The Pineal Gland Development and its Physiology in Fetus and Neonate

Chapter 31

The Pineal Gland Development and its Physiology in Fetus and Neonate Suzana Elena Voiculescu*, Diana Le Duc†,‡, Adrian Eugen Rosca* and Ana-Maria Zagrean* *Division of Physiology and Neuroscience, Department of Functional Sciences, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, † Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany, ‡ Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany

Key Clinical Changes






The pineal gland does not begin secreting melatonin until 3–5 months after birth and coincides with the typical time when sleep patterns are better established in the neonate. The fetus is dependent on maternal melatonin crossing the placenta. Fetuses display rhythmicity of melatonin and behavior that parallel maternal levels and activity. Postnatal production of melatonin is further delayed in premature babies. Melatonin has been proposed to affect many aspects of fetal development, but further study is needed to confirm these roles.

31.1 INTRODUCTION The pineal gland is a nervous system component, a neuroendocrine translator, that in mammals and humans expresses photoperiodicity and a secretory function, all of which are related to and coordinated with the circadian rhythm. Its main hormone and the most studied one is melatonin. The functions of melatonin are a subject of recent research and have been shown to extend to many domains of human physiology. Classically, melatonin is an endogenous synchronizer, and its secretion imprints rhythms in various body functions via the hypothalamus suprachiasmatic nucleus (SCN): body heat, sleep/wake cycle, cortisol secretion, blood pressure, cellular divisions, and immune system function. Little is known about melatonin’s fetal functions and physiology. The passage of maternal melatonin through the placenta exposes the fetus to a daily rhythm of low concentrations during the day and high concentrations at night. Consequently, melatonin is likely involved in inducing a circadian rhythm to fetal physiology and organs (Fig. 31.1).

31.2 PINEAL DEVELOPMENT AND CIRCADIAN RHYTHM ONTOGENESIS The pineal gland, which is responsible for the circadian endocrine melatonin production, develops from an area of the neuroepithelium that lines the roof of the third ventricle in the prenatal brain. Its maturation continues postnatally with a growth in size until about 2 years of age.1 A dynamic and intricate regulatory network of transcription factors is necessary for pineal gland development, among which homeobox transcription factors Pax6, Otx2, and Lhx9 seem to play an essential role.2, 3 These transcription factors are responsible for regulating pinealocyte specification and prenatal proliferation. In their absence, the pineal gland fails to develop. Hartley and colleagues showed that treating surgically removed neonatal rat pineal glands with norepinephrine, a superior cervical ganglia transmitter, renders their gene expression profile very close to the in vivo state. These findings suggested that, despite the postnatal maturation of the gland, the pineal-defining transcriptome is established prior to birth.4 After birth, the newborn no longer receives an infusion of melatonin from the maternal circulation, except through maternal milk, in the case of breastfeeding. Over the following 6 to 8 weeks, the child develops its own circadian rhythm regulated by melatonin secreted by the pineal gland.5 Detectable circadian variations in melatonin become most apparent Maternal-Fetal and Neonatal Endocrinology. https://doi.org/10.1016/B978-0-12-814823-5.00031-3 Copyright © 2020 Elsevier Inc. All rights reserved.

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FIG. 31.1 Role of melatonin in the maternal-placental-fetal system. Light detected by the eyes of the mother is transmitted to the circadian pacemaker in the suprachiasmatic nucleus (SCN), which sends a neural signal to the pineal gland to regulate the circadian rhythm of melatonin secretion. Melatonin synthesis is upregulated in pregnant women, possibly via placental signaling to the maternal pineal gland. Melatonin modulates circadian endocrine rhythms and ensures protection via free radical scavenging, indirect antioxidant effects, and immune regulation. Melatonin acts on its MT1/MT2 receptors to promote fetal growth and development. ROS, reactive oxygen species; NO, nitric oxide.

from the 3rd to 6th month of life, which is the period when the newborn develops a normal sleep rhythm. However, the maximal rise in the nocturnal melatonin secretion amplitude occurs between the 4th and 7th year of life.6 Circadian rhythm development in humans is a controversial subject with scant human data. We shall instead make some inferences from rodents, which are the most used experimental models. In rats, circadian rhythms per se develop after birth, but in the human fetuses, oscillations have been identified beginning with the 24th intrauterine week, with components of the circadian system appearing well before this. In postnatal rats, basal corticosterone shows 24-h oscillations, beginning at postnatal day 22 (P22).7 A rhythm in activity period is present starting around day 9 or 10 after birth, and body temperature rhythm begins in the first week after birth.8, 9 There are various aspects of fetal physiology, such as body movement, hormonal levels, and heart activity, that exhibit a circadian rhythm, especially during late gestation.10 It appears that these functions are regulated at least in part by the fetal suprachiasmatic nucleus (SCN) that was first discovered in rodents by Reppert and Schwartz in 1984.11 It has been shown that fetal tissues contain circadian clock systems that resemble the adult ones, and these rhythms may be regulated by signals coming from the mother across the placenta.10, 12 Clock gene expression in fetal and embryonic tissues has been observed mostly in murine models. Mouse embryos express clock genes starting with day 10 of gestation, and this expression increases until day 19, just before birth.13 The fetal rat SCN exhibits a 24-h rhythm in metabolic activity (specifically use of glucose),11 and in the expression of various genes, including c-Fos and Avp.14 Clock genes are also expressed in the fetal liver, but their expression seems to be arrhythmic.15 A daily variation of hepatic clock genes develops gradually in the postnatal period, with full rhythmicity apparent by postnatal day 30.12

