1. By:
Evan Abdulkarim MAHMOOD
Supervisor:
Doç. Dr. Tahir KAHRAMAN

2. Introduction Of Melatonin
Melatonin, chemically (N-acetyl-5-methoxy
tryptamine) is a hormone secreted by pineal
gland in the brain. Melatonin produced by
the retina and the gastrointestinal (GI)
tractacts as a paracrine hormone.
It found in a wide spectrum of organisms
including, animals, plants, bacteria and fungi
.It helps regulate other hormones and
maintains the body's circadian rhythm.
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3. Melatonin And Age
Some researchers also believe that
melatonin levels may be related to aging.
For example, young children have the
highest levels of nighttime melatonin.
Researchers believe these levels drop as
we age. Some people think lower levels
of melatonin may explain why some
older adults have sleep problems and
tend to go to bed and wake up earlier
than when they were younger.
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4. Chemical Structure of Melatonin
Melatonin has the molecular formula (C13H16N2O2), and it
has many chemical names such as (N-Acetyl-5-
methoxytryptamine, 73-31-4 Circadian, 5-methoxy-n-
acetyltryptamine), and the IUPAC name o melatonin is ( N-[2-
(5-methoxy-1H-indol-3-yl)ethyl]acetamide).
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5. Synthesis of Melatonin
Melatonin (N-acetyl-5-methoxytryptamine) is
primarily synthesized and secreted by the
pineal gland . The synthesis of melatonin in
the pineal gland involves several steps.
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6. Synthesis of Melatonin
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7. Synthesis of Melatonin
Melatonin is rapidly metabolized, primarily in the liver, to 6-
hydroxymelatonin. A series of reactions next yield N-acetyl-
5-methoxy-6-hydroxytryptamine that, depending upon the
chemical environment, is conjugated to either sulfate or
glucuronide
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8. Synthesis of Melatonin
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9. Melatonin Secretion
Under natural environment, melatonin is secreted during the
night in the healthy human, as in all other species. Melatonin
being a lipophilic molecule, it is not stored but directly
released by diffusion of the pineal gland and released into
the cerebrospinal fluid and the circulation. Although the eye
contributes significally to circulating melatonin levels in a
few species(sea bass, frog, quail, pigeon), retinal melatonin
acts primarily within the eye
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10. Melatonin Secretion
In humans, serum concentrations of melatonin is
low during the day and is significally higher at night
with peak between 02:00 am and 04:00 am, when
measured with high-specificity assay. The onset of
secretion usually takes place around 09:00 pm-
02:00 am and the offset around 07:00 am-09:00 am
in adults in the temperature zone.
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11. Melatonin Secretion
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12. Regulating System of Melatonin Secretion
Melatonin synthesis in the pineal gland is modulated by
light/dark information that is detected by the photosensitive
ganglion cells of the retina .Specifically, the signal passes
through the suprachiasmatic nucleus to the pineal gland
where specific “dark” and “light”-induced neural and
endocrine signals co-coordinately regulate melatonin
secretion. Synthesis of melatonin is inhibited by light and
permitted by darkness peaking in the middle of the night in
both diurnal and nocturnal animals.
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13. Regulating System of Melatonin Secretion
The function of melatonin released from the pineal
gland may be also modulated by the local release of
gonadotropin-releasing hormone (GnRH) from the
hypothalamus (as in the figure below)
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14. Regulating System of Melatonin Secretion
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15. Pathophysiology of Melatonin Secretion
Alteration of 24 hour melatonin profiles can be
associated with a large variety of pathological
situations. Some of the changes may have a
pathogenetic relationship with major disease
process. Also, since an abnormality at any level of
the reregulating system unspecifically modifies
melatonin secretion, other changes are more a
consequence of the existing disorder.
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16. Melatonin Catabolism
Melatonin produced by the pineal gland is released
into the circulation and gains access to various
fluids, tissues and cellular compartments. Because
this highly lipophilic hormone is not stored in the
pineal gland, the profile of its plasma levels reflects
pineal activity. More than 90% of circulating
melatonin is deactivated by the liver. Melatonin is
first hydroxylated at the 6-position by a hepatic
cytochrome.
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17. Melatonin Catabolism
Within the brain, melatonin is degenerated via oxidative
pyrrole-ring cleavage. N1-acetyl-N2-formyl-5-
methoxykynuramine (AFMK), a product of this reaction, is
subsequently deformylated by either arylamine formamidase
or hemoperoxidase to N1-acetyl-5-methoxykynuramine
(AMK)
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18. Melatonin in food and in the gastrointestinal tract
Melatonin is a natural compound of almost ubiquitous
occurrence. Its presence was demonstrated in all major taxa
of organisms, as far as tested, including bacteria, unicellular
eukaryotes, macroalgae, plants, fungi and invertebrate
animals. Several studies dealt with melatonin in edible plants
.One can conclude that relevant quantities of melatonin are
present in most vegetables, fruit, nuts and cereals.
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19. Melatonin in food and in the gastrointestinal tract
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20. Melatonin in food and in the gastrointestinal tract
However, the precise melatonin contents are sometimes
affected by some uncertainties which results from particular
methodological problems arising in material from
photoautotrophic organisms. First, melatonin can be easily
destroyed by oxidants during extraction, and, second, false
positive and false negative data are easily obtained due to the
presence of secondary plant metabolites, either mimicking
melatonin or interfering with it in the assays.
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21. Metabolic Functions of Melatonin
Circadian rhythm is any biological process that displays an
endogenous, entrainable oscillation of about 24 hours.
In humans and most diurnal mammals, melatonin is secreted
at night with a strong circadian rhythm and maximum
plasma levels that occur around 2 to 4 AM.
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Circadian Rhythm Effect1

