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Melatonin abstracts

Melatonin Abstracts

Melatonin maintains mitochondrial membrane potential and attenuates activation of initiator (casp-9)
and effector caspases (casp-3/casp-7) and PARP in UVR-exposed HaCaT keratinocytes
T. W. Fischer, M. A. Zmijewski,J. Wortsman and A. Slominski, J. Pineal Res. 2008; 44:397–407

Melatonin is a recognized antioxidant with high potential as a protective agent in many conditions related
to oxidative stress such as neurodegenerative diseases, ischemia/reperfusion syndromes, sepsis and aging.
These processes may be favorably affected by melatonin through its radical scavenging properties and/or
antiapoptotic activity. Also, there is increasing evidence that these effects of melatonin could be relevant in
keratinocytes, the main cell population of the skin where it would contribute to protection against damage
induced by ultraviolet radiation (UVR). We therefore investigated the kinetics of UVR-induced apoptosis in
cultured keratinocytes characterizing the morphological and mitochondrial changes, the caspases-
dependent apoptotic pathways and involvement of poly(ADPribose) polymerase (PARP) activation as well
as the protective effects of melatonin. When irradiated with UVB radiation (50 mJ/cm2), melatonin treated,
cultured keratinocytes were more confluent, showed less cell blebbing, more uniform shape and less
nuclear condensation as compared to irradiated, nonmelatonin-treated controls. Preincubation with
melatonin also led to normalization of the decreased UVR-induced mitochondrial membrane potential.
These melatonin effects were followed by suppression of the activation of mitochondrial pathway-related
initiator caspase 9 (casp-9), but not of death receptor-dependent casp-8 between 24 and 48 hr after UVR
exposure. Melatonin down-regulated effector caspases (casp-3/casp-7) at 24–48 hr post-UV irradiation and
reduced PARP activation at 24 hr. Thus, melatonin is particularly active in UV-irradiated keratinocytes
maintaining the mitochondrial membrane potential, inhibiting the consecutive activation of the intrinsic
apoptotic pathway and reducing PARP activation. In conclusion, these data provide detailed evidence for
specific antiapoptotic mechanisms of melatonin in UVR-induced damage of human keratinocytes.

The cutaneous serotoninergic / melatoninergic system: securing a place under the sun

Andrzej Slominski, Jacobo Wortsman and Desmond J. Tobin, FASEB J. 19, 176-194 (2005)

It was recently discovered that mammalian skin can produce serotonin and transform it into melatonin.
Pathways for the biosynthesis and biodegradation of serotonin and melatonin have been characterized in
human and rodent skin and in their major cellular populations. Moreover, receptors for serotonin and
melatonin receptors are expressed in keratinocytes, melanocytes, and fibroblasts and these mediate
phenotypic actions on cellular proliferation and differentiation. Melatonin exerts receptor-independent
effects, including activation of pathways protective of oxidative stress and the modification of cellular
metabolism. While serotonin is known to have several roles in skin-e.g., proedema, vasodilatory,
proinflammatory, and pruritogenic-melatonin has been experimentally implicated in hair growth cycling,
pigmentation physiology, and melanoma control. Thus, the widespread expression of a cutaneous
seorotoninergic/melatoninergic syste,m(s) indicates considerable selektivity of action to facilitate intra-,
auto-, or paracrine mechanisms that define and influence skin function in a highly compartmentalized
manner. Notably, the cutaneous melatoninergic system is organized to respond to continuous stimulation
in contrast to the pineal gland, which (being insulated from the external environment) responds to
discontinuous activation by the circadian clock. Overall, the cutaneous serotoninergic/melatoninergic
system could counteract or buffer external (environmental) or internal stresses to preserve the biological
integrity of the organ and to maintain its homeostasis.
Constitutive and UV-induced metabolism of melatonin in keratinocytes and cell-free systems