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Quite opposite form the fetal SCN and liver, the adrenal clock appears to be functional late during pregnancy.16 In rats, the SCN begins to develop around embryonic day (ED) 14 and continues until ED 17. Neurogenesis stops at ED 18, but a progressive maturation in morphology occurs until the 10th day after birth, when synaptic density reaches adult levels. Synaptogenesis happens mostly after birth, but a small number of synapses have been identified, beginning with ED 19.17 At this time, a rhythm in activity of the internal SCN becomes evident.11 Honma et al. found important clues that point to the existence of a maternofetal coordination of circadian rhythms in fetal rats before ED 10, before the SCN is formed. In this experiment, the authors observed that reversal of the light-dark cycle of the pregnant mother at day 10 of pregnancy resulted in an effective reversal of the pup’s hormonal rhythm.18, 19 As to the onset of prenatal entrainment of the circadian oscillation, two possibilities exist. One is that the fetal circadian oscillation entrains to the maternal circadian rhythm before day 10 of gestation and the entrainment continues to the end of pregnancy. If the maternal circadian system is disrupted by the SCN lesion during pregnancy, the fetal circadian oscillation starts to free run, resulting in a negative phase angle difference to the rhythm developed in the control pups. Alternatively, it is possible that the fetal oscillation is unable to entrain to the maternal circadian system until the latter stages of gestation. In this case, we must postulate the phase of oscillation to be preset genetically; this has not been substantiated experimentally yet. Peripheral circadian systems develop in fetuses before the SCN does and are probably regulated by maternal rhythms. A series of experiments in rats and hamsters showed that fetal circadian systems synchronization is lost after destruction of the maternal SCN.20 SCN of the human fetus becomes functional and begins to present periodic 24-h oscillations at midterm (20–25 weeks post conception).21 This coincides with the first fetal movements felt by the mother. Also, between 24 and 26 weeks of gestation, the eyelids are not fused anymore, and eye movements may be detected by ultrasonography. In the last trimester, the fetal biological clock develops, and it is sensitive to maternal circadian rhythms, to which it responds by hormonal, behavioral, and sleep fluctuations.21 Sladek et al. studied clock genes profile (Per 1, Per2, Cry1, Bmal1, and Clock) at ED 19, and postpartum days 3 and 10 in rats.12 ED 19 was chosen because at this specific time, neurogenesis of the SCN is complete. All studied genes are present in the SCN, but they either do not have a rhythmic expression, or the amplitude of their expression is too low to be detected. The same study showed a different expression at postnatal day 3, when a high expression of Per1, Per2, Cry1 and Bmal1 is detected, in contrast with the Clock gene. The aim of this study was to discover the development of the clockwork during ontogenesis. Daily profiles of Per1, Per2, Cry1, Bmal1, and Clock mRNA in the SCN of fetuses at the embryonic day 19 and of newborn rats at the postnatal day 3 and 10 were assessed. In addition, daily profiles of PER1, PER2, and CRY1 proteins at ED19 were measured. As early as at ED19, all the studied clock genes were already expressed in the SCN. However, no SCN rhythm in their expression was detected; Per1, Cry1, and Clock mRNA levels were low, whereas Bmal1 mRNA levels were high and Per2 mRNA levels were medium. Moreover, no rhythms of PER1, PER2, and CRY1 were detectable. At P3, rhythms in Per1, Per2, Cry1, and Bmal1, but not in Clock mRNA, were expressed in the SCN. The rhythm matured gradually; at P10, the amplitude of Per1, Per2, and Bmal1 mRNA rhythms were more pronounced than at P3. Altogether, the data show a gradual development of both the positive and negative elements of the molecular clockwork, from no detectable rhythmicity at ED19 to highly developed rhythms at P10.12 In conclusion, the animal literature has shown that the constitutive elements of the biological clocks are present during late fetal development, and the molecular elements of these pathways are at least inducible. The specific maternal signal that induces fetal rhythms is not yet identified, but the main candidate is melatonin. The fetal organism is clearly influenced by many variables in the mother, such as behavior, metabolism, endocrine activity, and cardiovascular function.

