SEARCH

SEARCH BY CITATION

Keywords:

  • development;
  • growth;
  • infant;
  • melatonin;
  • premature;
  • therapy

Abstract

  1. Top of page
  2. Abstract
  3. Functions of melatonin
  4. Fetal and neonatal melatonin secretion
  5. Melatonin as a tissue protector
  6. Postnatal melatonin studies
  7. Should short gestation instants be given melatonin supplementation?
  8. References

Abstract:  Pineal melatonin regulates circadian rhythms and influences sleep. Melatonin also has protective actions against tissue damage from free-radicals and other toxins. Evidence is presented that this indoleamine is involved in pre- and postnatal brain (and ocular) development and intrauterine growth. In the absence of maternal melatonin, short gestation infants have a prolonged period of melatonin deficiency. Melatonin supplementation, which has a benign safety profile, may help reduce complications in the neonatal period that are associated with short gestation. We believe that this treatment might result in a wide range of health benefits, improved quality of life and reduced healthcare costs.

The fetus receives melatonin from the mother, but following premature delivery there may be a period of prolonged melatonin deficiency. The purpose of this presentation is to suggest that this deficiency may be harmful because this neurohormone has important functions in the fetus. It is hoped that this article will promote further discussion and research in this field.

Functions of melatonin

  1. Top of page
  2. Abstract
  3. Functions of melatonin
  4. Fetal and neonatal melatonin secretion
  5. Melatonin as a tissue protector
  6. Postnatal melatonin studies
  7. Should short gestation instants be given melatonin supplementation?
  8. References

Melatonin (N-acetyl-5-methoxytriptamine) is a small lipid and water-soluble indoleamine molecule which can easily cross membrane barriers. The circulating melatonin is mainly produced by the pinealocytes in the pineal gland. Normally, secretion begins in the evening and lasts until the morning. Light causes specialized retinal ganglion cells to send information to the suprachiasmatic nuclei of the hypothalamus and through the sympathetic pathway to the pineal gland. Light exposure inhibits melatonin secretion while darkness promotes it. Besides the retina, the suprachiasmatic nuclei also receive numerous inputs from other brain areas [1].

Blood melatonin exhibits a circadian rhythm and influences the sleep–wake cycle which changes the physiology from day time to night time in a well co-ordinated manner. Due to its antioxidant and free radical scavenging activities, melatonin is a neuro- and somatic tissue protector [2–4]. There is evidence to suggest that melatonin has immunological [5], hematological [6], gastrointestinal [7], renal [8], anticonvulsant [9], cytoskeletal modulator [10] and other functions, some of which are not well defined.

Most organs have their own circadian clocks and they may produce minute amounts of melatonin which act locally [11]. Pineal melatonin also assists in the synchronization of these clocks and the circadian rhythmicity of all tissues pre- and postnatally [12–14]. The autonomic nervous system and the synthesis and release of hormones are also under circadian control [15, 16]. Internal desynchronization leads to desynchronization of cellular oscillators and affects metabolism of all cells [17].

Disturbed circadian rhythms are not only associated with sleep disorders but also with impaired health [18]. Children with multiple developmental, neuropsychiatric and health difficulties often have an associated melatonin deficiency [19]. When the circadian rhythms are restored, their behavior, mood, development, intellectual functioning, health and even seizure control may improve [9, 20].

The most rapid development of the human brain is during the last trimester of pregnancy and in the neonatal period. Fetuses and newborns spend 16–18 hr/day asleep, most of it being in rapid eye movement (REM) state [21]. REM sleep deprivation in developing animals results in diminished brain growth because neuronal activation occurs mainly during this sleep phase [22].

There is also increasing evidence that circadian gene regulation is important for normal embryonic development [23]. In vitro experiments with human tissues showed that cell proliferation was under the control of the daily rise and fall of melatonin levels. This circadian influence was seen in studies with preadipocytes [24], myocytes [25], epithelial cell growth in rectal crypts [26], bone cells [27], and bone marrow and blood cells [28]. The lack of circadian rhythm in animal models suppresses neurogenesis [29, 30].

