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DOI: 10.1201/9781003300502-16
16
Melatonin and the Brain
Shabana Bibi, Sana Javed, Farah Alam Gill, Shopnil Akash,
Hitesh Chopra, Ammara Saleem, and Rashid Hussain
16.1 INTRODUCTION
Melatonin (MT) is a molecule observed in plants and animals that grows naturally. It is well- studied
in living things as a hormone naturally produced at night by the pineal gland located in the brain,
and it has been connected to the regulation of the sleep- wake feedback loop [1]. MT is a chemical
that has been connected to the body’s intrinsic immune system. MT has already been proven to be
2].
very well span a broad spectrum [3]. MT has the ability to restrict human physiological rhythms,
lessen related conditions such as lethargy and sleepiness, clean free radical living things, improve
the immune system, and produce cytotoxic activity [4].
MT- containing food products are famous and recognized as favourable health supplements.
Biological rhythms have evolved in order to modify natural roles to particular times of daytime or
nighttime [5]. The said time helps to regulate the diurnal sleep and wake cycles, in addition to regu-
lating body temperature and secretion of different hormones as per their requirement. Neural signals
are sent to nucleus cells from the membrane of the retina, which transmits messages regarding the
photoperiodic condition to the pineal gland, which in turn creates and emits hormones, transferring
the clock signal all through the body [6].
MT synthesis takes place 24 hours a day. At night, even so, more is generated and released into
the bloodstream. The living human reconstructs about 30 g of per day, with the highest concentra-
tion in the blood happening during the mid- dark period of time. This hormone is not crystalized in
the pineal gland; it is absorbable into the bloodline and well- decomposed in the liver [7]. MT can be
connected with haemoglobin and albumin protein inside the systemic spreading, but it is primarily
translocated off albumin. MT’s amphiphilic nature enables it to easily travel through normal cells
and morpho- physiological, including the blood- brain barrier. MT has been discovered to rearrange
lipid membranes utilizing two- dimensional X- ray diffraction readings, with the last impacts relying
on its accumulation [8].
Thereby, at small concentrations, MT- enriched spots were discovered in the cell tissue layer;
nevertheless, at high concentrations, an extremely involved homogeneous MT structure was detect-
able all across the tissue layer [9
tain MT could help to raise the serum levels of this compound [5]. MT is produced by organ systems,
as well as the endocrine gland, retina, bone marrow, skin, gastrointestinal tract, and lymphocytes,
and it is digested through diets rich in this substance [9].
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Plant-based Foods and their Implications in Brain Health
Figure 16.1 depicts the MT’s primary roles and mechanisms in the human body; it promotes
health by controlling the regulation of different pathways in the body. It may also be recognized
as a curative choice for handling diseases. MT is normally non- toxic and secure; however, at
larger concentrations, only slight adverse effects such as lightheadedness, migraine, vomiting, and
tiredness have been observed [8].
16.2 DIETARY SOURCES OF MELATONIN
16.2.1 animal foodS
The material of MT in food products, on the other hand, varies considerably among organisms.
one individual living thing in both animal and plant foods [5]. Plant foods with the minimum MT
material are fruits, while seedlings and leaves possess the greatest [10].
FIGURE 16.1 The primary functions of melatonins in human beings.
319
Melatonin and the Brain
Moreover, MT was discovered in colostrum at equivalent concentrations to that discovered in
plasma, which might advantage newborn babies who possess the found repetitive absorption of
liquors enclosed detectable MT [11].
16.2.2 plant foodS
MT has been observed in a diverse array of widely consumed fruits. Strawberries, cherries, and
distinctions. MT levels in grape skin, tart cherry skin, and strawberry skin varied from 8.9 to 158.9
discovered in a broad scope of day- to- day utilized vegetables, but it is unperceivable in potatoes
and cost- effective in beetroots [5]. Tomatoes and peppers are among the most researched, and they
contain the top levels of MT accumulation in every vegetable group [12].
MT has been observed throughout many dicotyledonous and vegetative growth plants, with
levels ranging from 189 ng/ g DW in white mustard and 129 ng/ g DW in black mustard [13].