31.3 MELATONIN SYNTHESIS Much of what is known about melatonin and pineal gland function comes from studies of adult humans and animals, and these data are summarized in this section. Melatonin (N-acetyl-5 methoxy tryptamine) is a 232 kDa molecular weight indoleamine, synthesized from the essential amino acid tryptophan, via serotonin. Melatonin synthesis primary takes place in the pineal gland. In adults, ectopic melatonin produced by other organs is released in the blood in minimum amounts, having more likely an autocrine or paracrine function than a systemic endocrine function.2 The pineal gland is a component of the nervous system, being a neuroendocrine translator, by having the capacity to transform a nerve impulse into a neurotransmitter secretion. In invertebrates, it also has a photoreception function, which is lost in mammals and humans. Melatonin and the synthesis pathway enzymes may be identified at multiple levels in the organism such as retina, nervous organs (cortex, raphe nuclei, striatum), gastrointestinal tract (stomach, intestine), testis, ovary, lymphocytes, lens,

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cochlea, and skin.22 Recently, it has been proposed that it is synthesized in mitochondria.23 High levels of melatonin have been measured in these organelles,24 which are a major source of free radicals. Pinealocytes secrete melatonin directly into the blood or cerebrospinal fluid. The SCN in the hypothalamus is the major regulator of melatonin release, acting through a multisynaptic pathway. The SCN sends fibers to the superior thoracic spinal cord, and they leave the cord to synapse in the first sympathetic paravertebral ganglion C1. Postganglionic fibers reach the pinealocytes through noradrenergic synapses.25 In darkness, norepinephrine is released in the synaptic cleft and acts on beta 1 adrenergic receptors, leading to an intracellular cAMP production and subsequently higher melatonin synthesis.15, 26, 27 cAMP activates N-acetyl transferase enzyme, which catalyzes serotonin to N-acetyl serotonin conversion, the latter being then converted to melatonin with the help of hydroxy-indole-O-methyl transferase (HIOMT). Although pineal cells are not directly photoreceptive, they do respond to sunlight versus darkness. Optic information reaches the SCN from the retina through the retinal hypothalamic tract, made from axons of a subpopulation of retinal ganglionic cells, melanopsin-positive, that represents 1%–2% of all retinal ganglion cells. In turn, melatonin activates SCN neurons, whose axons project to the adjacent hypothalamic nuclei, synchronizing some of the circadian system components such as body heat, sleep/wake cycle, feeding rhythm, and corticotropin/corticosteroids production. The SCN receives serotonergic afferent fibers from the raphe nuclei in the midbrain, especially from the median nucleus.28, 29 It has been shown that serotonin modulates the manner that light influences SCN, by controlling glutamate release from the retinal hypothalamic tract.30 Apart from the 24-h circadian rhythm of melatonin secretion (24  4 h in most organisms, 25 h in humans), a variation of secretion with age has also been identified. In humans, melatonin secretion reaches a maximum between 1 and 3 years of age, and then its concentration begins to fall progressively from puberty until 70 years, when it is about 10% of its peak value.31

31.3.1

Melatonin Sources for the Fetus

Inferior vertebrates demonstrate secretion of melatonin secretion during embryonic development. Human fetuses and newborns do not produce melatonin. Instead, they are dependent on maternal melatonin, which is transferred via the placenta or maternal milk. The human pineal gland does not produce melatonin until 3–5 months after birth. In premature babies, this delay is even longer, proportional to the degree of prematurity. The fetal SCN expresses melatonin receptors, and melatonin is one of the few hormones able to cross the placental barrier.5, 32 The primary and only source for melatonin in the fetus is the mother via the placenta. Very active melatonin rhythms have been measured in pregnant mammals,33, 34 which are mirrored and closely paralleled in the fetuses. Melatonin rapidly crosses the placenta, as demonstrated in rodents, sheep, and primates.35, 36

31.4

MELATONIN AND OOGENESIS

It has been shown that melatonin has a positive action in human gametogenesis because of a direct action at the level of the ovary. The molecule concentrates at ovary level when injected in the systemic circulation.33 There are studies that have identified a high concentration of melatonin in the preovulation follicular liquid, higher than in the serum,33 and that this concentration depends on follicular maturation. It has been stipulated that melatonin has an antioxidative importance in this situation, as follicular maturation is associated with a high production of free radicals. In addition, melatonin can increase glutathione peroxidase activity in the human chorion.34 Melatonin has also been studied in the context of assisted reproduction, and it has been shown that it enhances oocyte quality and success rate of in vitro fertilization procedure, when administered before FIV cycle initialization and continued during the entire pregnancy. The fertilization rate was 50% higher in the melatonin-treated group versus controls.37, 38

31.5

PINEAL DURING DEVELOPMENT

The outcome of the pregnancy is modified by the environment in which the mother works or lives. Night shifts enhance the risk for prematurity, low birth weight, abortion, and reduced fertility.39 This may be explained in part by a shorter sleep period. The FSH concentration of women who sleep <8 h per night is reduced by 20%.40 Plasma concentrations of melatonin and prolactin at 0200 h were significantly lower in nurses working at night than others of the resting group, but plasma concentrations of LH and FSH did not differ between the two groups. These results indicate that night shift suppresses the ovarian function by affecting the circadian rhythm of melatonin and prolactin.