22. Metabolic Functions of Melatonin
The main function of melatonin is to mediate dark signals,
with possible implications in the control of circadian
rhythmicity and seasonality.
With darkness at night there is melatonin secretion phases
with sleep and circadian cycle.
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Circadian Rhythm Effect1

23. Metabolic Functions of Melatonin
The role of melatonin for the seasonal changes in physiology
and behavior of various photoperiodic species has been
extensively documented for a long time.
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Circadian Rhythm Effect1
In winter nights there is increases duration of
melatonin secretion. Summer nights
melatonin secretion reduces with longer
days.

24. Metabolic Functions of Melatonin
Melatonin is a very potent free radical scavenger
recipient and a general antioxidant. As an
antioxidant melatonin binds potently the toxic
hydroxyl and hyperoxide radicals. The antioxidant
properties of melatonin have been proved in
homogenized tissues and in living organisms
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Antioxidant Effect2

25. Metabolic Functions of Melatonin
The antioxidant activity of melatonin may reduce damage
caused by some types of Parkinson's disease, may play a role
in preventing cardiac arrhythmia and may increase longevity
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Antioxidant Effect2

26. Metabolic Functions of Melatonin
Any positive immunological effect is thought to result from
melatonin acting on high affinity receptors (MT1 and MT2)
expressed in immune competent cells. In preclinical studies,
melatonin may enhance cytokine production.
Some studies also suggest that melatonin might be useful
fighting infectious disease including viral and bacterial
infections. In preclinical studies, melatonin may enhance
cytokine production. And by doing this counteracts acquired
immune deficiencies.
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Immune System Effect3

27. Metabolic Functions of Melatonin
Endogenous melatonin in human lymphocytes has
been related to interleukin-2 (IL-2) production and
to the expression of IL-2 receptor This suggests that
melatonin is involved in the clonal expansion of
antigen-stimulated human T lymphocytes.
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Immune System Effect3

28. Melatonin Related Disease
The role of melatonin in pregnancy and embryo
fetal development has hardly been discussed, but
there is clear evidence of a strong connection
between fetal normal development and melatonin.
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Role of Melatonin in Embryo Fetal Development1
First, the embryo and fetus are dependent on maternal melatonin,
as the pineal gland becomes mature after birth. Melatonin
crosses all physiological barriers without being modified,
including the placental one and has been involved in placental
function in animals and human.

