Transcript Hormonal regulation and circadian rhytms

Hormonal regulation and
circadian rhytms
Alice Skoumalová
Central and peripheral clocks in mammals
Organized in a hierarchical manner
Central oscillator:
Peripheral oscillators :
 controls the behavioral rhythm
 slave oscillators
 reset by external light signal
 regulate local rhythms
 reset by feeding
A model for feedback loops of mammalian
circadian clock
External synchronization of the SCN to light-dark cycles
A circadian rhytm is 24-hour cycle in the physiological
processes of living beings:
 Circadian rhytms are endogenously generated; modulated by external
signals (day/night rhytm)
 Circadian rhytms - brain wave activity, hormone production, cell
regeneration and other biological activities linked to this daily cycle
Regulation of a circadian rhytm
1. The information about illumination from the retina (retinal ganglion cells with
melanopsin); the retinohypothalamic tract
2. The circadian "clock" in the suprachiasmatic nucleus (SCN)
3. The SCN interprets the information on day lenght and passes it on to the
pineal gland which then secretes the hormone melatonin (secretion of
melatonin peaks at night)
Melatonin participates in various physiological functions according to 24-hour
cycle
Melatonin:
 Ubiquitously in nature (one of the most phylogenetically ancient of all
biological signaling mechanisms)
 A potent antioxidant (its primary function)
Melatonin is involved in various physiological functions:
Circadian rhytm regulation, sleep propensity, control of sleep/wake rhytm, blood
pressure regulation, immune function, retinal functions, detoxification of free
radicals, control of tumor growth, bone protection, the regulation of
bicarbonate secretion in the GI tract
Melatonin is primarily secreted by the pineal gland; synthesis also occurs
in other cells and organs
Melatonin secretion is synchronized to the light/dark cycle, with a
nocturnal maximum
Exogenous administration
Circadian rhytm sleep disorders (CRSD), insomnia, cancer, neurodegenerative
diseases, disorders of the immune function, oxidative damage
Melatonin in plants
 in high concentrations (protection from oxidative damage)
 many plants represent an excellent dietary source of melatonin as an
antioxidant nutrient
The majority of herbs used in traditional Chinese medicine for retarding agerelated changes and for treating diseases associated with the generation of
free radicals contain the highest levels of melatonin
Melatonin synthesis
The pineal gland
The retina
Lymphocytes
The GI tract
Bone marrow cells
Platelets
Skin
Serotonin N transferase: the rate-limiting enzyme
Pineal melatonin production exhibits a circadian rhytm
 low level during daytime, high level during night
The retinohypothalamic tract: the regulation of pineal melatonin biosynthesis
The retina→The suprachiasmatic nucleus (SCN) →The spinal cord (intermediolateral
horn cells) →The superior cervical ganglion→The pineal gland
Melatonin metabolism
 Melatonin is not stored; diffuses out into the capillary blood
and cerebrospinal fluid
In the liver: melatonin is first hydroxylated to 6-hydroxymelatonin
(by cytochrome P450 mono-oxygenases) and conjugated with sulfate
In the pineal gland and the retina: melatonin can be deacetylated
to 5-methoxytryptamine (by melatonin-deacetylating enzymes)
Melatonin can be metabolized
nonenzymatically:
In all cells: It is converted into cyclic 3hydroxymelatonin when it directly
scavenges two hydroxyl radicals (OH•)
In the brain: a substantial fraction of
melatonin is metabolized to kynuramine
derivates (the kynuric pathway)
The kynuramine derivates- the antioxidant
and anti-inflammatory properties
1. N-acetyl-N-formyl-5-methoxykynuramine
(AFMK)
2. N-acetyl-5-methoxykynuramine (AMK)
Melatonin exerts actions in almost every cell in the body
1. Melatonin receptors-receptor mediated effects
2. Melatonin diffuses through membranes easily-receptor
independent effects
Melatonin produces effects in:
Receptor-independent:
1. Free radical scavenging properties
2. Inhibition of calmodulin
-an attenuation of cAMP-dependent signaling cascades
-decrease ER binding and activation of ERE-containing genes
3. Regulation of the quinone reductase 2 activity
Receptor-dependent:
1. G-protein coupled receptors (MT1 or MT2)
- an attenuation of cAMP-dependent signaling cascades
- inhibition of ER
2. The mitogen activated protein kinase cascade (MEK/ERK)
Melatonin
Scavenging of reactive oxygen
species (ROS), reactive nitrogen
species (RNS) and organic
radicals
MT1, MT2
Circadian pacemaker:
suprachiasmatic nucleus
Seasonal breeding
(hypothalamus and other
organs relevant to
reproduction)
Immune system (B cells, T
cells, NK cells, thymocytes,
bone marrow)
Vasomotor control:
constriction via MT1 dilation
via MT2
Quinone reductase
2 (MT3)
CNS: antiexcitatory
effects, avoidance of Ca2+
overload
Elimination of toxic
quinones
Cytoskeletal effects: binding
to calmodulin, activation of
protein kinase C
Direct inhibition of
mitochondrial permeability
transition pore opening
Prevention of
apoptosis
Upregulation of antioxidant
and downregulation of
prooxidant enzymes
Attenuation of
mitochondrial electron
leakage
Decrease of free radicals
and other oxidants
Melatonin as an antioxidant
More efficient than other antioxidants; devoid of pro-oxidant side-effects
1. Scavenging of free radicals
2. Up-regulation of antioxidant enzymes
3. Direct inhibition of free radical formation