16.2.3 juiCeS and beverageS
MT levels were measured in famous hard liquor such as drinks and champagne [14]. MT was
assumed to be produced synthetically sometimes during yeast due to yeast fermentation, in addition
to becoming obtained from essential factors [15].
16.3 BIOAVAILABILITY OF MELATONIN IN HUMANS
As it relates to MT bioactivity, a variety of studies have been conducted, with outcomes varying
in MT items relating to absorption, metabolism, and eradication have also been reported for diverse
persons [16]. These outcomes obviously show the need for serious research into the pharmacokin-
etics and pharmacodynamics of MT [17].
16.4 MELATONIN SYNTHESIS AND METABOLISM
MT is generated in pinealocytes from tryptophan. This synthesis is accomplished in four
two- step process. These enzymes are N- acetyltransferase (NAT), an antagonist of MT, and
hydroxyindole- O- methyltransferase (HIOMT). The regulation of that kind of synthesis differs
according to the day/ night rhythm, with the formulation reaching its highest point at night [18]
(Figure 16.2).
The synthesis of MT takes place in the pinealocytes, the cellular units of the pineal gland. The
biosynthesis of MT starts with the active absorption of the amino acid tryptophan from the blood.
First, 5- hydroxy- tryptophan is formed through tryptophanehydroxylase (TH). Subsequently, the
transformation into serotonin (5- hydroxy- tryptamine) takes place by the enzyme aromatic- amino-
acid- decarboxylase (AAMD). The next step is the transformation of serotonin into N- acetylserotonin
through N- acetyltransferase (NAT), which is the limiting step for MT synthesis. Finally, the synthesis
of MT (N- acetyl- 5- methoxy- tryiptamine) through the enzyme hydroxyindole- O- methyltransferase
(HIOMT) takes place. A variety of variables affect the frequency of this procedure. The existence of
in these biosynthetic pathways [19]. MT levels increase in such circumstances. Nevertheless, the
nutrients folate and B6 are needed for this procedure. Folate is necessary even throughout the
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Plant-based Foods and their Implications in Brain Health
methylation procedure. B6 vitamins are frequently linked to tryptophan decarboxylation. MT formu-
lation will not occur if they are not present in the environment [20].
16.5 PHARMACOKINETIC PROPERTIES OF MELATONIN
MT metabolic activity is less widely acknowledged than fabrication. 6- OH MT is one of the more
important MT metabolites [21]. MT has been suggested as the ultimate biosynthesis of MT for so
many centuries, but now it is comprehended that there is no separate breakdown product [22]. MT
metabolic activity is, in reality, a very process ensures. MT is hydrolyzed in three ways: enzym-
atic, pseudo enzymatic, and through reactive oxygen species (ROS) interactions [23]. AFMK may
be the next MT biological substance produced through one pseudo enzymatic procedure. It has
been proved that haemoglobin and some other iron- containing hemoproteins communicate with MT
to establish AFMK as well as other metabolic products. In this performing action, the oxophoryl
hemoprotein damages MT and attempts to break down to form AFMK [24].
The main protein involved in the conversion of MT in animals is CP450 [16]. This enzyme is
noticed in a wide range of tissues, most noticeably the liver. Indoleamine 2, 3- dioxygenase is the
main protein necessary for MT metabolism in the brain (IDO). AFMK is generated as a side effect
of enzyme production. MT could also be digested nonenzymatically, which is shocking. As a conse-
quence of the interaction with ROS, so many substances are constituted. It is hard to evaluate which
route is more present in the body. Metabolism is the consequence of connections with ROS under
serious oxidative stress. Sixty- seven percent of MT throughout plasma adheres to albumin. MT has
a half- life of 3– 45 minutes. As it is water soluble and has fatty acids, it can directly enter connective
25].
FIGURE 16.2 Process of synthesis of melatonin in the human body.
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Melatonin and the Brain
16.6 MELATONIN RECEPTORS
MT is readily soluble in both water and lipids. MT this property allows it to easily cross the
membranes. Recent studies showed that the cell nucleus is the site where MT is abundantly found
26]. Researchers observed during their in
vitro quantitative studies on MT agonist 2- iodomelatonin that MT receptors are present in the brain
and peripheral tissues [27].