Fetal and neonatal melatonin secretion

  1. Top of page
  2. Abstract
  3. Functions of melatonin
  4. Fetal and neonatal melatonin secretion
  5. Melatonin as a tissue protector
  6. Postnatal melatonin studies
  7. Should short gestation instants be given melatonin supplementation?
  8. References

The fetus receives melatonin from the mother [31]. Through the placenta melatonin readily passes to all fetal tissues [32] and as a result, maternal melatonin drives fetal circadian rhythms [33]. In newborn mice, maternal melatonin concentration is the highest in the brain than in other tissues, and declines during the first postnatal week by over 90% [34]. After birth, the full-term neonate does not produce melatonin for 2–4 months, leading to transient melatonin deficiency [35–40]. Although the suprachiasmatic nuclei and the pineal gland appear to mature in early fetal life [37], the neurological circuitry controlling these structures does not [41, 42]. Therefore, in the absence of maternal melatonin, the emergence of circadian rhythms is dependent on neurodevelopmental maturation rather than on the environment [43].

Prematurity itself does not hasten the maturation of the neurological network controlling melatonin secretion. The onset of pineal melatonin secretion is even more delayed when there is exposure to neurological insults [36, 39]. Therefore, in premature neonates the melatonin deficiency is more prolonged [35, 36, 38, 39]. An infant born 3–4 months prematurely may lack significant melatonin levels for 7–8 months or longer. Melatonin in the nocturnal breast milk does not correct this deficiency [44, 45] and does not affect neonatal morbidity [46–49].

Melatonin as a tissue protector

  1. Top of page
  2. Abstract
  3. Functions of melatonin
  4. Fetal and neonatal melatonin secretion
  5. Melatonin as a tissue protector
  6. Postnatal melatonin studies
  7. Should short gestation instants be given melatonin supplementation?
  8. References

In fetal animals endogenous and exogenous melatonin offers protection against a variety of insults, such as hyperthermia [50], ischemia [51, 52], lipopolysaccharide [53], trauma [54–56], ethanol [57], phenylketonuria [58], umbilical cord occlusion [59] and induced maternal epilepsy [60]. When pregnant animals and their fetuses in these studies were made melatonin deficient by pinealectomy or exposure to constant light, the damage from neurological and somatic insults was always less marked when the deficiency was corrected by pharmacological doses of melatonin [61–65].

Many, but not all, functions of melatonin are expressed through receptor sites. Melatonin receptors are widespread in human [66] and animal tissues [67], more so in pre- and postnatal than in later age groups [11, 68, 69]. They are even detected in neural stem cells [70]. The presence of melatonin receptors in fetal organs from early in gestation suggests that melatonin is involved in prenatal development.

It is increasingly believed that pre- and postnatal daily rise and fall of melatonin levels have an impact on the development of the brain [71]. The offspring of melatonin-deficient animals exhibit reduced cerebellar size [58, 65], decreased hippocampal growth [56, 72], delayed maturation of the reproductive organs [73], impaired health [62], delayed neurodevelopment [64, 74] and have higher incidence of malformations [75]. Melatonin deficiency also appears to be associated with intrauterine growth retardation, while melatonin supplementation may prevent it [53, 73]. In postnatal avian species and mammals melatonin deficiency leads to scoliosis as a result of asymmetric growth [61, 63] and abnormal ocular development [76].