Fischer T. W., Sweatman T. W., Semak L., Sayre R. M., Wortsman J. and Slominski A., FASEB J. 20, E897-E907
Melatonin, which can be produced in the skin, exerts a protective effect against damage induced by UV
radiation (UVR). We have investigated the effect of UVB, the most damaging component of UVR, on
melatonin metabolism in HaCaT keratinocytes and in a cell-free system. Four metabolites were identified
by HPLC and LC-MS: 6-hydroxymelatonin, N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK), 2-
hydroxymelatonin (the main intermediate between melatonin and AFMK), and 4- hydroxymelatonin.
Concentrations of these photoproducts were directly proportional to UVR-dose and to melatonin substrate
content, and their accumulation was time-dependent. The UVR-dependent increase of AFMK and 2-
hydroxymelatonin was also detected in keratinocytes, where it was accompanied by simultaneous
consumption of intracellular melatonin. Of note, melatonin and its two major metabolites, 2-
hydroxymelatonin and AFMK, were also detected in untreated keratinocytes, neither irradiated nor
preincubated with melatonin. Thus, intracellular melatonin metabolism is enhanced under exposure to
UVR. The additional biological activity of these individual melatonin metabolites increases the spectrum of
potential actions of the recently identified cutaneous melatoninergic system.

Melatonin reduces UV-induced reactive oxygen species in a dose-dependent manner in IL-3-stimulated

Fischer TW, Scholz G, Knoll B, Hipler UC, Elsner P., J Pineal Res. 2001 Aug;31(1):39-45.

Reactive oxygen species (ROS) are presumed to be involved in inflammatory UV reactions of the skin. This
in vitro study was performed to investigate the suppressive effect of melatonin in interleukin-3 (IL-3)
stimulated leukocytes. Neutrophilic granulocytes were isolated from EDTA-treated whole blood and placed
in a phosphate-buffered saline (PBS) containing IL-3. Cell suspensions were either treated with PBS
(control) or with increasing doses of melatonin (0.1, 0.5, 1, 2, 3, 5, 7.5, 10 mmol). One PBS solution was left
unirradiated and the other nine solutions (PBS and melatonin) were irradiated with 750 mJ/cm2 UVB light
(280-360 nm, max: 310 nm). Radical formation was measured by the chemiluminescence technique. UV-
irradiated leukocytes showed a 5-fold higher radical formation than unirradiated leukocytes. Melatonin, in
increasing doses in powers of ten, led to a maximum 030309 - 3 - suppression of free radicals at 10 nmol
(P= 0.01) and 1 mmol melatonin (P= 0.001), showing a biphasic, non-linear, dose response relationship.
Melatonin, given in amounts of 0.1-10 mmol, led to a direct dose-dependent suppression of ROS. Radical
formation was suppressed significantly in a range from 0.5 to 10 mmol (P= 0.001). Melatonin is known to
function as a radical scavenger and antioxidant; some of these melatonin effects may be receptor
independent, while others may be receptor dependent.

Melatonin suppresses reactive oxygen species induced by UV irradiation in leukocytes

Fischer TW, Scholz G, Knoll B, Hipler UC, Elsner P., J Pineal Res. 2004 Sep;37(2):107-12.

An investigation of the antioxidative UV protective effect of melatonin was performed in an in vitro
irradiation model with leukocytes. Leukocytes were isolated from EDTA-treated whole blood and taken up
in phosphate-buffered saline (PBS). Five of 10 aliquots were incubated with 2 mmol/L melatonin and 5 with
PBS as a control. The samples were irradiated by UV light (280-360 nm, max: 310 nm) at doses between 75
and 300 mJ/cm(2) or left unirradiated. Radical formation was measured using the chemiluminescence
technique. Staining with trypan blue was performed to assess cell viability. Melatonin significantly
suppressed radical formation in cell solutions irradiated from 75 to 300 mJ/cm(2) (P </= 0.001). Controls
showed an increase of reactive oxygen species (ROS) formation as a sign of oxidative stress when irradiated
with increasing UV doses and a maximum ROS formativ under 300 mJ/cm(2) UV light. The cytotoxicity of
UV light was reduced by melatonin up to a UV dose of 1.5 J/cm(2). Leukocytes were suitable cells for the
evaluation of the efficacy of melatonin as a radical scavenger under UV light. The results confirm that the
clinically observed UV protective effects of melatonin may be at least partially based on its radical
scavenging properties.

