Melatonin biosynthesis in the mammalian pineal gland

Rhythmic production of melatonin by the mammalian pineal occurs in response to noradrenergic stimulation which produces a cascade of biochemical events within the pinealocyte. In the rat, massive changes in NAT activity result from an increase in intracellular c-AMP levels produced by a synergistic interaction whereby an alpha 1 activation amplifies beta-adrenergic stimulation. The intracellular events mediating this effect are described. A major aspect of the temporal control of melatonin production is the programmed down-regulation of responses to noradrenergic stimulation once the initial surge of c-AMP is produced. Noradrenergic activation of the gland also influences other enzymic functions, including tryptophan hydroxylase and HIOMT activities, and produces a dramatic increase in intracellular c-GMP levels. Other neurotransmitters and neuropeptides, e.g. VIP, may also influence pineal function and comparisons are made between the rat, the subject of the bulk of experimental studies, and other species.     

Development of melatonin rhythm in the pineal gland and eyes of chick embryo

A melatonin rhythm was observed in the pineals of 18-day-old chick embryos incubated under a light-dark regime of 186 h. A low pineal melatonin content was found during the light phase of the day. Concentrations started to increase 2 h after dark onset and reached maximum levels after 4 h of darkness. The amplitude of the pineal melatonin rhythm increased considerably after 2 days and night-time concentrations in 20-day-old embryos were more than 5 times higher than in 18-day-old ones. Significant day/night differences in melatonin production were found both in pineals and eyes. Exposure of eggs to 1 h of light during the dark period decreased the high melatonin concentrations in the eyes but not in the pineals of the 20-day-old chick embryo. The results suggest that in this precocial bird at least part of the circadian system may already operate during embryonic life.     

Melatonin: presence and formation in invertebrates

In vertebrates, it is now clearly demonstrated that the pineal gland is implicated in conveying photoperiodic information via the daily pattern of melatonin secretion. Invertebrates, like vertebrates, use photoperiodic changes as a temporal cue to initiate physiological processes such as reproduction or diapause. How this information is integrated in invertebrates remains an unsolved question. Our review will be an attempt to evaluate the possible role of melatonin in conveying photoperiodic information in invertebrates. It is now well demonstrated in both vertebrates and invertebrates that melatonin as well as its precursors or synthesizing enzymes are present in various organs implicated in photoreceptive processes or in circadian pacemaking. Melatonin, serotonin or N-acetyltransferase have been found in the head, the eyes, the optic lobe and the brain of various invertebrate species. In some species it has also been shown that melatonin is produced rhythmically with high concentrations reached during the dark period. Moreover, the physiological effects of melatonin on various periodic processes such as rhythmic contractions in coelenterates, fissioning of asexual planarians or reproductive events in flies have been reported in the literature. All these results support the hypothesis (refs 36, 37) that melatonin is not solely a pineal hormone but that it may be an evolutionary conservative molecule principally involved in the transduction of photoperiodic information in all living organisms.     

Melatonin and circadian control in mammals

Summary Although pinealectomy has little influence on the circadian locomotor rhythms of laboratory rats, administration of the pineal hormone melatonin has profound effects. Evidence for this comes from studies in which pharmacological doses of melatonin are administered under conditions of external desynchronization, internal desynchronization, steady state light-dark conditions, and phase shifts of the zeitgeber. Taken together with recent findings on melatonin receptor concentration in the rat hypothalamus, particularly at the level of the suprachiasmatic nuclei, these results suggest that melatonin is a potent synchronizer of rat circadian rhythms and has a direct action on the circadian pacemaker. It is possible, therefore, that the natural role of endogenous melatonin is to act as an internal zeitgeber for the total circadian structure of mammals at the level of cell, tissue, organ, whole organism and interaction of that organism with environmental photoperiod changes.     

Effects of estrogens and progesterone upon the biosynthesis of melatonin by the pineal gland

Zusammenfassung Da die Aktivität der Pinealdrüse bei weiblichen Ratten mit dem Cyklus wechselt, wurde die Wirkung von Oe tradiol und Progesteron auf ihre Aktivität bei kastrierten weiblichen Ratten untersucht. Oestradiol bewirkte Gewichtsabnahme und Funktionssteigerung, während Progesteron die Pinealis-Aktivität herabsetzte.     

Melatonin decreases the amplitude of the b-wave of the human electroretinogram

In a double-blind placebo crossover study of 13 healthy volunteers, the pineal hormone melatonin (10 mg) was given at 4 pm, and the electroretinogram measured under conditions of dark and light adaptation. A significant diminution of b-wave amplitude was found under both photopic (=5.4 V, p<0.05) and scotopic conditions (=7.4 V, p<0.01). These data indicate that melatonin may transduce the dark signal at the level of the retina as well as the pineal. Acute administration of melatonin decreases sensitivity to light.     

