Functions of MELATONIN

MELATONIN stimulates immune system / immunomodulator

Evidence suggests an immuno-enhancing function for MELATONIN - stimulation of natural killer cell activity, cytokine expression and inhibition of immune cell apoptosis have been reported.

• A constant light condition and drug-induced inhibition of MELATONIN synthesis in mice is associated with suppressed humoral an cellular immunological responses

Guerrero JM, Reiter RJ. MELATONIN-immune system relationships. Curr Top Med Chem 2002;2:167-79.

• MELATONIN can interact with cells in lymphoid organs
• There is bidirectional interaction between pineal gland and I.S.    Since interleukins and cytokines (interferon gamma) affect MELATONIN synthesis/release

Withyachumnarnkul B, Nonaka KO, Santana C, et al. Interferon-gamma modulates MELATONIN production in rat pineal glands in organ culture. J Interferon Res 1990;10:403-11.

• MELATONIN provides a link between the neuroendocrine and immune systems.   May be explored in diseases that present daily rhythmic symptoms, such as rheumatoid arthritis and nocturnal asthma.

• Animal research has shown that inhibition of MELATONIN synthesis weakens cell-mediated immunity (acquired immunity where T lymphocytes have predominant role) and humoral immunity (immune response, mainly against bacterial invasion, mediated by B cells).

Pandi-Perumal SR, Srinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B, Hardeland R. MELATONIN: Nature's most versatile biological signal? FEBS J. 2006 Jul;273(13):2813-38. PubMed

MELATONIN increases production of interleukin 2 and 6 (IL-2 and IL-6). MELATONIN receptors are found in lymphatic tissue, which supports the premise that MELATONIN has a direct regulating effect on the immune system. A study evaluating IL-6 during nocturnal sleep,sleep deprivation and different sleep stages concluded that:

"Loss of sleep may serve to decrease nocturnal IL-6 levels, with effects on the integrity of immune system functioning. Alternatively, given the association between sleep stages and IL-6 levels, depressed or aged populations who show increased amounts of REM sleep and a relative loss of slow wave sleep may have elevated nocturnal concentrations of IL-6 with implications for inflammatory disease risk."

Laura Redwine, Richard L. Hauger, J. Christian Gillin and Michael Irwin. Effects of Sleep and Sleep Deprivation on Interleukin-6, Growth Hormone, Cortisol, and MELATONIN Levels in Humans. Home Archive Oct 2000 85 (10): 3597 JCEM

MELATONIN is a powerful antioxidant

MELATONIN helps protect the body from cell damage caused by free radicals:

• Direct scavenger of OH^• (hydroxyl radical),O₂•-(superoxide radical), and NO^• (Nitric oxide), ONOO^-(Peroxynitrite anion), ¹O₂ (singlet oxygen), and possibly LOO^•(peroxyl radical);
• Neuroprotective - Can easily cross cell membranes and the blood-brain barrier.

Kilic E, Özdemir YG, Bolay H, Kelestimur H, Dalkara I. Pinealectomy aggravates and melatonin administration attenuates brain damage in focal ischemia. J Cerebr Blood Flow Metab 19:511-516, 1999.Medline

Baydas, G., H. Canatan and A. Turkoglu, 2002. Comparative analysis of the protective effects of melatonin and vitamin E on streptozocin induced diabetes mellitus. J. Pineal Res., 32: 225-230.PubMed

• "Suicidal antioxidant"- unlike other antioxidants (such as vitamin C), MELATONIN can not be renewed (i.e. it does not undergo redox cycling, the ability of a molecule to repeatedly undergo reduction and oxidation to regain antioxidant property).
• Demonstrated to prevent some carcinogenic damage to DNA.   Stops mechanism by which damaged DNA causes cancer.
• Increases body's "in-house" antioxidant glutathione.  Is equally effective as this important antioxidant
• Debated as equal to vitamin E as a chain-breaking antioxidant against peroxyl radical.   Produced by lipid peroxidation, which e.g. damages cell membranes altering cellular function. The resulting cell membrane rigidity associated with aging;
• Scavenges initiating radicals and breakdown products from lipid peroxidation.    Assured by the fact that it scavenges ¹O₂, ONOO^-and OH^•, all of which are sufficiently reactive to initiate the peroxidative process. Prevents otherwise harmful changes to membrane fluidity and function.
• Greatly reduced inflammatory response.    Both ONOO^- and NO^• are believed to be the mediators of the inflammation in animals treated with carrageenan

Beckman J.S., Koppenol W.H. Nitric oxide, superoxide, and peroxynitrite: The good, the bad and ugly// Am. J. Physiol.-1996

• Protected against brain injury caused by ROS release in newborn rats
• -   May reduce damage caused by some types of Parkinson's disease
• May play a role in preventing cardiac arrhythmia
• May increase longevity.    Shown to increase average life span of mice by 20% in some studies.
• Protects against sunburn.    Scientists at University of Zurich found that MELATONIN protects against UV radiation if topically applied before skin exposure;
• Role in repairing burned skin.    In a study in Brain Research Bulletin, MELATONIN levels rose six hours after burn injury, then fell to normal.
• May prevent cataract formation
• In small amounts, causes skin cells to proliferate.    In large amounts it stops proliferation. People with psoriasis and atopic eczema have peak MELATONIN in the day (instead of at night), and low levels at night; not too surprising in that some scientists consider the skin to be another gland.