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Suppression of maternal melatonin secretion in rats, through continuous light exposure in the second half of the pregnancy, slows intrauterine development and alters mRNA expression of Clock and Clock related genes. It also negatively influences corticosterone secretion by altering its secretion rhythm, lowers ACTH- dependent corticosterone secretion in vitro, and reduces Clock genes expression. All these changes are reversable with melatonin administration.20 A study in sheep showed that melatonin administration to pregnant mothers inhibits noradrenalin-induced fetal cerebral artery vasoconstriction, glycerol release from brown adipose tissue, and ACTH-induced cortisol secretion from the fetal adrenal gland. Low corticosterone levels or modified circadian secretion of corticosterone may explain the growth abnormalities mentioned before.41 Mice with a Clock Delta 19 mutation were used to determine whether fetal development within a genetically disrupted circadian environment affects pregnancy outcomes and alters the metabolic health of offspring. Circadian abnormality caused hyperleptinemia and excessive adipose tissue development by 3 months after birth. It also leads to altered glucose tolerance and insulin resistance at 1 year.42 Multiple animal studies have associated alterations in maternal circadian rhythms during pregnancy with increased risk of different severe pathologies in the fetuses, including metabolic syndrome, obesity, psychiatric conditions (schizophrenia, attention deficit, autistic spectrum disorders).43 Melatonin may be essential in the normal development of the placenta; this specific function being in the first place sustained by a high expression of melatonin receptors in the placenta, early during pregnancy.44 Synthetizing enzymes and melatonin receptors are expressed in the human placenta throughout pregnancy and promote syncytium formation.45 Melatonin generating system is expressed throughout pregnancy (from week 7 to term) in placental tissues. AANAT and HIOMT show maximal expression at the third trimester of pregnancy. MT1 receptor expression is maximal at the first trimester compared to the second and third trimesters, while MT2 receptor expression does not change significantly during pregnancy. During primary villous cytotrophoblast syncytialization, MT1 receptor expression increases, while MT2 receptor expression decreases. Treatment of primary villous cytotrophoblast with an increasing concentration of melatonin raises syncytium formation and b-hCG secretion.45

31.5.1

Melatonin Levels in the Neonatal Period

Serum samples in the first day of life have been measured in a study that shows a relationship between melatonin concentration and birth weight. If the mean birth weight was <1500 g, melatonin serum level was 63.2 pg/mL, and it has been shown to increase gradually to 79.3 pg/mL at 7 days. If birth weight was >1500 g, melatonin level was 104 pg/mL, and increased at 109.4 at 7 days.46 There are studies that have reported different melatonin concentrations in the umbilical artery (UA) and vein (UV), depending on the mode of delivery. The melatonin concentration was not significantly different between UA and UV blood both at daytime and at nighttime. Both in UA and in UV, the melatonin concentration was significantly higher at nighttime than at daytime. Compared with the C-section group, melatonin in the vaginal deliveries group was significantly higher both at night- and daytime. Melatonin both in UA and in UV was found to be not significantly different between patients with and without risk factors for stress including pregnancy complications (e.g., preeclampsia) and intrapartum complications (e.g., emergency section, pathological doppler, and pathological cardiotocography).47

31.6 DYNAMICS OF MELATONIN SECRETION DURING NORMAL AND PATHOLOGICAL PREGNANCIES Serum melatonin concentrations in women exhibit changes in both physiological and pathological pregnancies compared with nonpregnant controls. Although there are no fetal data, these maternal values are in turn expected to determine the fetal concentrations and impact fetal development and behavior. Also, maternal melatonin titers are not constant during the 40 weeks of pregnancy, but they show specific dynamics, which are also presumed to be reflected in what would be present in simultaneous fetal values (see the table with maternal normal levels in Chapter 2).22 Daytime serum melatonin concentrations were lower in women bearing singletons as compared with women with twins, or pregnancies affected by preeclampsia or intrauterine growth retardation. Nocturnal serum melatonin in mothers increased after 24 weeks of gestation, with highest levels after 32 weeks. Such values were significantly higher in twin pregnancies after 28 weeks of gestation than in single pregnancies, whereas the patients with severe preeclampsia showed lower serum melatonin levels than in women with mild preeclampsia or normal pregnancies after 32 weeks.23