Melatonin increases survival of HaCaT keratinocytes by suppressing UV-induced apoptosis

Fischer TW, Zbytek B, Sayre RM, Apostolov EO, Basnakian AG, Sweatman TW, Wortsman J, Elsner P,
Slominski A., J Pineal Res. 2006 Jan;40(1):18-26.

Melatonin is a potent antioxidant and direct radical scavenger. As keratinocytes represent the major
population in the skin and UV light causes damage to these cells, the possible protective effects of
melatonin against UV-induced cell damage in HaCaT keratinocytes were investigated in vitro. Cells were
preincubated with melatonin at graded concentrations from 10(-9) to 10(-3) m for 30 min prior to UV
irradiation at doses of 25 and 50 mJ/cm2. Biological markers of cellular viability such as DNA synthesis and
colony-forming efficiency as well as molecular markers of apoptosis were measured. DNA synthesis was
determined by [3H]-thymidine incorporation into insoluble cellular fraction, clonogenicity through plating
efficiency experiments and apoptosis by the terminal deoxynucleotidyl transferase-mediated dUTP nick-
end labeling (TUNEL) assay. DNA synthesis experiments showed a strong protective effect by preincubation
with melatonin at concentrations of 10(-4) m (P < 0.01) and 10(-3) m (P < 0.001). Additional postirradiation
treatment with melatonin showed no increase in the pre-UV incubation protective effect. These results
indicate that preincubation is a requirement for melatonin to exert its protective effects. The mechanism of
melatonin's protective effect (10(-6) to 10(-3) m) includes inhibition of apoptosis as measured by TUNEL
assay. Moreover, the biological significance of these effects is supported by clonogenic studies showing a
significantly higher number of colonies in cultures treated with melatonin compared to controls. Thus,
pretreatment with melatonin led to strong protection against UVB-induced damage in keratinocytes.

HaCaT cell proliferation influenced by melatonin

Hipler U.C., Fischer T.W. and Elsner P., Skin Pharmacol Appl Skin Physiol, 16, 379-385 (2003)

The hormone melatonin is characterized by numerous pharmacological effects. The influence of melatonin
on the growth of the human hair follicle was shown in previous investigations. In the present study, the
effects of melatonin were investigated by means of proliferation tests of HaCaT keratinocytes using the
[3H]thymidine incorporation, a fluorescence assay with Hoechst dye 33342 and the ATP bioluminescence
assay. The aim of the study was to find melatonin concentrations suitable for treatments of the skin and
whether there is a cytotoxic effect on HaCaT cells. The different proliferative activity of melatonin
depending on its concentration and the time of incubation could be shown in all investigations.

A review of the evidence supporting melatonin's role as an antioxidant

Reiter R. J., Melchiorri D., Sewerynek E., Poeggeler B., Barlow-Walden L., J. Chuang J., Ortiz G. G., and Cuna-
Castroviejo D., J Pineal Res 18, no. 1:1-11 (1995)

This survey summarizes the findings, accumulated within the last 2 years, concerning melatonin's role
in defending against toxic free radicals. Free radicals are chemical constituents that have an unpaired
electron in their outer orbital and, because of this feature, are highly reactive. Inspired oxygen, which
sustains life, also is harmful because up to 5% of the oxygen (O2) taken in is converted to oxygen-free
radicals. The addition of a single electron to O2 produces the superoxide anion radical (O2-.); O2-. Is
catalytic-reduced by superoxide dismutase, to hydrogen peroxide (H2O2). Although H2O2 is not itself a free
radical, it can be toxic at high concentrations and, more importantly, it can be reduced to the hydroxyl
radical (.OH). The .OH is the most toxic of the oxygen-based radicals and it wreaks Harc within cells,
particularly with macromolecules. In recent in vitro studies, melatonin was shown to be a very efficient
neutralizer of the .OH; indeed, in the system used to test its free radical scavenging ability it was found to
be significantly more effective than the well known antioxidant, glutatione (GSH), in doing so. Likewise,
melatonin has been shown to stimulate glutathione peroxidase (GSHPx) activity in neural tissue; GSH-PX
metabolizes reduced glutathione to its oxidized form and in doing so it converts H2O2 to H2O, thereby
reducing generation of the .OH by eliminating its precursor. More recent studies have shown that
melatonin is also a more efficient scavenger of the peroxyl radical than is vitamin E. The peroxyl radical is
generated during lipid peroxidation and propagates the chain reaction that leads to massive lipid
destruction in cell membranes. In vivo studies have demonstrated that melatonin is remarkably potent in
protecting against free radical damage induced by a variety of means. Thus, DNA damage resulting from
either the exposure of animals to the chemical karcinogen safrole or to ionizing radiation is markedly
reduced when melatonin is co-administered. Likewise, the induction of cataracts, generally accepted as
being a consequence of free radical attack on lenticular macromolecules, in newborn rats injected with a
GSH-depleting drug are prevented when the animals are given daily melatonin injections. Also, paraquat-
induced lipid peroxidation in the lungs of rats is overcome when they also receive melatonin during the
exposure period. Paraquat is a highly toxic herbicide that inflicts at least part of its damage by generating
free radicals.
Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant
and free radical scavenger

