Melatonin: A Cutaneous Perspective on its Production, Metabolism, and Functions.

Melatonin, an evolutionarily ancient derivative of serotonin with hormonal properties, is the main neuroendocrine secretory product of the pineal gland. Although melatonin is best known to regulate circadian rhythmicity and lower vertebrate skin pigmentation, the full spectrum of functional activities of this free radical-scavenging molecule, which also induces/promotes complex antioxidative and DNA repair systems, includes immunomodulatory, thermoregulatory, and antitumor properties. Because this plethora of functional melatonin properties still awaits to be fully appreciated by dermatologists, the current review synthesizes the main features that render melatonin a promising candidate for the management of several dermatoses associated with substantial oxidative damage. We also review why melatonin promises to be useful in skin cancer prevention, skin photo- and radioprotection, and as an inducer of repair mechanisms that facilitate the recovery of human skin from environmental damage. The fact that human skin and hair follicles not only express functional melatonin receptors but also engage in substantial, extrapineal melatonin synthesis further encourages one to systematically explore how the skin's melatonin system can be therapeutically targeted in future clinical dermatology and enrolled for preventive medicine strategies.

Profiles of gonadotropin-inhibitory hormone and melatonin during the sex change and maturation of cinnamon clownfish, Amphiprion melanopus.

The present study aimed to determine the relationship between melatonin and gonadotropin-inhibitory hormone (GnIH) and their effect on reproduction in cinnamon clownfish, Amphiprion melanopus. Accordingly, we investigated the expression pattern of GnIH, GnIH receptor (GnIH-R), and melatonin receptor (MT-R1) mRNA and protein, as well as the plasma levels of melatonin, during sex change in cinnamon clownfish. We found that GnIH and MT-R1 mRNA and melatonin activity were higher in fish with mature brain than in fish with developing gonads, and using double immunofluorescence staining, we found that both GnIH and MT-R1 proteins were co-expressed in the hypothalamus of cinnamon clownfish. These findings support the hypothesis that melatonin plays an important role in the negative regulation of maturation and GnIH regulation during reproduction.

Melatonin enhances chondrogenic differentiation of human mesenchymal stem cells.

Intramembranous ossification and endochondral ossification are two ways through which bone formation and fracture healing occur. Accumulating amounts of evidence suggests that melatonin affects osteoblast differentiation, but little is known about the effects of melatonin on the process of chondrogenic differentiation. In this study, the effects of melatonin on human mesenchymal stem cells (MSCs) undergoing chondrogenic differentiation were investigated. Cells were induced along chondrogenic differentiation via high-density micromass culture in chondrogenic medium containing vehicle or 50 nm melatonin. Histological study and quantitative analysis of glycosaminoglycan (GAG) showed induced cartilage tissues to be larger and richer in GAG, collagen type II and collagen type X in the melatonin group than in the untreated controls. Real-time RT-PCR analysis demonstrated that melatonin treatment significantly up-regulated the expression of the genes involved in chondrogenic differentiation, including aggrecan (ACAN), collagen type II (COL2A1), collagen type X (COL10A1), SRY (sex-determining region Y)-box 9 (SOX9), runt-related transcription factor 2 (RUNX2) and the potent inducer of chondrogenic differentiation, bone morphogenetic protein 2 (BMP2). And the expression of melatonin membrane receptors (MT) MT1 and MT2 were detected in the chondrogenic-induced-MSCs by immunofluorescence staining. Luzindole, a melatonin receptor antagonist, was found to partially block the ability of melatonin to increase the size and GAG synthesis of the induced cartilage tissues, as well as to completely reverse the effect of melatonin on the gene expression of ACAN, COL2A1, COL10A1, SOX9 and BMP2 after 7 days of differentiation. These findings demonstrate that melatonin enhances chondrogenic differentiation of human MSCs at least partially through melatonin receptors.

Melatonin and hypothalamic-pituitary-gonadal axis.

Melatonin (N-acetyl-5-methoxy-tryptamine), a principal product of the pineal gland, is produced mainly during the dark phase of the circadian cycle. This hormone plays a crucial role in the regulation of circadian and seasonal changes in various aspects of physiology and neuroendocrine functions. In mammals, melatonin can influence sexual maturation and reproductive functions via activation of its receptors and binding sites in the hypothalamic-pituitary-gonadal (HPG) axis. This review summarizes current knowledge of melatonin on the hypothalamus, pituitary gland, and gonads. We also review recent progress in clinical applications of melatonin or potentials of using melatonin, as a reducer of oxidative stress, to improve reproductive functions for the diseases such as women infertility.

Efficient synthesis of [¹¹C]ramelteon as a positron emission tomography probe for imaging melatonin receptors involved in circadian rhythms.

