Presented by

K.Harshitha

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

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.

Food sources

Production:

In higher animals, melatonin is produced by pinealocytes inthe pineal gland (located in the brain) and also by the retina , lens and GI tract.

It is naturally synthesized from the amino acid tryptophanMelatonin 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.

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)

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.

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.

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.

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.

MT1 Agonists

Promote sleep via MT1Receptor in SCN regulating

Sleep/wake cycle

Physiological Sleep

MT1

Sleep promotion

Melatonin receptor agonist

Biosynthesis of melatonin:

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.

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.

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.

Physiological role of melatonin:

Antioxidant

Immune system

Cancer

Dreaming

Sleep

Menstrual Benefits

Other

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

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

- .

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).

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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

Causes of Low Melatonin Levels:

Alcohol

Vitamin B12

Caffeine

NSAID anti-inflammatory medication

Beta-blocker medication

Glucocorticoid medication

Cigarettes

Antidepressants

Frequent stress

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

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:

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.

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.

Thank you