Tan DX, Reiter RJ, Manchester LC, Yan MT, El-Sawi M, Sainz RM, Mayo JC, Kohen R, Allegra M, Hardeland R.,
Curr Top Med Chem. 2002 Feb;2(2):181-97.

Melatonin was found to be a potent free radical scavenger in 1993. Since then over 800 publications have
directly or indirectly confirmed this observation. Melatonin scavenges a variety of reactive oxygen and
nitrogen species including hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide and
peroxynitrite anion. Based on the analyses of structure-activity relationships, the indole moiety of the
melatonin molecule is the reactive center of interaction with oxidants due to its high resonance stability
and very low activation energy barrier towards the free radical reactions. However, the methoxy and amide
side chains also contribute significantly to melatonin's antioxidant capacity. The NC=O structure in the C3
amide side chain is the functional group. The carbonyl group in the structure of N-C=O is key for melatonin
to scavenge the second reactive species and the nitrogen in the N-C=O structure is necessary for melatonin
to form the new five membered ring after melatonin's interaction with a reactive species. The methoxy
group in C5 appears to keep melatonin from exhibiting prooxidative activity. If the methoxy group is
replaced by a hydroxyl group, under some in vitro conditions, the antioxidant capacity of this molecule may
be enhanced. However, the cost of this change are decreased lipophility and increased prooxidative
potential. Therefore, in in vivo studies the antioxidant efficacy of melatonin appears to be superior to its
hydroxylated counterpart. The mechanisms of melatonin's interaction with reactive species probably
involves donation of an elektron to form the melatoninyl cation radical or through an radical addition at the
site C3. Other possibilities include hydrogen donation from the nitrogen atom or substitution at position
C2, C4 and C7 and nitrosation. Melatonin also has the ability to repair damaged biomolecules as shown by
the fact that it converts the guanosine radical to guanosine by electron transfer. Unlike the classical
antioxidants, melatonin is devoid of prooxidative activity and all known intermediates generated by the
interaction of melatonin with reactive species are also free radical scavengers. This phenomenon is defined
as the free radical scavenging cascade reaction of the melatonin family. Due to this cascade, one melatonin
molecule has the potential to scavenge up to 4 or more reactive species. This makes melatonin very
effective as an antioxidant. Under in vivo conditions, melatonin is often several times more potent than
vitamin C and E in protecting tissues from oxidative injury when compared at an equivalent dosage
(micromol/kg). Future research in the field of melatonin as a free radical scavenger might be focused on: 1),
signal transduction and antioxidant enzyme gene expression induced by melatonin and its metabolites, 2),
melatonin levels in tissues and in cells, 3), melatonin structure modifications, 4), melatonin and its
metabolites in plants and, 5), clinical trials using melatonin to treat free radiál related diseases such as
Alzheimer's, Parkinson's, stroke and heart disease.

Melatonin: a principal neuroimmunoregulatory and anti-stress hormone: its anti-aging effects.