29. Melatonin Related Disease
Maternal melatonin enters the fetal circulation
transplacentally providing photoperiodic information
to the fetus and by that influencing the internal
rhythms of the offspring.
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Role of Melatonin in Embryo Fetal Development1
Melatonin administration started prior to IVF-cycles, continued
during pregnancy and was associated with improved pregnancy
outcomes. Melatonin receptors are widespread in the human
fetus from early fetal development. In addition, it appears that
the fetuses’ sleep patterns develop in the late pregnancy,
melatonin being the regulating factor.

30. Melatonin Related Disease
Melatonin is produced about 90 minutes after falling asleep in a fully
darkened room. It pushes you into a deeper sleep. Production is light
sensitive and regulatory "sensors" have been found in the retina.
Several studies have shown that irregular sleeping habits and sleeping
in synthetic light, lower the production of the hormone and are also
associated with higher breast cancer levels. Conversely, blind women
develop less breast cancer.
Research has shown that melatonin regulates excess estrogen levels
and excess IGF-1 levels. Both drive cancer and IARC has declared
lack of sleep a carcinogen. Melatonin is thus an anti-cancer agent.
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Effect of Melatonin in Cancer Disease2

31. Melatonin Related Disease
Studies demonstrated that melatonin inhibits cholangiocyte
hyperplasia in bile duct ligation (BDL) by interaction with
MT1 receptor. Specifically, administration of melatonin to
cholestatic BDL decreased ductal mass and improved serum
chemistry and reduced the expression of the clock genes, cyclic
adenosine monophosphate cAMP levels, protein kinas A (PKA)
phosphorylation in cholangiocyte.
Local modulation of melatonin synthesis may be important for
management for the balance between biliary proliferation/ loss
in cholangiopthies.
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Effect of Melatonin in Biliary Growth / Damage3

32. Melatonin Related Disease
In support of the concept that melatonin protects the
liver from selected pathological perturbations, a
recent study has shown that this hormone protects
against apoptosis during acetaminophen-induced
acute liver failure . The findings suggest that
melatonin may be an effective antioxidant agent
able to reduce liver fibrosis
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Effect of Melatonin in Liver Damage4
The protective effect of melatonin on liver function has also
been demonstrated during ethanol administration. For example,
melatonin reduces alcoholic liver injury by reducing oxidative
stress, inflammatory response, and apoptosis .

33. Melatonin Related Disease
Acute pancreatitis is a disease, which could be manifested as
either a mild edematous form or a more severe necrotizing
pancreatitis which has a poor prognosis.
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Effect of Melatonin in Pancreatic Prevention5

34. Melatonin Related Disease
Both melatonin and its precursor have been demonstrated to
protect the pancreas against acute pancreatitis and to reduce
pancreatic tissue damage. In the pancreas melatonin and L-
tryptophan activate complex mechanisms which involve direct
scavenging of the radical oxygen and nitrogen species, activation
of antioxidant enzymes (catalase, superoxide dysmutase,
glutation peroxidase), reduction of pro-inflammatory cytokines
and prostaglandins, activation of heat shock protein, and a
decrease of necrosis and increase of regeneration in the pancreas
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Effect of Melatonin in Pancreatic Prevention5
Acute pancreatitis is a disease, which could be manifested as either a mild
edematous form or a more severe necrotizing pancreatitis which has a poor
prognosis.

35. Melatonin Related Disease
There are several arguments for the idea that endogenous
melatonin produced in the pineal gland and in the
gastrointestinal system could be the part of a native mechanisms
for protecting the pancreas against acute damage:
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Effect of Melatonin in Pancreatic Prevention5
1
• The melatonin precursor L-tryptophan exerts similar protective effect as melatonin
2
• Application of the melatonin receptor antagonist, luzindole aggravates acute pancreatitis
3
• Pinealectomy results in the exacerbation of acute pancreatitis
4
• Low melatonin plasma levels are associated with an increased risk of severe acute
pancreatitis.

