Melatonin is a hormone.It causes sleep...

1. Presented by
K.Harshitha

2. Contents
•Introduction
•Source of melatonin
•Melatonin receptors
•Biosynthesis melatonin
•Physiological role of melatonin
•Therapeutic uses
•Causes of low melatonin levels
•Adverse effects
•Conclusion
•References

3. Melatonin
Arone Lerner was discovered this hormone in 1958.
Melatonin also known chemically as N-acetyl-5
methoxytryptamine.
It is a naturally occuring compound found in all living
creatures from algae to humans at levels that vary in
daily cycles.
It is known as “Hormone of darkness”.
 it is secreted in darkness in both day-active (diurnal) and
night-active (nocturnal).
Many biological effects of melatonin are produced
through activation of Melatonin receptors.

4. Food sources

5. Production:
In higher animals, melatonin is produced by pinealocytes in
the pineal gland (located in the brain) and also by the
retina , lens and GI tract.
It is naturally synthesized from the amino acid tryptophan
Melatonin produced in the pineal gland acts as an
endocrine hormone since it is released into the blood.
By contrast, melatonin produced by the retina and the
gastrointestinal (GI) tract acts as a paracrine hormone.
production of melatonin by the pineal gland is under the
influence of the suprachiasmatic nucleus (SCN) of the
hypothalamus which receives information from the retina
about the daily pattern of light and darkness.

6. Contd…………
 The light/dark information reaches the SCN via
the inner retinal ganglion cells which are
intrinsically photosensitive ,photoreceptor cells
those involved in the visual system.
 These cells represent approximately 2% of retinal
ganglion cells in humans and express the non-
visual photo pigment Melanopsin.
 The sensitivity of melanopsin fits with that of a
vitamin A based photo pigment with a peak
sensitivity at 484 nm (blue light)

7. Contd………..
 This photoperiod cue entrains the circadian
rhythm, and the resultant production of specific
“dark” and “ light” induced neural and endocrine
signals regulates behavioral and physiological
circadian rhythms.
 Melatonin may also be produced by a variety of
peripheral cells such as bone marrow cells
lymphocytes and epithelial cells.
 Usually, the melatonin concentration in these cells
is much higher than that found in the blood but it
does not seem to be regulated by the photoperiod.

9. Role of the SCN in the Sleep-Wake cycle
During the day, the SCN
emits an alerting signal
that helps maintain
Wakefulness.
At night, the alerting
signal is attenuated,
facilitating the onset
of sleep.

10. Secretion:
Melatonin secretion starts at 3-4 months of age.
Peak levels at 1-3 years of age.
Slightly lower levels through early adulthood.
Peak levels for 70 year old is ¼ of levels for young adult.
Metabolism:
Liver is the 1st site for metabolism & clears >90% of
circulation melatonin.
Melatonin is 1st hydroxylated then excreted in urine as
sulphate & glucoronide conjugates.
About 1 % of melatonin remains unchanged in urine.

11. Melatonin receptors:
 Found in central nervous system and peripheral
Tissues.
 In brain MT1 and MT2 receptors are found in
membranes of neurons of (SCN).
 MTI and MT2 are G - protein-couple receptors.
 MT3 receptor is also found which is poorly
understood.

12. MT1 Agonists
Promote sleep via MT1
Receptor in SCNregulating
Sleep/wake cycle
Physiological Sleep
MT1
Sleep promotion
Melatonin receptor agonist

13. Biosynthesis of melatonin:

15. Melatonin in Animals:
 Melatonin can suppress libido by inhibiting secretion of
(LH) and (FSH) especially in mammals that have a
breeding season when daylight hours are long.
The reproduction of long-day breeders is repressed by
melatonin and the reproduction of short-day breeders is
stimulated by melatonin.
In animals ,circulating levels of the hormone melatonin vary
in a daily cycle.
During the night, melatonin regulates leptin lowering
the levels.

16. Melatonin in Humans:
The melatonin signal forms part of the system that
regulates the sleep-wake cycle.
 Infants melatonin levels become regular in about the
third month after birth, with the highest levels
measured between midnight and (8 AM).
In humans, 90% of melatonin is cleared through the
liver, a small amount is excreted in urine and a small
amount is found in saliva.