Pierpaoli W, Maestroni GJ. Immunol Lett. 1987 Dec; 16(3-4):355-61

Major environmental variables such as daily and seasonal changes of light and temperature regulace the
daily circadian variations of synthesis and release of the pineal neurohormone N-acetyl-5-
methoxytryptamine (melatonin). Melatonin has now been shown to be a potent immunoregulatory agent,
and to be able to antagonize the immunosuppressive effects of acute anxiety stress in mice, as measured
by antibody production, by thymus weight, and by the capacity of stressed- and mening melatonin-treated
mice to react against a lethal virus. Both psychogenic factors and infectious agents such as viruses can act
as "stressors" and induce an immunosuppression. Their combination is a determinant for the course of
infectious diseases and, perhaps, cancer. Circadian (evening) melatonin possesses thus the singular ability
to up-regulate the immunosuppression of stressed mice. This effect of melatonin is not exerted directly on
immunocompetent cells, but mediated via the endogenous opioid system upon antigen-activation of T
cells. Melatonin being a short-lived hormone with negligible side-effects which is rapidly degraded and
eliminated by the body, the use of melatonin offers a new approach to the physiological control of stress
and stress-related infectious diseases. In addition, melatonin could be used for the potentiation of primary
immunization (vaccination) against antigens of the most varied nature which do not evoke a robust or
longlasting secondary (memory) response. The regulatory function of pineal melatonin is discussed also in
relation to hematopoiesis, to its oncostatic effects, and to its possible dual role in reproduction physiology
and generation of immunocompetence and tolerance during ontogeny.

Melatonin in the skin: synthesis,metabolism and functions

Andrzej Slominski, Desmond J. Tobin, Michal A. Zmijewski, Jacobo Wortsman and Ralf Paus, Trends in
Endocrinology and Metabolism Vol. 1, Elsevier (Review 2007)
Melatonin, a ubiquitous methoxyindole, is produced by and metabolized in the skin. Melatonin affects skin
functions and structures through actions mediated by cell-surface and putative-nuclear receptors
expressed in skin cells. Melatonin has both receptor-dependent and receptor-independent effects that
protect against oxidative stress and can attenuate ultraviolet radiationinduced damage. The widespread
expression and pleiotropic activity of the cutaneous melatoninergic system provides for a high level of cell-
specific selectivity. Moreover, intra-, auto- and para-crine mechanisms equip this system with exquisite
functional selectivity. The properties of endogenous melatonin suggest that this molecule is an important
effector of stress responses in the skin. In this way, melatonin actions may counteract or buffer both
environmental and endogenous stressors to maintain skin integrity.
Melatonin increases anagen hair rate in women with androgenetic alopecia or difuse alopecia: results of
a pilot randomized controlled trial

Department of Dermatology and Allergology, Friedrich-Schiller-University, Erfurter Straße 35, D-07740 Jena,
Germany, *ASAT Applied Science and Technology, Zug, Switzerland, British Journal of Dermatology 2004;
150: 341 -345

In addition to the well-known hormonal influences of testosterone and dihydrotestosterone on the hair
cycle, melatonin has been reported to have a beneficial effect on hair growth in animals. The effect of
melatonin on hair growth in humans has not been investigated so far.

To examine whether topically applied melatonin influences anagen and telogen hair rate in women with
androgenetic or diffuse hair loss.

A double-blind, randomized, placebo-controlled study was conducted in 40 women suffering from diffuse
alopecia or androgenetic alopecia. A 0,1% melatonin or a placebo solution was applied on the scalp once
daily for 6 months and trichograms were performed to assess anagen and telogen hair rate. To monitor
effects of treatment on physiological melatonin levels, blood samples were taken over the whole study

Melatonin led to a significantly increased anagen hair rate in occipital hair in women with androgenetic hair
loss compared with placebo (n = 12; P = 0.012). For frontal hair, melatonin gave a significant increase in the
group with diffuse alopecia (n = 28; P = 0.046). The occipital hair samples of patients with diffuse alopecia
and the frontal hair counts of those with androgenetic alopecia also showed an increase of anagen hair, but
differences were not significant. Plasma melatonin levels increased under treatment with melatonin, but
did not exceed the physiological night peak.

To the authors’ knowledge, this pilot study is the first to show that topically applied melatonin might
influence hair growth in humans in vivo. The mode of action is not known, but the effect might result from
an induction of anagen phase.


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