Sites Of Melatonin Synthesis Research Articles

Postnatal Development of the Circadian Rhythmicity of Human Pineal Melatonin Synthesis and Secretion (Systematic Review).

Introduction: According to current knowledge, at birth, the pineal gland and melatonin receptors are already present and the suprachiasmatic nucleus is largely functional, and noradrenaline, the key pineal transmitter, can be detected in the early foetal period. It is still unclear why the pineal gland is not able to start its own pulsatile synthesis and secretion of melatonin in the first months of life, and as a result, infants during this time are dependent on an external supply of melatonin. Method: The causes and consequences of this physiological melatonin deficiency in human infancy are examined in a systematic review of the literature, in which 40 of 115 initially selected publications were evaluated in detail. The references of these studies were checked for relevant studies on this topic. References from previous reviews by the author were taken into account. Results: The development and differentiation of the pineal gland, the pinealocytes, as the site of melatonin synthesis, and the development and synaptic coupling of the associated predominantly noradrenergic neural pathways and vessels and the associated Lhx4 homebox only occurs during the first year of life. Discussion: The resulting physiological melatonin deficiency is associated with sleep disorders, infant colic, and increased crying in babies. Intervention studies indicate that this deficiency should be compensated for through breastfeeding, the administration of nonpooled donor milk, or through industrially produced chrononutrition made from nonpooled cow's milk with melatonin-poor day milk and melatonin-rich night milk.

Melatonin immunoreactivity of epidermal skin is higher in the evening than morning but does not account for erythema sensitivity

ABSTRACT The skin is a site of melatonin synthesis, and melatonin has a role in protecting against ultraviolet radiation-induced damage. Ultraviolet B (UVB) induced erythema seems to vary between morning and evening. We investigated whether epidermal melatonin immunoreactivities in the morning differed from those in the evening, and whether UVB-induced erythema was associated with these melatonin immunoreactivities in healthy volunteers. Erythema sensitivity of the skin was determined in the morning and in the evening by scoring the Minimal Erythema Dose and quantifying the erythema index (EI). We took biopsies from the non-UVB-exposed skin of healthy volunteers (n = 39) in the morning and in the evening to study melatonin immunoreactivity with immunohistochemistry (IHC). In the IHC staining, there was more melatonin immunoreactivity in the evening than in the morning (p < .001). Erythema was more pronounced in the evening than in the morning irradiated skin (p < .001). The graded amount of melatonin immunoreactivity in the samples was not associated with the EI. We discovered melatonin immunoreactivity of the non-irradiated skin to vary diurnally. However, endogenous skin melatonin does not seem to be the reason why NB-UVB induces more erythema in the evening than in the morning.

Melatonin: an endogenous miraculous indolamine, fights against cancer progression.

Melatonin is an amphipathic indolamine molecule ubiquitously present in all organisms ranging from cyanobacteria to humans. The pineal gland is the site of melatonin synthesis and secretion under the influence of the retinohypothalamic tract. Some extrapineal tissues (skin, lens, gastrointestinal tract, testis, ovary, lymphocytes, and astrocytes) also enable to produce melatonin. Physiologically, melatonin regulates various functions like circadian rhythm, sleep-wake cycle, gonadal activity, redox homeostasis, neuroprotection, immune-modulation, and anticancer effects in the body. Inappropriate melatonin secretion advances the aging process, tumorigenesis, visceral adiposity, etc. METHODS: For the preparation of this review, I had reviewed the literature on the multidimensional activities of melatonin from the NCBI website database PubMed, Springer Nature, Science Direct (Elsevier), Wiley Online ResearchGate, and Google Scholar databases to search relevant articles. Specifically, I focused on the roles and mechanisms of action of melatonin in cancer prevention. The actions of melatonin are primarily mediated by G-protein coupled MT1 and MT2 receptors; however, several intracellular protein and nuclear receptors can modulate the activity. Normal levels of the melatonin protect the cells from adverse effects including carcinogenesis. Therapeutically, melatonin has chronomedicinal value; it also shows a remarkable anticancer property. The oncostatic action of melatonin is multidimensional, associated with the advancement of apoptosis, the arrest of the cell cycle, inhibition of metastasis, and antioxidant activity. The present review has emphasized the mechanism of the anti-neoplastic activity of melatonin that increases the possibilities of the new approaches in cancer therapy.

Local melatoninergic system as the protector of skin integrity.