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31.7

MELATONIN ANTIOXIDATIVE PROPERTIES DURING FETAL DEVELOPMENT

Melatonin is known for its antioxidative role, being a direct scavenger for hydroxyl groups and peroxynitrite (or other nitrogen reactive species). The mechanism is formation of melatonin groups during its reaction with different radicals, leading to superoxide anions detoxification. More than this, not only melatonin has the capacity of neutralizing free radicals, but also its metabolites that result during the antioxidative fight.48 Some of them are even more efficient than the melatonin molecule itself.43 Melatonin raises the antioxidative potential of the organism by stimulating antioxidative enzyme production and glutathione quantity in the cells.49 Melatonin maintains mitochondrial homeostasis; it reduces free radical formation at this level and protects ATP synthesis by direct stimulation of enzymatic complexes I and IV, thus maintaining mitochondrial energy production. Melatonin provides mitochondrial protection, having antiapoptotic effects and keeping mitochondrial integrity. It has the ability to scavenge free oxygen and nitrogen reactive species at mitochondrial level, by this preventing disruption of the membrane and of the electron transport chain (ETC). Melatonin also protects mitochondrial DNA (mtDNA). It inhibits the pathological opening of the mitochondrial permeability transition pore (mPTP). Under normal conditions, this pore allows free exchange of low molecular weight molecules, having an alternating open/close behavior. Under pathological conditions, it gets blocked in a continuous open state and leads to mitochondrial rupture. The inhibition of apoptosis is reached by directly preventing nitro-oxidative damage, and by lowering the expression of the proapoptotic protein BAX. Leakage of cytochrome C is thus prevented, and apoptosis cascade propagation is inhibited (Fig. 31.2). Melatonin appears to act in a similar way at the level of the placenta: it scavenges free radicals,29 reduces lipid peroxidation, and enhances antioxidative enzymes production (SOD, glutathione peroxidase and glutathione reductase).50 The placenta represents a major source of free radicals. Peroxidation makers, such as lipid hydroxy peroxide and malondialdehyde, are higher in pregnant versus nonpregnant women.51 Lipid peroxidation begins in the second trimester and progressively increases until delivery.52 Under normal conditions, these processes that induce oxidative stress are well regulated by placental antioxidative enzymes such as SOD, CAT, GPx, glutathione reductase, glutathione S transferase, and glucose 6 phosphate dehydrogenase. A recent study shows that SOD and CAT levels increase during pregnancy and GPx level lowers in mothers.53 Melatonin level is low in pregnant women that associate preeclampsia or intrauterine growth restriction, and this may be explained through a low antioxidative capacity. Oxidative stress is considered an important cause for intrauterine growth restriction. Some studies show that placental dysfunction leads to a chronic hypoxemic state to which the organism adapts by inhibiting fetal growth.54 Intrauterine FIG. 31.2 Melatonin function in the mitochondria. Melatonin reduces free radical formation and protects ATP synthesis by direct stimulation of enzymatic complexes I and IV. Melatonin scavenges free oxygen and nitrogen reactive species at mitochondrial level, by this preventing disruption of the membrane and of the electron transport chain (ETC). It also protects mitochondrial DNA (mtDNA) and inhibits the pathological opening of the mitochondrial permeability transition pore (mPTP). Inhibition of apoptosis is reached by directly preventing nitrooxidative damage, and by lowering the expression of the proapoptotic protein BAX. Leakage of cytochrome C is thus prevented, and apoptosis cascade propagation is inhibited.

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growth restriction is associated with high mortality risk, premature birth, nervous system developmental abnormalities, and potentially severe deficits, such as cerebral palsy.54,55 Fetal distress in human infants has been associated with a high level of ROS production and a reduction of melatonin secretion during the first 3 months after birth.46 Urinary excretion of 6-sulphatoxy melatonin (6SaMT), a metabolite of melatonin, is reduced in response to infants subjected to life-threatening conditions. Diurnal 6SaMT rhythms in these children exhibit lower 24-h mean values. A follow-up in 6 weeks shows an increased excretion in all groups, which suggests that in these infants there is delayed ontogenesis of melatonin secretion and not a long-term impairment of secretion.46

31.8 MELATONIN AND NEURODEVELOPMENT Melatonin has been shown to have important functions in neurodevelopment, highlighted by the presence of its receptors in the central nervous system of the fetus. The literature describes two types of melatonin receptors: ML1 (high affinity) and ML2 (low affinity). ML1 receptors are further subclassified in Mel1A (MT1), Mel1B (MT2), and Mel1C. The latter are not present in mammals. All of them are classic G-coupled receptors, which inhibit adenylate-cyclase.49 There are a lot of available animal studies that determine the presence of MT receptors in the nervous structures in different species. Melatonin receptors appear to be more highly expressed in developing embryos and neonates than in adults.56–58 This may suggest a role of melatonin and the pineal gland in fetal and neonatal development. Indeed, melatonin administration in zebrafish has a positive effect on cell proliferation and accelerates embryonic development. Melatonin has a role in extending the safe limit of proliferation rate at night to allow more rapid development when potentially damaging ultraviolet light is absent.57 In contrast, melatonin receptor antagonists delay neurogenesis in the habenulae, suggesting that melatonin is required for the cell cycle exit of neural progenitors.59 Moreover, following a metabolic insult in the developing rodent brain, melatonin stimulates the proliferation and differentiation of neuronal stem cells,60 and increases axonal sprouting and the expression of axonal markers.61 In Siberian hamsters, melatonin receptors are first identified during development at gestational day 10, in the primitive pharynx. Until days 12 till 14, these receptors are also present in the nasopharynx, the Rathke pouch, caudal arteries, and the thyroid gland during its migration along the thyroglossal duct. At day 16, the Rathke pouch differentiates into the hypophysis, which continues to express specific receptors until birth. Thyroid receptors are no longer identifiable from day 16 until birth.62 In sheep, melatonin receptors were found in the medial cerebral artery, brown adipose tissue, and adrenal gland.41 Melatonin receptors are also present in the median eminence. The hypophyseal concentration of 125I-melatonin was highest at ED day 20 in sheep fetuses, progressively lowering after birth until the 29th day, when it reached 10% out of the aforementioned value. In contrast, the median eminence receptor concentration remains the same through the entire developmental period.41 Fetal melatonin receptor expression appears to be influenced by the secretion of maternal melatonin. One study compared expression and density of receptors in the fetal brain of rat siblings from mothers with or without pinealectomy. At birth, it appears that in both cases, receptors are expressed by the same nervous organs, but pups born from pinealectomized mothers have a 20% lower receptor density. By day 9 after birth, when pups begin to secrete their own melatonin, these differences disappeared. The conclusion of this study was that melatonin is not essential for the expression of its receptors in fetuses, but it does enhance their density.63 Melatonin receptors have been identified in human embryos and fetuses, both in the central nervous system and peripheral organs, such as endocrine glands. One study shows the presence of specific, GTP-sensitive for binding of 2[(125) I] iodomelatonin in the leptomeninges, cerebellum, thalamus, hypothalamus, and brain stem. In the hypothalamus, one of the specific areas is the SCN itself, but receptors are also present in the arcuate, ventromedial and mamillary nuclei. At the level of the brain stem, there are melatonin receptor-positive areas in the nuclei of cranial nerves, such as oculomotor, trochlear, trigeminal motor and sensory, facial, and cochlear.64

