings have implications for disease processes, eg, neurodegenerative and cardiovascular diseases, which involve free radicals and for aging itself, which also is believed to be related to accumulated oxidative damage.

    1: Neurochem Int 1995 Dec;27(6):453-60
    The role of the neurohormone melatonin as a buffer against macromolecular oxidative damage.

    Reiter RJ.
    Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio 78284-7762, USA.
    This paper summarizes the recent findings which show that the neural hormone melatonin is a free radical scavenger and general antioxidant. When compared with other antioxidants melatonin seems to have greater efficacy in protecting against cellular oxidative stress. These findings illustrate that melatonin preserves macromolecules including DNA, protein and lipid from oxidative damage following the administration of the chemical carcinogen, safrole, after exposure to ionizing radiation, following glutathione depletion, and after administration of the free radical generating herbicide, paraquat. In vitro evidence shows that melatonin is a potent scavenger of the highly toxic hydroxyl radical and in vitro evidence suggests that melatonin is an important and powerful antioxidant. Considering its high lipophilicity and its non-toxic nature as well as its ability to readily cross the blood-brain barrier, the neurohormone melatonin may prove to be an effective and important molecule in the antioxidative defense system, especially in the central nervous system. Besides the ease with which melatonin enters the brain, neurons seem to accumulate readily this hormone.
    1: Ann N Y Acad Sci 2001 Jun;939:200-15
    Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system.
    Reiter RJ, Acuna-Castroviejo D, Tan DX, Burkhardt S.
    Department of Cellular and Structural Biology, Mail Code 7762, The University of Texas Health Science Center At San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. Reiter@uthscsa.edu
    This review briefly summarizes the multiple actions by which melatonin reduces the damaging effects of free radicals and reactive oxygen and nitrogen species. It is well documented that melatonin protects macromolecules from oxidative damage in all subcellular compartments. This is consistent with the protection by melatonin of lipids and proteins, as well as both nuclear and mitochondrial DNA. Melatonin achieves this widespread protection by means of its ubiquitous actions as a direct free radical scavenger and an indirect antioxidant. Thus, melatonin directly scavenges a variety of free radicals and reactive species including the hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide, peroxynitrite anion, and peroxynitrous acid. Furthermore, melatonin stimulates a number of antioxidative enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. Additionally, melatonin experimentally enhances intracellular glutathione (another important antioxidant) levels by stimulating the rate-limiting enzyme in its synthesis, gamma-glutamylcysteine synthase. Melatonin also inhibits the proxidative enzymes nitric oxide synthase and lipoxygenase. Finally, there is evidence that melatonin stabilizes cellular membranes, thereby probably helping them resist oxidative damage. Most recently, melatonin has been shown to increase the efficiency of the electron transport chain and, as a consequence, to reduce election leakage and the generation of free radicals. These multiple actions make melatonin a potentially useful agent in the treatment of neurological disorders that have oxidative damage as part of their etiological basis.

    Anticarcinogenic actions of melatonin which involve antioxidative processes: comparison with other antioxidants. Karbownik M, Lewinski A, Reiter RJ.
    Department of Cellular and Structural Biology, University of Texas Health Science Center, Mail Code 7762, 7703 Floyd Curl Drive, San Antonio, TX 78299-3900, USA.
    The complex processes of carcinogenesis often involve oxidative stress. Numerous indicators of oxidative damage are enhanced as the result of the action of carcinogens. Several antioxidants, with different efficacies, protect against oxidative abuse caused by carcinogens. Recently, melatonin (N-acetyl-5-methoxytryptamine) and related indoleamines have attracted attention because of their high antioxidant and anticarcinogenic activity. Some antioxidants, e.g. ascorbic acid, play an ambivalent role in antioxidative defense, since, under specific conditions, they are strongly prooxidant. Among known antioxidants, melatonin has been an often investigated experimental agent in reducing cancer initiation and inhibiting the growth of established tumors. The indoleamine has been shown to protect macromolecules from oxidative mutilation induced by carcinogens. In these studies, a variety of in vitro and in vivo models were used and numerous indices of oxidative damage were evaluated. The protective effects of melatonin and several other indoleamine antioxidants against cellular damage caused by carcinogens make them potential supplements in the treatment or co-treatment at several stages of cancer.