36. Melatonin Related Disease
A deficient production of melatonin or (Hypomelatonism) can
result in anxiety and mood disorders, lowered basal body
temperature insomnia, elevated estrogen/progesterone ratio, and
immune suppression associated with cancer.
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Melatonin Deficiency and Excess6

37. Melatonin Related Disease
And there are many reasons that cause to low melatonin levels
such as (alcohol, Vitamin B12, caffeine, Beta-blocker
medications, Cigarettes, Frequent stress, antidepressants).
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Melatonin Deficiency and Excess6
Alcohol
Vitamin
B12
Caffeine
Beta-
Blocker
medications
Cigarettes
Frequent
stress
Anti-
depressants

38. Melatonin Related Disease
Excess melatonin or we can say (hypermelatonism) is associated
with seasonal affective disorder (SAD), lowered
estrogen/progesterone ratio, low thyroid and adrenal function,
and hypotension, extreme fatigue and lack of energy, increased
need for sleep, carbohydrate cravings, exposure to light improve
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Melatonin Deficiency and Excess6

39. Melatonin Related Disease
Melatonin is known to possess several properties of value for
healthy aging, as a direct and indirect antioxidant, protectant and
modulator of mitochondrial function, anti excitotoxic agent,
enhancer of circadian amplitude, immune modulator and
neuroprotector.
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Melatonin and Other Related Disease7

40. Melatonin Related Disease
It is level tend to decrease in the course of senescence and are
more strongly reduced in several neurodegenerative disorders,
especially Alzheimer’s disease, and in disease related to insulin
resistance such as diabetes type 2. Although the role of
melatonin in aging and age-related diseases has been repeatedly
discussed, the newly emerged concept of inflammaging, that is,
the contribution of low-grade inflammation to senescence
progression has not been the focus of melatonin research
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Melatonin and Other Related Disease7

42. References
Lerner AB, Case JD, Takahashi Y, Lee TH, Mori W, (1958) Isolation of
melatonin, the pineal factor that lightens melanocytes. J Am Chem
Sci, 89, 2857–2858.
Bubenik, G.A., (2002) Gastrointestinal melatonin: Localization, function, and
clinical relevance. Dig Dis Sci, 47, 2336–2348.
Hardeland R, Poeggeler B: (2003) Non-vertebrate melatonin. J Pineal Res,
34:233-241.
Maestroni GJ. : (2001) The immunotherapeutic potential of melatonin. Expert
Open Investing Drugs, 10(3):467-76.
Tahan V, Ozaras R, Canbakan B.: (2004) Melatonin reduces
dimethylnitrosamine-induced liver fibrosis in rats. J PinealRes
;37:78-84.
Renzi A, DeMorrow S, Onori P : (2013) Modulation of the biliary expression
of arylalkylamine N-acetyltransferase alters the autocrine
proliferative responses ofcholangiocytes in rats. Hepatology;
57:1130-41.
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43. References
Tahan V, Ozaras R, Canbakan B.: (2004) Melatonin reduces
dimethylnitrosamine-induced liver fibrosis in rats. J PinealRes
;37:78-84.
Hu S, Yin S, Jiang X.: (2009) Melatonin protects against alcoholic liver injury
by attenuating oxidative stress, inflammatory response, and
apoptosis. Eur J Pharmacol ;616:287-92.
Ru¨ diger Hardeland a , Daniel P. Cardinali b, Gregory M. Brown c,
Seithikurippu R. Pandi-Perumal, : (2015) Melatonin and brain
inflammaging, Progress in Neurobiology 127–128 46–63.
Klein DC, Ganguly S, Coon S,. (2002) Proteins and photoneuroendocrine
transduction: role in controlling the daily rhythm in melatonin.
Biochem Soc Trans; 30:365-73.
Jolanta B. Zawilska, (2009) Melatonin and biological rhythms.
Pharmacological Reports, , 61, 383–410.
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