Abnormal brain development and intrauterine growth restriction are frequently demonstrated in very premature human neonates [77–80]. Brain imaging may show decreased cerebellar volume [81–83], small corpus callosum [84, 85], reduced volumes of caudate nuclei, hippocampus, total brain [86] and a smaller brain stem [83]. In a recent study [87], 113 extremely preterm infants had serial brain magnetic resonance imaging soon after premature delivery until term-corrected age. The findings indicated that longer exposure to extrauterine environment was associated with the proportionate reduction of cortical surface area and more severe neurocognitive impairments. This association was thought to be due to reduced connectivity rather than destructive lesions. It was suggested that the coordinated growth of the brain is vulnerable to immunological, nutritional or pharmacological factors associated with premature exposure to the extrautarine environment. Impaired head growth among premature infants has also been shown to parallel both the severity of retinopathy of prematurity and insulin-like growth factor-1 deficit [88]. Insulin-like growth factor-1 is known to be low after premature birth and it is associated with abnormal blood vessel growth in the retina. Melatonin deficiency is associated with reduced insulin-like growth factor-1 in animal studies [89], while in cultured human granulosa cells melatonin stimulates its release [90]. Melatonin may also protect against a variety of pre- and postnatal ocular diseases [91].

Postnatal melatonin studies

  1. Top of page
  2. Abstract
  3. Functions of melatonin
  4. Fetal and neonatal melatonin secretion
  5. Melatonin as a tissue protector
  6. Postnatal melatonin studies
  7. Should short gestation instants be given melatonin supplementation?
  8. References

Short-term melatonin therapy, using pharmacological doses, has been carried out in premature and full-term neonates without side effects. Melatonin therapy appears to benefit respiratory distress syndrome [92], sepsis [93], hypoxic-ischemic insults [94] and oxidative stress following surgery [95].

In animal models melatonin supplementation protected against streptococcal meningitis in vivo and in vitro [96], pyelonephritis [97], and different types of brain injury [55, 98–102]. It reduced edema following middle cerebral artery occlusion [103], inhibited experimental proliferative vitreoretinopathy [104], and protected against ultraviolet-B exposure to the lens [105]. Exogenous melatonin aided the recovery from spinal cord injury [106, 107], sciatic nerve transection [72], alleviated the effects of retrograde optic nerve transection [54] and protected against drug toxicity [108].

Should short gestation instants be given melatonin supplementation?

  1. Top of page
  2. Abstract
  3. Functions of melatonin
  4. Fetal and neonatal melatonin secretion
  5. Melatonin as a tissue protector
  6. Postnatal melatonin studies
  7. Should short gestation instants be given melatonin supplementation?
  8. References

From the previous discussion it is evident that the melatonin drives circadian rhythms, aids in the synchronization of circadian rhythmicity in all tissues, and disturbances of melatonin secretion are associated with impaired health. Furthermore, pre- and postnatal somatic and brain tissue growth and gene regulation required for development are also under circadian control. Full-term neonates normally have a transient melatonin deficiency, which is much more prolonged in preterm infants. Abnormal brain and ocular development and intrauterine growth retardation are frequently demonstrated in very premature infants. Studies in animal models suggest that these are related to melatonin deficiency and can be corrected with melatonin supplementation. Melatonin is a tissue protector and this protection increases with higher pharmacological doses. Based on these observations, prolonged melatonin deficiency in very premature infants appears to represent a major health problem which may benefit from melatonin supplementation.

Environmental changes creating ‘day and night cycles’ appear to be ineffective for hastening the onset of melatonin secretion [109] because it is dependent upon the maturation of the premature infant's brain. Therefore, nocturnal melatonin supplementation is the best way to establish a circadian rhythm because it resembles the maternally driven circadian rhythm. Continuous 24-hr supplementation may be disastrous [110].

As sustained-release melatonin products are not available for infants, fast-release (intravenous or liquid formulations) may be used. These products are only effective for 3–4 hr because the half-life of melatonin is <1 hr. Therefore continuous nocturnal administration of 2–4 mg of melatonin through intravenous routes or feeding tubes would be ideal. Alternatively, a larger pharmacological oral dose of 2–3 mg could be given at ‘bed time’ and repeated in the middle of the night. The oral dose must be larger because of poor bioavailability [111]. However, this method of administration would be less desirable because uneven melatonin levels would be created. Our literature review shows that melatonin is not prescribed according to weight. Although premature and full-term infants have been treated with pharmacological doses, without apparent adverse effects, dose studies in neonates have not been carried out. Therefore, further research should establish the ideal therapeutic doses for use in premature infants.