MT is also found in many other tissues of the body, like veins, ovaries, small and large intestines,
28].
16.6.1 mt1 reCeptor
by blocking the adenylate cyclase enzyme in the target organ [26]. It is discovered in the cardiovas-
cular vessels, and it governs circadian rhythms and regulates vessel compression. The MT1 receptor
is recognized to be manufactured in sectors beyond the peripheral and brain tissue [29].
16.6.2 mt2 reCeptor
The enhancement of cardiovascular vessels is caused by a binding site involved in retinal human
They are almost always discovered in the hypothalamus, retina, kidney, and heart tissue [29].
16.6.3 mt3 reCeptor
MT3 receptor seems to be similar to the MT2 receptor. Its structure is 95% exactly equivalent to that
of the living thing quinone reductase 2 enzyme [30
The MT3 receptor’s action diminishes intraocular pressure by the ability to inhibit leukotriene-
induced leukocyte adhesion [31].
16.6.4 retinoiC aCid reCeptor- related orphan reCeptor (ror)
Nuclear hormone receptors (NRs) are a group of signal transduction factors that regulate meta-
estimated 13% of Approved drugs. RORa, RORb, and ROR are NR subgroups [32]. The most sig-
peripheral nerves. MT unites with RORs, uncovering its bioactivities. RORs also have immune and
metabolic regulatory oversight features [36]. RORs (particularly the RORa subtype) are essential
antioxidant properties by affecting transcription factors via RORs discovered in the cell nucleus.
MT is believed to have anti- neurodegenerative characteristics via ROR receptor sites due to these
characteristics [33].
16.7 MECHANISM OF ACTION OF MT
Light and dark exposure affects the secretion of MT, which in turn regulates the circadian rhythm
or the sleep- wake cycle. Apart from regulating other functions of the body like immune activity,
dreaming, fertility and reproduction, learning and memory, and mood control, the main function of
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Plant-based Foods and their Implications in Brain Health
MT is regulating the sleep- wake cycle. MT performs this activity by lowering the body temperature
and chemically causing drowsiness [34].
Although there are different pathways involved in MT functioning, the most popular one is
3]. It includes melatonin receptor 1 (MT1)
and melatonin receptor 2 (MT2). MT1 inhibits the cAMP signal transduction pathway by acting
on decreased or no activity of adenylate cyclase and activating phospholipase C, thus releasing
the arachidonate. MT receptors are expressed in multiple tissues of the body and are basically
G protein- coupled receptors. In the central nervous system (CNS), expression sites for MT 1
receptors include the suprachiasmatic nucleus (SCN), hippocampus, substantia nigra, cerebellum,
and central dopaminergic pathway. Apart from the aforementioned areas, MT1 is also expressed
in the retina, coronary circulation, aorta, immune system, skin, kidney, liver, gall bladder, ovary,
testis, and memory glands [35]. Similarly, the MT2 receptor expression area is mainly CNS. But
it is also found in cardiac, aortic, and coronary tissue, myometrium and granulose cells, lungs,
adipocytes, and duodenum. MT2 receptor binding with MT increases protein kinase C (PKC)
activity by affecting phospholipase C (PLC). It also hinders guanylyl cyclase activity by forming
cyclic guanosine monophosphate (cGMP) and decreasing the formation of cAMP by inhibiting
36].
Along with these pathway activities, melatonin also participates in some other intracellular actions.
It binds to cytosolic calmodulin on one hand and with two receptors of the Z retinoid nuclear
receptors family on the other hand and thus plays a role in immune modulation, different enzyme
summarized in Table 16.1 [37].
Nuclear hormone receptors i.e. ROR, belong to the transcription factor family [38]. It is located
in the brain and peripheral nervous system and helps in generating stress responses [39], regulating
metabolism and immune reaction after interacting with MT [40]. It also has a crucial role in circa-
of these RORs present in the cell nucleus [41].
MT also exerts some receptor- independent functions besides its receptor- dependent activities
[38]. These independent functions include reduction in free radical formation in mitochondria,
[1] (Table 16.1).