The human skin is not only a target for the protective actions of melatonin, but also a site of melatonin synthesis and metabolism, suggesting an important role for a local melatoninergic system in protection against ultraviolet radiation (UVR) induced damages. While melatonin exerts many effects on cell physiology and tissue homeostasis via membrane bound melatonin receptors, the strong protective effects of melatonin against the UVR-induced skin damage including DNA repair/protection seen at its high (pharmocological) concentrations indicate that these are mainly mediated through receptor-independent mechanisms or perhaps through activation of putative melatonin nuclear receptors. The destructive effects of the UVR are significantly counteracted or modulated by melatonin in the context of a complex intracutaneous melatoninergic anti-oxidative system with UVR-enhanced or UVR-independent melatonin metabolites. Therefore, endogenous intracutaneous melatonin production, together with topically-applied exogenous melatonin or metabolites would be expected to represent one of the most potent anti-oxidative defense systems against the UV-induced damage to the skin. In summary, we propose that melatonin can be exploited therapeutically as a protective agent or as a survival factor with anti-genotoxic properties or as a “guardian” of the genome and cellular integrity with clinical applications in UVR-induced pathology that includes carcinogenesis and skin aging.

Aspects cellulaires du vieillissement de la glande pinéale chez la musaraigne, Crocidura russula

The Greater White-toothed shrew Crocidura russula is short-lived species and the phase of senescence is greatly elongated in captivity. The loss of rhythmicity of biological functions that accompanies its aging is also well documented. C. russula is thus an excellent model to test the effects of aging on biological clocks. Melatonin is a key hormone in the synchronization of behaviors, metabolisms and physiological regulations with environmental factors. In the present work we want to know if the loss of rhythmicity and the reduced melatonin levels registered by the second year of life in this species could be associated to modified ultrastructural features of the pineal parenchyma, site of melatonin synthesis. Transmission electron microscopy (TEM) analysis of young (1–4 months) and old (25–28 months) shrew's pineals show that in older individuals, the parenchyma undergoes alterations affecting mainly nucleus, mitochondria and endoplasmic reticulum cisternae, with increased numbers of dense bodies and the formation of many concretions as well as a depletion of secretory products. These changes suggest a process of slowing pinealocytes metabolism which could explain the gradual reduction of melatonin levels registered during aging in C. russula.

The existence of extrapineal locations for melatonin synthesis in the one-humped camel (Camelus dromedarius)

We studied the sites of melatonin synthesis which was measured using the radioimmunoassay technique in the eye retina, skin, Harderian gland, liver tissue and jejunal mucosa in the immature and mature (non-rutting and rutting) Camelus dromedarius. For the first time, melatonin hormone was found in extrapineal sources in camel. These sites included the retina, skin, Harderian gland, liver and jejunal mucosa. The levels of melatonin in these sites reached 80.7, 33.5, 84.6, 548.9 and 2024.1 pg/mg, respectively, in the immature camel. In the mature non-rutting camel, during the non-mating season, the level of melatonin was estimated at 73.7, 41.1, 86.3, 1942.6 and 44112.0 pg/mg, respectively, giving a generally high level. In the mating rutting camel during the winter season, the melatonin level exhibited a level of 77.2, 39.5, 82.0, 930.9 and 14644.0 pg/mg, respectively, with an indication of a general decrease with the exception of the retinal melatonin when compared to the non-rutting camel. It should be noted that the finding of the melatonin hormone in the skin has never been recorded before, and has never been estimated before in other animals. The results in the present investigation also revealed that the wild plants upon which camels usually feed contain a significant amount of melatonin (838.2 pg/g in Chloris gayana and 226.6 pg/g in Anabasis setifera). This could be one of the factors causing an increase in the level of melatonin in the blood and consequently influencing testicular regression during the non-rutting season.

MELATONIN CIRCADIAN RHYTHM IN THE RETINA OF MAMMALS

Melatonin has been traditionally considered to be derived principally from the pineal gland. However, several investigations have now demonstrated that melatonin synthesis occurs also in the retina (and in other organs as well) of several vertebrate classes, including mammals. As in the pineal, melatonin synthesis in the retina is elevated at night and reduced during the day. Since melatonin receptors are present in the retina and retinal melatonin does not contribute to the circulating levels, retinal melatonin probably acts locally as a neuromodulator. Melatonin synthesis in the retinas of mammals is under control of a circadian oscillator located within the retina itself, and circadian rhythms in melatonin synthesis and/or release have been described for several species of rodents. These rhythms are present in vivo, persist in vitro, are entrained by light, and are temperature compensated. The recent cloning of the gene responsible for the synthesis of the enzyme arylalkylamine N-acetyltransferase (the only enzyme unique to the melatonin synthetic pathway) will facilitate localizing the cellular site of melatonin synthesis in the retina and investigating the molecular mechanism responsible for the generation of retinal melatonin rhythmicity. Melatonin has been implicated in many retinal functions, and the levels of melatonin and dopamine appear to regulate several aspects of retinal physiology that relate to light and dark adaptation. In conclusion, it seems that retinal melatonin is involved in several functions, but its precise role is yet to be understood. (Chronobiology International, 17(5), 599–612, 2000)

Tryptophan hydroxylase is expressed by photoreceptors in Xenopus laevis retina.