Neurodegenerative diseases (Alzheimer‘s, Parkinson‘s and Huntington‘s
disease) - potential role of melatonin
Melatonin as an oncostatic substance
Melatonin inhibits the carcinogenesis
1. Antioxidant activity
2. Modulation of the estrogen signalling pathway


Melatonin has demonstrated oncostatic effects against a variety of
tumor cells: estrogen-positive breast cancer cell lines, ovarian carcinoma
cell lines, endometrial carcinoma, human uveal melanoma cells, prostate
tumor cells, intestinal tumors
Melatonin ameliorates side effects of antitumoral therapeutic regimens
(myelotoxicity, lymphocytopenia)
Melatonin‘s immunomodulatory function
Melatonin has an immunomodulatory role
1. Enhances the production of cytokines
2. Antiapoptotic and antioxidant actions
3. Direct effect on the regulation of the immune system (via receptors)


Inhibition of melatonin synthesis results in the attenuation of cellular
and humoral responses: exogenous melatonin counteracts
immunodeficiences
The role of melatonin in the pathogenesis of autoimmune diseases: the
increased prevalence of auto-immune diseases at winter (long nights,
increased levels of melatonin)
Melatonin as a hypnotic
Melatonin promotes sleep in healthy humans
MT1 receptors in SCN
 The treatment of insomnia (particularly in individuals with melatonin
deficiency)
Melatonin as a chronobiotic molecule
Melatonin acts as an endogenouos synchronizer of bodily rhythms
MT2 receptors in SCN
 Implication in circadian rhythm sleep disorders
1. Shift-work disorder
2. Jet lag syndrom
3. Delayed sleep phase syndrome
4. Circadian rhythm disruption with ageing
Melatonin in depression
Altered levels and phase-shift of melatonin in depressed patients
MT1 receptors in the brain
 Melatonin has the potential value of being used as a therapeutic agent
in the treatment of mood disorders
Agomelatine (a melatonin agonist) has been tested in clinical studies
as a novel melatonergic antidepressant
GI melatonin
Melatonin is synthesized in the enterochromaffin cells of the GI tract and can
be released to the circulation
Functions in the GIT:
1. Increase duodenal mucosal secretion of bicarbonate - duodenal
protection against gastric acid
2. High concentration in the bile-prevents oxidative damage to the
intestinal epithelium caused by bile acids
3. Gastroprotective efficacy: as an antioxidant
Melatonin in cardiovascular diseases
Melatonin reduces blood pressure in hypertensive patients
1. Peripheral mechanism: vasodilatation via MT2
vasoconstriction via MT1 (cerebral vessels)
2. Central mechanism
Melatonin effects on bone
Melatonin causes inhibition of bone resorption (protects bone during treatment
with gluococorticoids that affect bone remodeling and cause osteoporosis)
1. Down-regulation of osteoclast activation
2. Direct inhibition of osteoclast function (antioxidant)
Melatonin in sexual maturation and in reproduction
1. Via MT receptors
2. Via nuclear receptors
 Melatonin inhibits the hypothalamic-pituitary-gonadal axis (important
for sexual maturation)
The decline in melatonin concentration is very important for the
initiation of puberty
 Melatonin down-regulates GnRH gene in a cyclicyl pattern over a 24-h
period; the pulsatile secretion of GnRH controls LH a FSH
Summary
 Melatonin is distributed widely in nature; it acts as a photoperiod messenger
molecule, transducing photoperiod changes to various cyclic function in
organism (reproduction, sleep-wake rhythms)
 Melatonin is very important antioxidant (primary function in evolution)
 Melatonin influences various cell mechanisms via receptors (plasmatic,
nuclear)
 Melatonin play a role in many pathological states: neurodegenerative
disorders, circadian rhythm sleep disorders, depression, cardiovascular
diseases, tumor growth, immune pathologies, bone resorption (potential
therapeutic agent)