The influence of melatonin supplementation on the onset of pineal melatonin secretion in infants has not been studied, but it is unlikely to impede it, because suppression from exogenous melatonin does not occur in older age groups when they are given supplements of the indoleamine. The establishment of appropriate circadian rhythms in humans, by any method, including melatonin therapy, normalizes endogenous melatonin secretion [112]. Therefore, the therapy could continue until the brain becomes sufficiently mature to drive pineal function. The best clinical evidence for this would be when, following a brief interruption of treatment, the sleep–wake rhythm continues as before, rather than breaking up. Estimation of the major urinary metabolite of melatonin, 6-sulphatoxymelatonin, in 24-hr urine samples would also be a useful measure.

There is general agreement that short-term melatonin therapy has a remarkably benign safety profile, even when neonates are treated with pharmacological doses [92–94]. Significant complications with long-term melatonin therapy in children and adults have not been reported, although these studies are few [113, 114]. None of the animal studies of maternal melatonin treatment and in postnatal life have shown treatment-related side effects [115, 116].

We hope that this presentation will lead to further consideration, scientific debate, and development of prospective research aimed at determining the potential value of melatonin supplementation in this at risk patient population. We believe the evidence reviewed here suggests that melatonin treatment may help reduce complications in the neonatal period that are associated with short gestation. We believe there is a potential for the reduction of mortality and morbidity in this population. There might be a wide range of health benefits, improved quality of life and reduction of healthcare costs.