31.9 MELATONIN AND PERINATAL NEUROPROTECTION Melatonin has a neuroprotective function in both adult and fetal brain. In adults, there are many studies that show it has a positive effect in neurodegenerative conditions such as Alzheimer’s or Parkinson diseases.65 The neuroprotective effect of melatonin in the fetal brain has not been extensively studied as compared with adults. One study shows that melatonin administration at 10 min after a hypoxic and acidemic episode in sheep fetuses lowers the risk of

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death and the number of activated microglia. It also reduces fetal brain inflammation and cell death.66 A recent study shows that melatonin treatment before and after temporary fetal asphyxia lowers oxidative stress by reducing free radical formation, lipid peroxidation, and cell death it the fetal brain.42 Maternal melatonin administration in an animal model of intrauterine growth restriction in sheep led to reduced oxidative stress and brain damage in newborn lambs.67 The neuroprotective potential of melatonin is shown also by its positive effect on norepinephrine-induced vasoconstriction in the medial cerebral artery.68 It also induces vasodilation in the umbilical blood vessels in an ovine model.69 Hypothermia represents an efficient therapeutic method used in newborns with neonatal encephalopathy, but even so, 50% suffer long-term consequences. Combined treatment method involving hypothermia associated with melatonin administration had a positive effect on cerebral energetic metabolism and neural apoptosis.70 Systemic melatonin administration in newborn rats with intracerebral bleeding leads to a lower degree of cortical atrophy, and better cognitive, sensory, and motor functions in the treated group.70 Fulia et al. measured malonaldehyde and nitrates before and after melatonin administration in human newborns with perinatal asphyxia. Treatment was applied during the first 6 h after birth, and products of lipid peroxidation were measured at 12 and 24 h. Lipid peroxidation products and nitrites levels went progressively down.71 Under pathologic circumstances, melatonin production is greatly influenced, and thus lower and delayed secretion may be found in infants who suffered from preterm delivery, preeclampsia, or growth restriction.3 However, endogenous melatonin production increases in critically ill children, possibly as a counterresponse to the elevated oxidative stress associated with serious diseases.72 Indeed, models of neonatal encephalopathy have shown a beneficial neuroprotective effect of melatonin.66, 69, 70 At birth, the periventricular white matter is highly susceptible to damage during hypoxic-ischemic episodes, given a blood-vessel density decrease in the region.34 Hypoxic damage may lead to necrotic lesions of the periventricular white matter, which are described as periventricular leukomalacia. Postasphyxia melatonin treatment (20 mg/kg infusion) attenuated the lipid peroxidation, and reduced the level of oxidative stress and the number of apoptotic cells in the cerebral white matter in midgestational fetal sheep.66 The protective effects of melatonin on the periventricular white matter of hypoxic neonatal brains were suggested to be due to its antioxidant properties.73 Likewise, hypoxic-ischemic brain injury in the neonates results in mitochondrial dysfunction and increased oxidative stress.74 Hypoxic-ischemic injury induces an increase in deferoxamine (DFO)-chelatable free iron in the rat cerebral cortex, followed by increase in oxidative stress, which may be prevented by melatonin administration.75 Melatonin treatment before or after hypoxic insults in immature rats was shown to provide a long-lasting benefit, suggesting that melatonin could represent a potentially safe approach to perinatal brain damage in humans.75 Human studies have shown melatonin toxicity to be extremely low when including data available from use in children with various neurologically disabling disorders,76 or even from administration to neonates with sepsis. Hence the neuroprotective outcomes of melatonin on the fetal brain could be assessed in human studies. A randomized controlled pilot study tested the clinical outcomes of melatonin in neonates with hypoxic-ischemic encephalopathy (HIE) including 45 newborns: 30 affected and 15 healthy controls. HIE infants were randomized into a hypothermia group (N ¼ 15), which received 72-h whole-body cooling, and a combined melatonin/hypothermia group (N ¼ 15), which received hypothermia and five daily enteral doses of melatonin at 10 mg/kg. Serum nitric oxide (NO), plasma superoxide dismutase (SOD), and melatonin levels were measured for the 45 probands on admission and after 5 days. The study concluded that compared with healthy neonates, the HIE groups had increased melatonin, SOD, and NO. However, after 5 days, the melatonin/hypothermia group had a significantly higher level of melatonin and decrease in NO and SOD. This group also had fewer seizures on follow-up electroencephalogram and fewer white matter abnormalities on MRI. Importantly, at 6 months, the melatonin/hypothermia group had significantly better survival rate without developmental or neurological abnormalities.77 Melatonin appears thus to be safe and beneficial in HIE treatment. However, larger randomized controlled trials are required before melatonin can be approved for usage in preventing the consequences of HIE.78 As with the other neuroprotective benefits described earlier in this section, melatonin treatment cannot be recommended for widespread human use due to the lack of data from definitive clinical trials.

