Hormonal regulation and circadian rhytms

Alice Skoumalová

Central and peripheral clocks in mammals

Organized in a hierarchical manner

Central oscillator:

controls the behavioral rhythm

reset by external light signal

Peripheral oscillators :

slave oscillators

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 rhytm1. The information about illumination from the retina (retinal ganglion cells with

melanopsin); the retinohypothalamic tract2. 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 administrationCircadian 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 age-related changes and for treating diseases associated with the generation of free radicals contain the highest levels of melatonin

Melatonin synthesis

Serotonin N transferase: the rate-limiting enzyme

The pineal gland

The retina

Lymphocytes

The GI tract

Bone marrow cells

Platelets

Skin

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 3-hydroxymelatonin 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

Circadian pacemaker: suprachiasmatic nucleus

Seasonal breeding (hypothalamus and other

organs relevant to reproduction)

Vasomotor control: constriction via MT1 dilation

via MT2

Immune system (B cells, T cells, NK cells, thymocytes,

bone marrow)

Scavenging of reactive oxygen species (ROS), reactive nitrogen

species (RNS) and organic radicals

Elimination of toxic quinones

CNS: antiexcitatory effects, avoidance of Ca2+

overload

Cytoskeletal effects: binding to calmodulin, activation of

protein kinase C

Upregulation of antioxidant and downregulation of prooxidant enzymes

Attenuation of mitochondrial electron

leakage

Decrease of free radicals and other oxidants

Prevention of apoptosis

Direct inhibition of mitochondrial permeability

transition pore opening

MT1, MT2

Quinone reductase 2 (MT3)

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)