17. Light dependence:
Production of melatonin is inhibited by light and
permitted by darkness. SO called "the hormone of
darkness“.
 Its onset called the Dim-Light Melatonin Onset
(DLMO).
Secretion in blood peaks in the middle of the night, and
gradually falls during the second half of the night, with
normal variations in timing according to an individual's
chronotype.
It is principally blue light, around 460 to 480nm that
suppresses melatonin.
Use of blue-blocking goggles the last hours before
bedtime advised for people who need to adjust to an
earlier bedtime, as melatonin promotes sleepiness.

18. Physiological role of melatonin:
Antioxidant
Immune system
Cancer
Dreaming
Sleep
Menstrual Benefits
Other

19. Anti- oxidant action of melatonin:
1.Direct anti-oxidant actions
Free radical scavenger of ROS
Free radical scavenger of RNS
2.In direct anti-oxidant actions
Stimulation of anti-oxidant enzymes
Stimulation of synthesis of glutathione
Synergistic actions of melatonin with
classical anti-oxidants

20. Melatonin as a scavenger of ROS:
Melatonin scavenger of Hydroxyl radical (OH):
Each molecule of melatonin scavengers 2 OH radicals.
Cyclic 3-Hydroxy melatonin itself has free radical
scavenging action and it is foot print molecule that
appears in urine.
Melatonin scavenger of superoxide(O2
- .
)
Melatonin scavenger O2
- .
in a pure chemical system
where a hypoxanthine/ xanthine system was used to
produce O2
- .

21. Melatonin scavenger of H2O2:
Melatonin is scavenger of H2O2 in a pure chemical
system.
A mechanism of the oxidation of melatonin by H2O2
was suggested on the basis of two major resulting
metabolite i.e., N- Acetyl-N-Formyl-5-Methoxy
kynuranine(AFMK)
Cyclic 3- hydroxy melatonin & AFMK function as
scavenger of toxic reactants as like as parent molecule
(i.e,Melatonin).

22. Melatonin scavenger of singlet oxygen:
 Melatonin neutralizer singlet O2 during which AFMK
was generated i.e., AFMK was the product when
melatonin was oxidized by singlet oxygen.
Melatonin scavenger of initiating agents of lipid
peroxidation.
Melatonin is highly efficient in limiting the
peroxidation of lipids. It is due to scavenging of
initiating agents(.OH,NOO-) rather than direct LOO.
scavenger.

23. Melatonin Scavenger of RNS:
Melatonin interacts with NO
.
only in the presence of
molecule oxygen.
The chief product of melatonin /NO
.
reaction is N-
nitromelatonin.
Indirect antioxidant actions of melatonin:
1.Melatonin stimulation of glutathione:
It stimulates the rate limiting enzyme
γ-Glutanylcysteine synthase,there increasing intracellular
GSH conc.
This action of melatonin ,unlike direct free radical
scavenging function of the indoleamine is likely mediated
by specific receptors.
The stimulation of GSH synthesis by melatonin could be a
major antioxidative action of melatonin.

24. Melatonin stimulation of antioxidant enzymes:
Melatonin stimulates GPx ,GR. The ability of melatonin
to regulate GSH by modulating enzyme activates appears
to involve an actions of melatonin at nuclear binding
site.
The other GSH metabolizing enzyme i.e., catalase also
increases it’s activity on response to melatonin.
GR requires the cofactor NADPH which is generated by
the antioxidant enzymes G-6-phosphate
dehydrogenase(G6PD).Melatonin also stimulates G6PD.
Melatonin enhances gene expression for antioxidant
enzymes either under base conditions or after their
inhibition by neurotonic agents.

25. Synergistic action of melatonin with classical
antioxidants:
Melatonin important actions at the level of
mitochondria are:
 It is efficient scavenger of ROS/RNS which are
abundant in mitochondria.
 Although mitochondria are incapable of GSH
synthesis they posses GPx &GR for GSH cyclins ,
both enzymes of which are stimulated by
melatonin.
 Melatonin has anti-apoptotic effects against
apoptic signals originating in mitochondria.
 Melatonin may be in higher conc. in
mitochondria than in the cell.

27. Other roles of melatonin as Antioxidant:
 It is extremely powerful antioxidant with a particular
role in the protection of nuclear and mitochondrial
DNA
 Melatonin that can protect against cancer by
eliminating free radicals.
 It does this by activating the cytokine system
(lymphocytic function).