31.10

MELATONIN AND BEHAVIOR

Melatonin modulates a sum of physiologic functions such as circadian rhythm, sleep induction, visual, reproductive, neuroendocrine, and immune system functions. It has roles in normal behavior, including learning, stress response,79–87 memory88 (especially short-term memory89), and pain perception.90–92

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Changes in melatonin secretion were found in a variety of psychiatric pathologies in humans: seasonal depressive disorder, bipolar disorder, depression, bulimia, anorexia, schizophrenia, panic attack, and obsessive-compulsive disorder. Memory is a complex process, occurring at an intense rate in the neonatal period and involving distinct phases: acquisition, consolidation, and retrieval. Using an active avoidance conditioning test, it was shown that fish learn better during the day and that melatonin has an adverse effect on mnemonic performance, while pinealectomy improves it.93 However, under stressful events, melatonin seemed to promote memory formation.94 Melatonin inhibits the modifications of synaptic strength, the basic cellular mechanism for memory.95 Yet the mechanism by which melatonin rhythmically influences cognitive processes remains unknown. Melatonin has broad-spectrum antioxidant properties and potentially modulates inflammation, neurogenesis, and neuroprotection. It seems thus possible that melatonin treatment will be beneficial for a wide range of neonatal conditions. Under these circumstances, the effect of melatonin on mnemonic performance should be better evaluated, given the crucial role of memory formation in the neonatal period. The pineal gland is a regulator of various functions, among which it influences nervous system function, through a complex interaction with neurotransmitter synthesis and activity, especially monoaminergic system function (serotonin, norepinephrine, and dopamine).

31.10.1

Serotonin

Serotonin is the main coordinator of circadian rhythms. In addition to the known relationship with melatonin on the synthetic pathway, there are other levels at which the two molecules interact. The SCN contains a dense serotonergic terminal plexus.30 It has been shown that a serotonin agonist administration modifies the SCN rhythm in rats,96 but the exact pathway through which serotonin influences its function is not known. A few pertinent hypotheses have emerged. One theory shows that serotonin stimulates potassium currents at a postsynaptic level, in a population of SCN neurons,97 and another shows there is a presynaptic influence of serotonin.98 Serotonin is known to influence the synchronization of circadian rhythms, as light does. But serotonin’s effect is more evident during day time, because serotonin administration during the night period failed to change Clock genes expression.99 This effect may be explained by the expression of serotonin receptors in a circadian manner.100 Serotonin is secreted by the raphe nuclei, while melatonin has an inhibitory effect on its neurons, through an MT1 modulated interaction.101

31.10.2

Norepinephrine

Melatonin synthesis at the pineal level depends on the normal function of the key enzyme aryl-alkyl N-acetyl transferase (AANAT), which catalyzes serotonin N acetylation and is active during the night.102 We might say even that AANAT function represents the circadian regulator at the pineal level. Nocturnal release of melatonin is a norepinephrine-dependent process, which induces AANAT synthesis.103

31.10.3

Dopamine

Dopamine is the precursor molecule for norepinephrine, being the neurotransmitter of sympathetic nerve endings that leave the pineal gland. The secretory cells present D4 dopamine receptors, and their expression is modulated by the light/dark cycle.104 In its turn, melatonin controls dopamine synthesis in specific brain regions such as the hypothalamus, the tubuleinfundibular area, and the ventral hippocampus.105 Some studies show melatonin might have a direct effect on dopamine receptors—for example, it raises D2 expression in the rat striated body.106 MT1 and MT2 localization overlaps D2 receptors at nervous system: hippocampus, cortex, hypothalamus and brain stem.107–109 More than this, it has been shown that dopamine receptor expression has a circadian rhythm, with a low concentration during the day.110

31.11

MELATONIN ROLE IN IMMUNOMODULATION IN THE FETUS AND NEONATE

While it is generally accepted that the pineal gland has neuroendocrine functions, its involvement in the immune system function has yet to be fully explored. Removal of the pineal gland in neonatal rats results in a reduced number of circulating immune cells, such as lymphocytes and leukocytes, and a worse outcome after an infectious insult.78 In a small study on septic newborn babies, melatonin was effective in reducing the levels of lipid peroxidation products and improving the