References

  1. Top of page
  2. Abstract
  3. Functions of melatonin
  4. Fetal and neonatal melatonin secretion
  5. Melatonin as a tissue protector
  6. Postnatal melatonin studies
  7. Should short gestation instants be given melatonin supplementation?
  8. References
  • 1
    Cardinali DP, Furio AM, Reyes MP et al. The use of chronobiotics in the resynchronization of the sleep-wake cycle. Cancer Causes Control 2006; 17:601609.
  • 2
    Reiter RJ, Melchiorri D, Sewerynek E et al. A review of the evidence supporting melatonin's role as an antioxidant. J Pineal Res 1995; 18:111.
  • 3
    Reiter RJ. Melatonin: clinical relevance. Best Pract Res Clin Endocrinol Metab 2003; 17:273285.
  • 4
    Leon J, Acuna-Castroviejo D, Escames G et al. Melatonin mitigates mitochondrial malfunction. J Pineal Res 2005; 38:19.
  • 5
    Maestroni GJ. Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer. Adv Exp Med Biol 1999; 467:217226.
  • 6
    Todisco M, Casaccia P, Rossi N. Severe bleeding symptoms in refractory idiopathic thrombocytopenic purpura: a case successfully treated with melatonin. Am J Ther 2003; 10:135136.
  • 7
    Bubenik GA. Localization, physiological significance and possible clinical implication of gastrointestinal melatonin. Biol Signals Recept 2001; 10:350366.
  • 8
    Van Gool JD, Nieuwenhuis E, Ten Doeschate IO et al. Subtypes in monosymptomatic nocturnal enuresis. II. Scand J Urol Nephrol Suppl 1999; 202:811.
  • 9
    Fauteck J, Schmidt H, Lerchl A et al. Melatonin in epilepsy: first results of replacement therapy and first clinical results. Biol Signals Recept 1999; 8:105110.
  • 10
    Benitez-King G. Melatonin as a cytoskeletal modulator: implications for cell physiology and disease. J Pineal Res 2006; 40:19.
  • 11
    Balsalobre A. Clock genes in mammalian peripheral tissues. Cell Tissue Res 2002; 309:193199.
  • 12
    Pevet P, Bothorel B, Slotten H et al. The chronobiotic properties of melatonin. Cell Tissue Res 2002; 309:183191.
  • 13
    Johnston JD, Messager S, Barrett P et al. Melatonin action in the pituitary: neuroendocrine synchronizer and developmental modulator? J Neuroendocrinol 2003; 15:405408.
  • 14
    Jimenez-Jorge S, Jimenez-Caliani AJ, Guerrero JM et al. Melatonin synthesis and melatonin-membrane receptor (MT1) expression during rat thymus development: role of the pineal gland. J Pineal Res 2005; 39:7783.
  • 15
    Buijs RM, Van Eden CG, Goncharuk VD et al. The biological clock tunes the organs of the body: timing by hormones and the autonomic nervous system. J Endocrinol 2003; 177:1726.
  • 16
    Hirayama J, Sassone-Corsi P. Structural and functional features of transcription factors controlling the circadian clock. Curr Opin Genet Dev 2005; 15:548556.
  • 17
    Haus E, Smolensky M. Biological clocks and shift work: circadian dysregulation and potential long-term effects. Cancer Causes Control 2006; 17:489500.
  • 18
    Arendt J. Melatonin and human rhythms. Chronobiol Int 2006; 23:2137.
  • 19
    Jan JE, Freeman RD. Melatonin therapy for circadian rhythm sleep disorders in children with multiple disabilities: what have we learned in the last decade? Dev Med Child Neurol 2004; 46:776782.
  • 20
    Bonilla E, Valero N, Chacin-Bonilla L et al. Melatonin and viral infections. J Pineal Res 2004; 36:7379.
  • 21
    Mirmiran M, Maas YG, Ariagno RL. Development of fetal and neonatal sleep and circadian rhythms. Sleep Med Rev 2003; 7:321334.
  • 22
    Morrissey MJ, Duntley SP, Anch AM et al. Active sleep and its role in the prevention of apoptosis in the developing brain. Med Hypotheses 2004; 62:876879.
  • 23
    Moser M, Fruhwirth M, Penter R et al. Why life oscillates – from a topographical towards a functional chronobiology. Cancer Causes Control 2006; 17:591599.
  • 24
    Zwirska-Korczala K, Jochem J, Adamczyk-Sowa M et al. Influence of melatonin on cell proliferation, antioxidative enzyme activities and lipid peroxidation in 3T3-L1 preadipocytes – an in vitro study. J Physiol Pharmacol 2005; 56(Suppl. 6):9199.
  • 25
    Schlabritz-Loutsevitch N, Hellner N, Middendorf R et al. The human myometrium as a target for melatonin. J Clin Endocrinol Metab 2003; 88:908913.
  • 26
    Marra G, Anti M, Percesepe A et al. Circadian variations of epithelial cell proliferation in human rectal crypts. Gastroenterology 1994; 106:982987.
  • 27
    Nakade O, Koyama H, Ariji H et al. Melatonin stimulates proliferation and type I collagen synthesis in human bone cells in vitro. J Pineal Res 1999; 27:106110.