MELATONIN enhances bone mass

Bone health.     Bone resorption is a process by which osteoclasts break down bone and release the minerals. MELATONIN has been shown to inhibit bone resorption and increase bone mass through its ability to down-regulate activation of osteoclasts.

Pandi-Perumal SR, Srinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B, Hardeland R. MELATONIN: Nature's most versatile biological signal? FEBS J. 2006 Jul;273(13):2813-38. PubMed

An adequate amount of ESTRADIOL is also needed for MELATONIN to benefit bone (a salivary ESTRADIOL test may be useful in cases where MELATONIN is low and bone loss is a concern).High CORTISOL levels also contribute to bone loss.

Raff H, Raff JL, Duthie EH, Wilson CR, Sasse EA, Rudman I, Mattson D. Elevated salivary cortisol in the evening in healthy elderly men and women: correlation with bone mineral density. J Gerontol A Biol Sci Med Sci. 1999 Sep;54(9):M479-83. PubMed

MELATONIN is an anti-cancer agent

At present, the validity of MELATONIN as an oncostatic agent seems well established.    The antitumor mechanisms of MELATONIN have been identified, including:

• Anti-proliferative actions
• Immuno-stimulatory effects on host anti-cancer defenses
• Antioxidant activity.

Circulating levels of MELATONIN are depressed in a wide variety of cancers.    Including breast, endometrial, prostate, lung, gastric and colon.

Bartsch C, Bartsch H.MELATONIN in cancer patients and in tumor-bearing animals. Adv Exp Med Biol. 1999;467:247-64. PubMed

There are, however, isolated reports of tumor growth stimulation, especially if MELATONIN is administered in the morning.    Indicating a circadian-stage dependency of antitumor action.

Bartsch H, Bartsch C. Effect of MELATONIN on experimental tumors under different photoperiods and times of administration. J Neural Transm 1981;52:269-79.

A recent controlled trial shows the possibility to improve chemotherapy - in terms of both survival and quality of life of patients with advanced disease by a concomitant administration of MELATONIN and cisplatinium etoposide in metastatic non small cell lung cancer.

Lissoni P, Chilelli M, Villa S, et al. Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and MELATONIN:

Breast Cancer

• Breast cancer risk was increased among subjects who frequently did not sleep during the period of the night when MELATONIN levels are typically at their highest.    There was also an indication of increased risk among subjects with the brightest bedrooms. Graveyard shiftwork was associated with increased breast cancer risk. Night shift work, Light at night, and Risk of breast cancer

• Breast Cancer research clearly shows solid links between low late-night MELATONINand increased breastcancer cell growth.   A study demonstrated that MELATONIN-rich blood suppressed the growth of human breast cancer xenografts and rat hepatomas. No growth suppression occurred in tumors perfused with MELATONIN-deficient blood collected from the same women after short-term ocular exposure to bright light at night.

Blask DE et al. MELATONIN-depleted blood from premenopausal women exposed to light at night stimulates growth of human breast cancer xenografts in nude rats. Cancer Res. 2005 Dec 1;65(23):11174-84. Pub Med

• CORTISOL levels are also tied to breast cancer risk.   Breast cancer patients with high average CORTISOL throughout the day and elevated CORTISOL at bedtime have earlier mortality, lower natural killer (NK) cell counts and decreased activity of NK cells The strength of the relationship between CORTISOL and MELATONINlevels

Sandra E. Sephton, Robert M. Sapolsky, Helena C. Kraemer, David SpiegelDiurnal Cortisol Rhythm as a Predictor of Breast Cancer Survival. Oxford Journals MedicineJNCI Volume92, Issue12 Pp. 994-1000 JNCI

Reduced MELATONIN production has been proposed as a likely factor in the significantly higher cancer rates in night workers.   In 2007, The World Health Organization cited late night shift work as a probable cancer-causing agent. When someone works in artificial light, they generally have lower MELATONIN, and without this antioxidant and suppressant of tumor development, they may be more likely to develop cancer.

Straif, Kurt; Baan, Robert; Grosse, Yann; Secretan, BéAtrice; Ghissassi, Fatiha El; Bouvard, VéRonique; Altieri, Andrea; Benbrahim-Tallaa, Lamia et al. (2007). "Carcinogenicity of shift-work, painting, and fire-fighting". The Lancet Oncology 8(12): 1065-6.