Ramelteon (TAK-375) is a novel melatonin receptor agonist that is used for clinical treatment of insomnia. The present report describes radiolabeling of ramelteon with the short-lived positron-emitter ¹¹C (T(1/2)=20.4 min) by 2 methods. One method was [¹¹C]methylation of an acetoamide precursor and the other was [¹¹C]acylation of the corresponding amine precursor. First, [¹¹C]methylation method showed the low reproducibility together with the production of many kinds of side products from which the [¹¹C-methyl]Ramelteon was separated with chemical purity of <28% and radiochemical purity of >98%. Whereas, the [¹¹C]acylation method showed high efficiency and reproducibility with a good radiochemical yield (22-43%, decay corrected), high chemical and radiochemical purities (>99% each), and high specific activity (43-162 GBq/µmol) (n=5) after HPLC purification. [¹¹C]Ramelteon is a potential positron emission tomography (PET) probe for imaging the melatonin receptor.

Autophagy upregulation and loss of NF-kappaB in oxidative stress-related immunodeficient SAMP8 mice.

Aged spleens from senescence-accelerated prone mice 8 (SAMP8) and senescence-accelerated resistant mice 1 (SAMR1) were examined to determine whether sex or melatonin had an effect on oxidative stress-related immune impairments. We observed that the immunosenescence of SAMP8 mice was associated with a redox imbalance, leading to an age-related increase in oxidative damage, resulting from a decrease in antioxidant defense and protease activity. Moreover, increased apoptotic cell death, a decrease in proliferative activity and the loss of NF-kappaB activation were also related to the immunodeficiency seen in SAMP8 compared to SAMR1 mice. Females demonstrated higher oxidative stress-related alterations in the immune response, and subsequent, melatonin treatment provided the best protective effects. Pathways involved in autophagy were upregulated in SAMP8 as an adaptive response to oxidative stress, in an attempt to rescue the cell from increased apoptosis and age-related immunodeficiency. However, the NF-kappaB signaling and autophagic processes were unaffected by treatment with melatonin. Therefore, we propose a key role for NF-kappaB signaling and autophagy in the oxidative stress-related immunosenescent spleens of SAMP8 mice.

Melatonin and the ovary: physiological and pathophysiological implications.

OBJECTIVE: To summarize the role of melatonin in the physiology and pathophysiology of the ovary. DESIGN: Review of literature. SETTING: University Health Science Center. RESULT(S): Melatonin plays an essential role in the pathogenesis of many reproductive processes. Human preovulatory follicular fluid (FF) contains higher concentrations of melatonin than does plasma, and melatonin receptors are present in ovarian granulosa cells (GC). Melatonin has been shown to have direct effects on ovarian function. Reactive oxygen species and apoptosis are involved in a number of reproductive events including folliculogenesis, follicular atresia, ovulation, oocyte maturation, and corpus luteum (CL) formation. Melatonin and its metabolites are powerful antioxidants; the primitive and primary function of melatonin may be its actions as a receptor-independent free radical scavenger and a broad-spectrum antioxidant. A large amount of scientific evidence supports a local role of melatonin in the human reproductive processes. The indole also has potential roles in the pathophysiology of endometriosis, polycystic ovary syndrome (PCOS), and premature ovarian failure (POF). CONCLUSION(S): We summarize the current understanding of melatonin's essential functions in the human ovary. Melatonin could become an important medication for improving ovarian function and oocyte quality, and open new opportunities for the management of several ovarian diseases.

Increased melatonin synthesis in pineal glands of rats in streptozotocin induced type 1 diabetes.

It is well-documented that melatonin influences insulin secretion. The effects are mediated by specific, high-affinity, pertussis-toxin-sensitive, G protein-coupled membrane receptors (MT(1) as well MT(2)), which are present in both the pancreatic tissue and islets of rats and humans, as well as in rat insulinoma cells (INS1). Via the Gi-protein-adenylatecyclase-3',5'-cyclic adenosine monophosphate (cAMP) and, possibly, the guanylatecyclase-cGMP pathways, melatonin decreases insulin secretion, whereas, by activating the Gq-protein-phospholipase C-IP(3) pathway, it has the opposite effect. For further analysis of the interactions between melatonin and insulin, diabetic rats were investigated with respect to melatonin synthesis in the pineal gland and plasma insulin levels. In this context, recent investigations have proven that type 2 diabetic rats and humans display decreased melatonin levels, whereas type 1 diabetic IDDM rats or those with diabetes induced by streptozotocin (STZ) of the present study show increased plasma melatonin levels and elevated AA-NAT-mRNA. Furthermore, the mRNA of pineal insulin receptors and beta1-adrenoceptors, including the clock genes Per1 and Bmal1 and the clock-controlled output gene Dbp, increases in both young and middle-aged STZ rats. The results therefore indicate that the decreased insulin levels in STZ-induced type 1 diabetes are associated with higher melatonin plasma levels. In good agreement with earlier investigations, it was shown that the elevated insulin levels observed in type 2 diabetes, are associated with decreased melatonin levels. The results thus prove that a melatonin-insulin antagonism exists. Astonishingly, notwithstanding the drastic metabolic disturbances in STZ-diabetic rats, the diurnal rhythms of the parameters investigated are maintained.