28. Contd…………….
 Melatonin is a direct scavenger of OH, and NO.
 Melatonin once oxidized cannot be reduced to its
former state because it forms several stable end
products upon reacting with free radicals Called
terminal or suicidal antioxidant.
 The antioxidant activity of melatonin may reduce
damage caused by some types of Parkinson's
disease may play a role in preventing cardiac
arrhythmia.

29. Melatonin in Immune System:
Immunological effect is thought to result from
melatonin acting on high affinity receptors (MT1
and MT2).
Melatonin may enhance cytokine production.
Melatonin might be useful fighting infectious
disease including viral, such as HIV and bacterial
infections , and cancer.
Endogenous melatonin in human lymphocytes has
been related to interleukin-2 (IL-2) production.

30. Cancer:
Melatonin has also been thought to fight against
cancer (especially prostate, breast and colon cancers).
Melatonin is inhibitory action of tumor growth.
The apparent melatonin induced suppression of
prolactin , when prolactin is a hormone that can
promote mammary cancer .
Several studies reported that , during the initial state
of tumor development , melatonin is increased an
early stage of cancer with malignant cells that do not
growth.

31. Melatonin in Dream:
Increase in vivid dreaming or frequency of dreams.
Extremely high doses of melatonin (50 mg) increased
REM sleep time and dream activity in both
narcoleptics and those without narcolepsy
80mg can induce sleep in adults.
Many drugs such as cannabis ,cocaine increase
melatonin synthesis.
Sleep:
Melatonin is “opening the sleep gate”
SCN is the site of internal biological clock.
Elevated melatonin level occur at night coincident
with sleep.

32. Melatonin’s Digestive Powers:
Melatonin works with cholecystokinin in the
digestive tract to decrease the likelihood and severity
of many symptoms associated with gastric ulcers
and colitis.
Menstrual Benefits:
When estradiol is administered to postmenopausal
women, their melatonin levels increase.
This occurs naturally throughout a woman’s life
before she reaches menopause, having a positive
effect on women’s menstrual cycles.

33. Other Functions:
Exogenous melatonin decreases leptin production.
Reported that melatonin intake reduced BP during
sleep, without effect of the heart rate.
One of the claimed action of melatonin that anti aging
effect.
Melatonin controls the circadian rhythm as well as
deep stages of sleep.
It increasing secretion of GnRH and sex hormones.
Inhibits growth and development of sex organs before
puberty.
Many biological effects of melatonin are produced
through activation of melatonin receptors.

34. Therapeutic uses:
Melatonin is used in the treatment of
Cancer
Immune disorders
Cardiovascular diseases
Depression
Seasonal effective sleep disorders
Sexual dysfunction
Fertility
Headache
Used as dietary supplement
Used to Prevent ischemic damage

35. Causes of Low Melatonin Levels:
Alcohol
Vitamin B12
Caffeine
NSAID anti-inflammatory medication
Beta-blocker medication
Glucocorticoid medication
Cigarettes
Antidepressants
Frequent stress

36. Adverse Effects:
• Some unwanted effects in some people especially
at high doses(3mg/day or more).
Nausea
Vivid dreams or night mares
Reduced blood flow
Hypothermia
Hormone fluctuations
Drowsiness , Dizziness
Confusion , Hallucinations
Fatigue
Menstrual irregularities

37. Recommended dose of melatonin:
 For most uses doses ranging from 0.3 to 5 mg once
daily (usually in the evening) seem to work well.
Some of the marketed products:

38. Summary:
 Finally when melatonin secretes it leads to sleep.
 Melatonin levels maintain the biological clock.
 It used to treat the cancer at early stages.
 It controls the BP and cardiac rhythm during sleep.
 It reduce damage in case of Parkinson's disease.
 It plays a particular role in the protection
of nuclear and mitochondrial DNA.
 Melatonin has also been found to help protect your
brain in the event of a traumatic brain injury.

39. References:
http://www.drugs.com/melatonin.html
Lewis, Alan (1999). Melatonin and the Biological Clock.
McGraw-Hill.
Hardeland R (2005). "Antioxidative protection by
melatonin: multiplicity of mechanisms from radical
detoxification to radical avoidance.". Endocrine .
Foundations of nutrition by bhavana sabarwal.
Rieter,J.R. The pineal gland and melatonin in relation to
aging; a summary of the theories and the
data.Exp.Gerontol. 30:199-212.
Ross and Wilson Anatomy and physiology in health
and illness.

40. Thank you