Lower nocturnal MELATONIN levels are associated withlarger tumors in patients with primary prostate cancer

Vijayalaxmi, Charles R. Thomas, Jr, Russel J. Reiter, Terence S. Herman. MELATONIN: From Basic Research to Cancer Treatment Clinics.Journal of Clinical Oncology, Vol 20, Issue 10 (May), 2002: 2575-2601JOCO

Endogenous MELATONIN stimulates anti-cancer defenses and exhibits anti-proliferative and antioxidant activity

Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of MELATONIN.Sleep Med Rev. 2005 Feb;9(1):11-24. PubMed

MELATONIN protects the GI tract and pancreas

MELATONIN is produced by enterochromaffin cells of the GI mucosa and discharged into the gut lumen.   Where, produced in amounts many times greater than the pineal gland, MELATONIN has several surprising roles protecting the GI tract from damage and preventing forms of gastritis.

• Although MELATONIN produced in the GI tract has a direct effect on GI tissues, its major influence on GI organs seems to occur indirectly via the brain-gut axis.    Since the GI tract source of MELATONIN also contributes to circulatory levels. Mechanisms affecting GI organs include peripheral receptors, sensory afferent (vagal or sympathetic) pathways and the central nervous system (CNS) acting on these organs via autonomic means.
• MELATONIN protects gastrointestinal esophageal mucosa and against various types of injury

Konturek SJ, Zayachkivska O, Havryluk XO, Brzozowski T, Sliwowski Z, Pawlik M, Konturek PC, Cze?nikiewicz-Guzik M, Gzhegotsky MR, Pawlik WW.Protective influence of MELATONIN against acute esophageal lesions involves prostaglandins, nitric oxide and sensory nerves. J Physiol Pharmacol. 2007 Jun;58(2):361-77.[PubMed]

• MELATONIN seems to control the lower esophageal sphincter (LES).  MELATONIN has been used successfully as an alternative to Proton pump inhibitors (PPIs), whose main action is a significant and long-lasting reduction of gastric acid production. Transient lower esophageal sphincter relaxation (TLESR) is a major mechanism of reflux in patients with GERD. Nitric oxide has an important role in TLESR. MELATONIN inhibits nitric oxide biosynthesis, providing an explanation of the regression of GERD symptoms when using MELATONIN and other nutrients
• MELATONIN controls gastrointestinal motility, havingan inhibitory action on gastric acid secretion

Jaworek J, Brzozowski T, Konturek SJ. MELATONIN as an organoprotector in the stomach and the pancreas. J Pineal Res. 2005;38:73-83. [PubMed]

Thor PJ, Krolczyk G, Gil K, Zurowski D, Nowak L. MELATONIN and serotonin effects on gastrointestinal motility. J Physiol Pharmacol. 2007;58 Suppl 6:97-103. [PubMed]

• MELATONIN protects duodenal (1^st part of small intestine) epithelium against gastric H+    By stimulating HCO₃^- secretion from enterocytes.

Konturek PC, Konturek SJ, Hahn EG. Duodenal alkaline secretion: its mechanisms and role in mucosal protection against gastric acid. Dig Liver Dis. 2004;36:505-512. [PubMed]

• Low levels of MELATONIN can lead to ulcers, gastroesophageal reflux disease (GERD) and sleep disorders.    Commonly, patients with GERD also have a sleep disorder.

de Souza Pereira R. Regression of an esophageal ulcer using a dietary supplement containing MELATONIN. J Pineal Res. 2006;40:355-356. [PubMed]

Pereira Rde S. Regression of gastroesophageal reflux disease symptoms using dietary supplementation with MELATONIN, vitamins and aminoacids: comparison with omeprazole. J Pineal Res. 2006;41:195-200. [PubMed]

• Stress / anxiety disorders.    May cause tryptophan depletion, and as a consequence, low MELATONIN levels, since MELATONIN is a metabolite of this amino acid found in certain protein foods.

Zimmermann RC, McDougle CJ, Schumacher M, Olcese J, Mason JW, Heninger GR, Price LH. Effects of acute tryptophan depletion on nocturnal MELATONIN secretion in humans. J Clin Endocrinol Metab. 1993;76:1160-1164. [PubMed]

• MELATONIN appears to be implicated in stimulation of pancreatic enzyme secretion after eating.    Mediated byMELATONIN-induced release of cholecystokinin, acting through entero-gastro-pancreatic reflexes.

Jaworek J, Brzozowski T, Konturek SJ. MELATONIN as an organoprotector in the stomach and the pancreas. J Pineal Res. 2005 Mar;38(2):73-83.

• MELATONIN's GI tract/ pancreas protective/healing mechanisms.   Increasing MELATONIN levels should be considered for its substantial role in prevention of gastric and pancreatic damage and in accelerating healing of gastric ulcers.

Damage-protective mechanisms of pancreas and GI tract.     MELATONIN prevents various forms of gastritis and pancreatitis, via:

- Activation of specific MT2-receptors

- Scavenges reactive oxygen species (ROS) -MELATONIN counteracts the increase in the ROS-induced lipid peroxidation and is partly responsible for preserving the activity of key anti-oxidizing enzymes such as superoxide dismutase(SOD)

Accelerates the healing of chronic gastric ulcerations

- By stimulating the microcirculation

- Interacting withinflammation-controlling prostaglandins, nitric oxide released from vascular endothelium, and/or sensory nerves and with their neuropeptides.