Serotonin has important roles, both as a neurotransmitter and as a precursor for melatonin synthesis. In the vertebrate retina, the role and the localization of serotonin have been controversial. Studies examining serotonin immunoreactivity and uptake of radiolabeled serotonin have localized serotonin to inner retinal neurons, particularly populations of amacrine cells, and have proposed that these cells are the sites of serotonin synthesis. However, other reports identify other cells, such as bipolars and photoreceptors, as serotonergic neurons. Tryptophan hydroxylase (TPH), the rate-limiting enzyme in the serotonin synthetic pathway, was recently cloned from Xenopus laevis retina, providing a specific probe for localization of serotonin synthesis. Here we demonstrate that the majority of retinal mRNA encoding TPH is present in photoreceptor cells in Xenopus laevis retina. These cells also contain TPH enzyme activity. Therefore, in addition to being the site of melatonin synthesis, the photoreceptor cells also synthesize serotonin, providing a supply of the substrate needed for the production of melatonin.

Localization of mRNA encoding the indolamine synthesizing enzyme, hydroxyindole- O-methyltransferase, in chicken pineal gland and retina by in situ hybridization

Hydroxyindole- O-methyltransferase (HIOMT) is the enzyme that catalyzes the final step in the synthesis of the hormone melatonin. We have examined the localization of expression of the mRNA encoding HIOMT by in situ hybridization in the 3-day-old and adult chicken retina and pineal gland. The riboprobe utilized for this study was transcribed from the complete coding region of HIOMT cDNA synthesized from retina RNA and amplified by polymerase chain reaction (PCR). High levels of HIOMT mRNA were present in the pinealocytes of the pineal gland. In the retina, the hybridization signal was localized to the photoreceptors. The retinal photoreceptors of the 3-day-old chick displayed a much lower level of hybridization than did the photoreceptors of the adult chicken. This study strongly suggests that the photoreceptors are the sites of melatonin synthesis in the retina.

Localization of hydroxyindole-O-methyltransferase-like immunoreactivity in photoreceptors and cone bipolar cells in the human retina: a light and electron microscope study.

The localization of the melatonin-synthesizing enzyme hydroxyindole-O-methyltransferase (HIOMT) was examined by light and electron microscopic immunocytochemistry in the human retina. HIOMT-like immunoreactivity was observed in the photoreceptor layers and the inner nuclear layer (INL). The immunoreactive cells in the INL were more numerous in the central retina than in the peripheral retina and sent processes to both the outer plexiform and inner plexiform layers. The HIOMT immunoreactivity in the inner plexiform layer (IPL) appeared as punctate terminals in the proximal and distal one-thirds of that layer. At the ultrastructural level, HIOMT-like immunoreactivity was localized to the cytoplasm of rod and cone photoreceptors and to a population of cone bipolar cells. HIOMT-immunoreactive bipolar cell dendrites were observed to make both invaginating and flat synaptic contacts with cone pedicles. No immunoreactive invaginating contacts in rod spherules were observed. HIOMT immunoreactivity was observed in the bipolar cell cytoplasm in the INL, and in the bipolar synaptic terminals in the IPL. These terminals contained synaptic ribbons, which formed synaptic contacts with unlabeled cells in the IPL. HIOMT radioenzymatic assays confirmed the presence of HIOMT in the human retina. Average HIOMT activity of eight donors was determined to be 15.0 pmol/mg protein/hour +/- 7.2 S.D. The ultrastructural localization of HIOMT observed in this study, combined with reports from other laboratories, suggests that the cytoplasm of the photoreceptors and a population of cone bipolar cells may be the sites of melatonin synthesis in the human retina.

Relationship between pineal N-acetyltransferase activity, pineal melatonin and serum melatonin in rats under different lighting conditions.

Pineal N-acetyltransferase (NATase) activity has often been used as an indicator of pineal melatonin (MT) production, and the rhythms of pineal and serum MT levels are assumed to be parallel. However, these issues require further examination in view of some recent findings. In the present study, the 24-hour rhythms of pineal NATase, pineal MT content and serum MT concentrations were examined in groups of rats exposed to four artificial lighting regimens: (a) 16 h of light, 8 h of darkness (LD 16:8) for 2 weeks; (b) LD 12:12 for 2 weeks; (c) LD 4:20 for 2 weeks, and (d) LD 4:20 for 4 weeks. Under the above lighting conditions, the rhythms of pineal NATase, serum and pineal MT contents when tested demonstrated a closely parallel relationship. These results supported the idea that pineal NATase accurately reflected MT synthesis and that the rhythms of pineal and serum MT content were in phase under long and short photoperiods, in spite of extrapineal sites of MT synthesis. Further, the results also demonstrated that the timing of the MT peaks in the serum and the pineal may depend on the length of the adaptation period to the environmental lighting. When the rats were housed under a short photoperiod (LD 4:20), the peak MT levels appeared in the middle of the dark period after 2 weeks but shifted towards the end of the dark period after 4 weeks.