First evidence of melatonin receptors distribution in the suprachiasmatic nucleus of tree shrew brain.

OBJECTIVE: In this study we investigated the distribution of melatonergic receptors in the tree shrew brain. The psychosocial stress in the tree shrew is a validated model of depression with disturbance of circadian rhythms. METHODS: Given the role of melatonin in the modulation of circadian rhythms, we determined by autoradiography the distribution of binding sites of 2-[125I]-MLT, a ligand for the two melatonergic receptors MT1 and MT2, in the tree shrew brain focusing mostly on the suprachiasmatic nucleus (SCN), the biological clock involved in resynchronization of circadian rhythms. We also analyzed the distribution of 2-[125I]-MLT in other brain areas involved in regulation of mood. RESULTS: Specific binding of 2-[125I]-MLT was found in the SCN. In addition, several structures in the tree shrew brain were labeled, among them the pars tuberalis, the cerebellum, structures of the hippocampal formation and dopaminergic areas such as the caudate putamen and nucleus accumbens, providing other potential targets of psychosocial stress in the tree shrew, in addition to the SCN. CONCLUSIONS: The demonstration of melatonergic receptors in these brain areas supports their probable involvement in the behavioural, neuroendocrine and circadian rhythms disturbances observed in the psychosocial stress model of depression in the tree shrew.

Asymmetric expression of melatonin receptor mRNA in bilateral paravertebral muscles in adolescent idiopathic scoliosis.

STUDY DESIGN: Comparison of melatonin receptor mRNA expression in bilateral paravertebral muscles in adolescent idiopathic scoliosis (AIS). OBJECTIVES.: To investigate the change of melatonin receptor mRNA expression in bilateral paravertebral muscles in AIS, congenital scoliosis (CS), and control in order to analyze its association to the pathogenesis of AIS. SUMMARY OF BACKGROUND DATA: Muscle imbalance and asymmetry of stretch receptors in the paravertebral muscles of patients with AIS were supposed to have a large role to play in the development and production of the deformity. Melatonin is a focus of studies of the mechanism underlying the development of scoliosis, and there is no research on the expression of melatonin receptors in the paravertebral muscles of patients with AIS. METHODS: Twenty cases with average age of 15.1 +/- 2.2 years and average Cobb angle of 56.2 degrees +/- 16.1 degrees, including 10 cases with Cobb angle >50 degrees and 10 cases with Cobb angle < or =50 degrees, were included in AIS group. The apical vertebrae were from T6 to T11. Twelve cases with an average age of 11.6 +/- 3.2 years and average Cobb angle of 59.2 degrees +/- 33.3 degrees were included in CS group. The apical vertebrae were from T7 to T12. Ten cases without scoliosis were in the control group. The mRNA expression of melatonin receptor subtype MT1 and MT2 was detected by the RT-PCR method. RESULTS: The MT2 mRNA expression on the concave side of the paravertebral muscle was higher than that on the convex side in AIS and CS groups (P < 0.05), but the MT1 mRNA expression showed no significant difference (P > 0.05). In the AIS group, the ratio of MT2 mRNA expression on the concave side compared with the convex side in cases with Cobb angle >50 degrees and cases with Cobb angle < or =50 degrees showed no significant difference (P > 0.05). The MT1 and MT2 mRNA expression showed no significant difference in control group (P > 0.05). CONCLUSION: The melatonin receptor expression in bilateral paravertebral muscles in AIS is asymmetric, which may be a secondary change. The bilateral asymmetry in force exerted on the scoliotic spine may be the cause.

Melatonin affects the temporal organization of the song of the zebra finch.

In birds and mammals, including humans, melatonin-binding sites are abundant in brain areas that have no known clock function. Although the role of such binding sites is still unclear, it is assumed that these sites link neural functions to circadian or circannual demands of neuroendocrine homeostasis and reproduction. To investigate a possible direct role of melatonin in motor control, we studied the song and neural song system of the zebra finch. Neurons of two sensory-motor areas of the descending song control circuit that are crucial for the organization of the song pattern, the HVC and RA, express the melatonin-1B receptor (Mel1B), while the hypoglossal motor neurons of the song circuit express melatonin-1C receptors (Mel1C). Application of melatonin to brain slices decreases the firing-rate of RA-neurons. Systemic administration of a Mel1B antagonist at the beginning of the night shortens the song and motif length and affects the song syllable lengths produced the next day. The temporal pattern of the song, however, does not undergo daily changes. Thus, melatonin is likely to affect a non-circadian motor pattern by local modulation of song control neurons and in consequence alters a sexual signal, the song of the zebra finch.