Concrement formation encountered in the rat pineal gland

Summary Morphological evidence is given for the concrement formation encountered in the rat pineal gland, the occurrence of which has not been reported so far (for the rat).     

Neither prolactin nor growth hormone restore the nocturnal rise in pineal N-acetyltransferase activity or melatonin content in hypophysectomized rats

Summary Hypophysectomy in adult male rats greatly attenuated the nocturnal rise in both pineal N-acetyltransferase (NAT) activity and melatonin content. High nighttime levels of NAT and melatonin were not restored by treating the animals with either prolactin or growth hormone, alone or in combination. Treating intact rats with bromocriptine, which depresses circulating prolactin levels, also was without effect on pineal melatonin synthesis. It appears that neither prolactin nor growth hormone are of major importance in determining pineal melatonin production.     

Melatonin biosynthesis in the thymus of humans and rats

Melatonin is an indoleamine widely distributed in the evolution that shows a great functional versatility, playing an important role as a transmitter of photoperiodic information and exhibiting antioxidant, oncostatic, anti-aging and immunomodulatory properties. In vertebrates, this molecule is produced by the pineal gland and other extrapineal sites. The present study was carried out to investigate the presence of melatonin in thymus and the possibility of an endogenous melatonin synthesis in this organ, in which T cells are matured. In this work, we demonstrate in humans and rats that thymus contains melatonin, expresses the mRNAs encoding N-acetyltransferase and hydroxyindol-O-methyltransferase, the two key enzymes of the melatonin synthesis, and has this biosynthetic machinery activated. In addition, rat thymocytes cultured for 24 h exhibited high levels of melatonin. The results presented here suggest that human and rat thymuses are able to synthesize melatonin, which could have intracrine, autocrine and paracrine functions. Received 30 September 2006; received after revision 30 December 2006; accepted 15 February 2007     

Ascorbic acid biosynthesis in the mammalian kidney

Summary The egg-laying mammals (Prototheria) synthesize L-ascorbic acid only inkidney, as is characteristic of reptiles. Bandicoots (Marsupialia) synthesize it in both kidney and liver. 2 other species of marsupials (kangaroos) synthesize it primairly in liver, but some individuals also synthesize in kidney.This study was supported by NSF grant INT77-15934; the Carnegie Museum of Natural History provided one field assistant. We thank M. Birney, D. Dellow, K. Jenness, and L. Robbins for field assistance, A. G. Lyne for providing the live bandicoots, and the New South Wales National Parks and Wildlife Service for issuance of collecting permits (SLF52 and SLF84).     

Ascorbic acid biosynthesis in the mammalian kidney

The egg-laying mammals (Prototheria) synthesize L-ascorbic acid only in kidney, as is characteristic of reptiles. Bandicoots (Marsupialia) synthesize it in both kidney and liver. 2 other species of marsupials (kangaroos) synthesize it primarily in liver, but some individuals also synthesize in kidney.     

Ultrastructure and biochemistry of the pineal organ in deep-sea lanternfishes (Myctophidae)

Summary Pineal structural and biochemical adaptations in lanternfishes included: 1) few photoreceptor outer segment discs; 2) conventional synapses between photoreceptors and pineal neurons; and 3) low levels (0–60 pg/pineal) of serotonin compared to those (>1.0 ng/pineal) in the goldfish pineal organ. These findings suggest reduced photosensory and/or neuroendocrine functions in these deep-sea fishes.     

Scanning electron microscope observations of the canaliculi in the rat pineal gland

Summary The scanning electron microscope has shown rich ramifications of the parenchymal canaliculi forming a three-dimensional network of anastomosing intercellular spaces in the rat pineal gland. Every pineal cell seems to be in contact with this channel system. An abundance of cellular processes can be found within the canaliculi which may play an important role in the histophysiology of the pineal body. Dedicated to Prof. Dr. med.W. Bargmann on the occasion of his 70th birthday.     

Ultrastructural evidence of a secretory process in the rat pineal gland.

Pericapillar spaces of the rat pineal gland belong to the most active sites of this organ. Neighborhood of sympathetic nerve endings, capillaries and pinealocyte processes facilitates possibly the synthesis and the secretion of methoxyindoles. Lipid droplets migrate through the pinealocyte cellular processes towards the terminal enlargement or poles, where they are secreted into the pericapillar space, and the possibility that indoleamines are included in the lipid droplets has been discussed.     

Evidence for in vitro release of neurophysin by the rat pineal gland

Summary Cultured pineal ependymal cells from rat fetuses release into their incubation media immunoreactive neurophysin. The presence of neurophysin was assessed by radioimmunoassay. The culture medium was found to contain 440 pg neurophysin per mg protein.