TABLE 16.1
Location, types, and properties of melatonin receptors [37]
Receptor Independent Receptor Dependent
Membrane (MT1, MT2) ROS and RNS like free radical
scavenging
Cytosol (Calmodulin) Nucleus (RZR, ROR)
Circadian modulation Ischaemia and repurfusion Enzyme regulation Antioxidant enzyme regulation
Sleep promotion Protection against UV radiation Immune modulation
Retinal physiology Ionizing radiation
Blood pressure modulation Drug toxicity
Seasonal reproduction Alcohol toxicity
Bone growth Heavy metal toxicity
*RZR: retinoid Z receptor, *ROS: reactive oxygen species, *ROR: retinoic acid orphan receptor, *RNS: reactive nitrogen
species, *MT1 & 2: melatonin receptor 1 & 2.
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Melatonin and the Brain
16.8 MELATONIN IN THE CENTRAL NERVOUS SYSTEM
MT regulation and synthesis and its synchronization in the human body are dependent upon and
42]. The dark period of the day allows
the release of MT, while the light period disseminates information through the central pacemaker
through the retinohypothelamic tract to inhibit MT synthesis by the retinohypothelamic pathway
[43
rhythm by producing its secretion in peaks throughout the 24 hr. These secretions are maximum
at night, particularly from 3 to 4 AM. This peak is at its lowest level at 6 to 7 AM in the morning.
MT secretion rises on a daily basis with a subsequent increase in sleep predisposition to occur.
-
ical changes in the body and brain, like lowering the mind's activity. Such sleep inclination
takes place about two hours with regard to the individual’s regular bedtime [44]. This rhythmic
secretion of MT by the brain is regulated by the suprachiasmatic nucleus (SCN) of the anterior
hypothalamus. MT is endogenously secreted by the pineal gland but in some quantity, it is also
synthesized by the eyes, skin, lymphocytes, bone marrow, thymus, and gastrointestinal tract.
The SCN is affected by light through retinal ganglion cells. The information from the eyes to the
SCN not only allows MT secretion but also delivers information to other areas of the brain regu-
lating pupil constriction and sleep induction [33]. Once information from melanopsins starts, it
then travels from the SCN to the pineal gland to the upper parts of cervical spinal cords, which
form the preganglionic part of the superior cervical ganglion (SCG) and possess sympathetic
chains. For the regulation of the pineal gland, norepinephrine is the most important neurotrans-
mitter [43]. SCN stimulated its release at night, while b1 adrenergic system blockers inhibit
MT secretion at night. Similarly, reduction in MT secretion level is also done by clonidine and
methylparatyrosine which inhibit presynaptic catecholamine. MT levels are elevated by using
catecholamine and neuropeptide Y. However, gamma- aminobutyric acid (GABA), glutamate,
and dopamine inhibit MT synthesis [45].
16.8.1 neuroproteCtive CapaCity
MT acts as a neuroprotective agent in multiple neurodegenerative diseases like amyotrophic lateral
sclerosis, Huntington’s disease, ischaemic brain injury, Parkinson’s disease and Alzheimer’s dis-
ease [45]. MT is also involved in maintaining proper balance and controlling body posture. It also
helps in brain development and prevents any adverse effects as a result of accidental damage to the
brain in the adult and prenatal stages since it is capable of crossing the blood- brain barrier and pla-
centa alike [34
-
action of its indole moiety with its receptors. These receptors, when activated, play a role in neur-
onal cell maintenance by either down- regulating the levels of brain- derived neurotrophic factor
(BDNF) [14]. In post- traumatic conditions, administration of MT individually, as well as with uri-
dine, results in decreasing brain oedema and lowering malondialdehyde levels. It also stimulates the
release of the blood- brain barrier and intracranial stresses, also the actions of superoxide dismutase
(SOD) and glutathione peroxidase (GPx).
The severity of 6- OHDA- induced Hemi- disease Parkinson’s can be reduced by increasing MT
bioavailability [16]. MT wants to treat these maladies by affecting cells by initiating several signal
pathways and blocking intrinsic apoptotic pathways [3]. MT has an impressive neuroprotective
part in decreasing cognitive impairment caused by sleep deprivation (SD), as well as restoring the
number of oxidative stress markers such as SOD and melonaldehyde (MDA) as well as NO activity
[46]. Figure 16.3
pipeline.