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survival and overall clinical outcome. This study was conducted to determine the changes in the clinical status and the serum levels of lipid peroxidation products (malondialdehyde [MDA] and 4-hydroxylalkenals [4-HDA]) in 10 septic newborns treated with the antioxidant melatonin, given within the first 12 h after diagnosis. Melatonin improved the clinical outcome of the septic newborns, as judged by measurement of sepsis-related serum parameters after 24 and 48 h. Three of 10 septic children who were not treated with melatonin died within 72 h after diagnosis of sepsis; none of the 10 septic newborns treated with melatonin died.111 Also, immune-modulating effects of melatonin have been widely inferred in adult humans who presented higher melatonin metabolites after a viral meningitis infection.112, 113 In the cultured rat pineal gland, lipopolysaccharide induced a downregulation of AANAT, the rate-limiting enzyme in melatonin synthesis, implying that infection may itself modulate the endogenous production of melatonin.114 These findings are suggestive of an involvement of melatonin in the host immune response. However, exogenous melatonin has shown effects in modulating the host immune response. Melatonin led to an increase in superoxide dismutase antioxidant activity, a reduction in nitric oxide levels, and a decrease in neuronal injury in a rabbit model of Streptococcus pneumoniae meningitis.115 Furthermore, in a rodent model of Klebsiella pneumoniae meningitis, melatonin reversed microglial activation and neuronal apoptosis in a dose-dependent manner.116 Hypoxia-ischemia at parturition is aggravated by bacterial infection of the immature brain.117 In a neonatal rat model of lipopolysaccharide (LPS)-sensitized hypoxic-ischemic brain injury, melatonin showed similar beneficial effects as in HIE, with overall reduced oxidative stress and inhibited neuronal apoptosis.118 Immunomodulation may also play a role in recovery after surgery. Gitto et al. reported on 10 neonates who received lung or abdominal surgery, and showed lower levels of interleukin-6 and interleukin-8, and a significant clinical improvement after administration of melatonin.119 Furthermore, melatonin was reported to be as effective as midazolam in achieving sedation and reducing preoperative anxiety in children.120

31.12

NORMAL RELATIONSHIP BETWEEN MOTHER AND FETAL CIRCADIAN RHYTHMS

Fetal programming is a newly emerged concept, which connects environmental characteristics present during embryonic and fetal development with an increased risk of different pathologies later in adult life. Beginning with conception and until birth, embryos and fetuses are exposed to a continuous complex flux of chemical signals coming from the maternal organism, with those that are able to cross the placental barrier having potential direct effects on development. Maternal risk factors during development such as gestational diabetes, intrauterine growth restriction, preeclampsia, maternal undernutrition, and maternal stress, may have an important influence on pregnancy outcome. The pathophysiological basis of this phenomenon could be the existence of high oxidative stress, which in turn may influence fetal development. As previously mentioned, nocturnal melatonin levels in pregnant women with preeclampsia were significantly lower compared with normal pregnancies (48.4  24.7 vs. 85.4  26.9 pg/mL). Blood pressure variations and the melatonin secretion rhythm seem to parallel each other daily during the preeclamptic pregnancy and until 2 months after birth.121 Another theory proposes the existence of an epigenetic mechanism, through DNA super structural changes, that come about as an adaptation to potentially harmful external factors exerted during pregnancy. It is believed that melatonin regulates this type of transmission and that it acts through nuclear receptors and not the aforementioned membrane ones. Their activation leads to ultrastructural DNA changes at the oocyte level.71 External factors that influence the maternal organism are not necessarily inducing somatic changes in the embryo or fetus, but may also influence the future development of psychiatric issues, behavioral changes, and even diseases. A study that involves this concept is one developed by Ezra Susser et al., who followed the effects of severe food deprivation in pregnant women during World War II.122 This study reported, among other things, the association of folate deficiency during pregnancy with neural tube defects. Another discovery was the identification of a high frequency of psychiatric conditions in children resulting from these pregnancies (especially schizophrenia), the risk being higher in those whose mothers were subjected to food deprivation during the second trimester.122, 123 This result has been confirmed by following studies.123 An extensive study on 3099 mother-child pairs that finished in 2014 followed the impact of the maternal state during gestation on adults resulting from these pregnancies. The conclusion was that the offspring of stressed mothers had a high risk of developing behavioral disorders and depression.124 There are also many available animal studies that point out maternal stress in utero can lead to behavioral abnormalities in the offspring at later ages. During pregnancy, the maternal organism adapts to support the growth of a full developed fetus, and to maintain maternal metabolic functions. One such adaptation is represented by changes in clock genes expression during pregnancy

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in the maternal liver and adipose tissue.15, 125 There are gestational adjustments in the rhythmicity of genes regulating lipogenesis and gluconeogenesis in these tissues.125 The importance of a normally functioning circadian system in mothers is further highlighted by evidence that disruptions in maternal circadian rhythm (night shifts in pregnant women, or continuous light exposure during pregnancy in animal studies) leads to negative fetal outcomes such as a higher miscarriage risk, preterm labor, low birth weight,126–128 behavioral alterations,129, 130 and psychiatric diseases. Whether these disruptions are directly the result of altered pineal function or melatonin release remains to be confirmed.

31.13

CONCLUSION

Melatonin appears to be an important regulator of complex embryo-fetal developmental processes. It induces circadian rhythmicity in the offspring and may have direct developmental effects on nervous and endocrine systems, while also protecting against damage from oxidative stress. Animal models have suggested that melatonin has neuroprotective effects. There is also new evidence of melatonin possibly being an epigenetic transducer. Further studies are required to confirm these postulated roles. Melatonin is currently an over-the-counter drug. It appears to have no acute adverse effects, based on a few clinical studies of small size that have been done in pregnant women. However, because melatonin’s safety or proposed extensive effects on fetal development have not been rigorously confirmed by animal or especially by human studies, it cannot be recommended for use by pregnant women at the present time.

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