  • 28
    Smaaland R, Sothern RB, Laerum OD et al. Rhythms in human bone marrow and blood cells. Chronobiol Int 2002; 19:101127.
  • 29
    Guzman-Marin R, Suntsova N, Methippara M et al. Sleep deprivation suppresses neurogenesis in the adult hippocampus of rats. Eur J Neurosci 2005; 22:21112116.
  • 30
    Tung A, Takase L, Fornal C et al. Effects of sleep deprivation and recovery sleep upon cell proliferation in adult rat dentate gyrus. Neuroscience 2005; 134:721723.
  • 31
    Okatani Y, Okamoto K, Hayashi K et al. Maternal-fetal transfer of melatonin in pregnant women near term. J Pineal Res 1998; 25:129134.
  • 32
    Lahiri DK, Ge YW, Sharman EH et al. Age-related changes in serum melatonin in mice: higher levels of combined melatonin and 6-hydroxymelatonin sulfate in the cerebral cortex than serum, heart, liver and kidney tissues. J Pineal Res 2004; 36:217223.
  • 33
    Breen S, Rees S, Walker D. The development of diurnal rhythmicity in fetal suprachiasmatic neurons as demonstrated by fos immunohistochemistry. Neuroscience 1996; 74:917926.
  • 34
    Bubenik GA, Pang SF. The role of serotonin and melatonin in gastrointestinal physiology: ontogeny, regulation of food intake, and mutual serotonin-melatonin feedback. J Pineal Res 1994; 16:9199.
  • 35
    Kennaway DJ, Stamp GE, Goble FC. Development of melatonin production in infants and the impact of prematurity. J Clin Endocrinol Metab 1992; 75:367369.
  • 36
    Kennaway DJ, Goble FC, Stamp GE. Factors influencing the development of melatonin rhythmicity in humans. J Clin Endocrinol Metab 1996; 81:15251532.
  • 37
    Seron-Ferre M, Torres-Farfan C, Forcelledo ML et al. The development of circadian rhythms in the fetus and neonate. Semin Perinatol 2001; 25:363370.
  • 38
    Sivan Y, Laudon M, Tauman R et al. Melatonin production in healthy infants: evidence for seasonal variations. Pediatr Res 2001; 49:6368.
  • 39
    Tauman R, Zisapel N, Laudon M et al. Melatonin production in infants. Pediatr Neurol 2002; 26:379382.
  • 40
    Ardura J, Gutierrez R, Andres J et al. Emergence and evolution of the circadian rhythm of melatonin in children. Horm Res 2003; 59:6672.
  • 41
    Commentz JC, Henke A, Dammann O et al. Decreasing melatonin and 6-hydroxymelatonin sulfate excretion with advancing gestational age in preterm and term newborn male infants. Eur J Endocrinol 1996; 135:184187.
  • 42
    Macchi MM, Bruce JN. Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol 2004; 25:177195.
  • 43
    Gertner S, Greenbaum CW, Sadeh A et al. Sleep-wake patterns in preterm infants and 6 month's home environment: implications for early cognitive development. Early Hum Dev 2002; 68:93102.
  • 44
    Illnerova H, Buresova M, Presl J. Melatonin rhythm in human milk. J Clin Endocrinol Metab 1993; 77:838841.
  • 45
    Cubero J, Valero V, Sanchez J et al. The circadian rhythm of tryptophan in breast milk affects the rhythms of 6-sulfatoxymelatonin and sleep in newborn. Neuro Endocrinol Lett 2005; 26:657661.
  • 46
    Furman L, Minich NM, Hack M. Breastfeeding of very low birth weight infants. J Hum Lact 1998; 14:2934.
  • 47
    Furman L, Taylor G, Minich N et al. The effect of maternal milk on neonatal morbidity of very low-birth-weight infants. Arch Pediatr Adolesc Med 2003; 157:6671.
  • 48
    Furman L, Minich N. Efficiency of breastfeeding as compared to bottle-feeding in very low birth weight (VLBW, <1.5 kg) infants. J Perinatol 2004; 24:706713.
  • 49
    Gitto E, Reiter RJ, Sabatino G et al. Correlation among cytokines, bronchopulmonary dysplasia and modality of ventilation in preterm newborns: improvement with melatonin treatment. J Pineal Res 2005; 39:287293.
  • 50
    Matsuzuka T, Sakamoto N, Ozawa M et al. Alleviation of maternal hyperthermia-induced early embryonic death by administration of melatonin to mice. J Pineal Res 2005; 39:217223.
  • 51
    Cuzzocrea S, Costantino G, Gitto E et al. Protective effects of melatonin in ischemic brain injury. J Pineal Res 2000; 29:217227.
  • 52
    Watanabe K, Wakatsuki A, Shinohara K et al. Maternally administered melatonin protects against ischemia and reperfusion-induced oxidative mitochondrial damage in premature fetal rat brain. J Pineal Res 2004; 37:276280.
  • 53
    Chen YH, Xu DX, Wang JP et al. Melatonin protects against lipopolysaccharide-induced intra-uterine fetal death and growth retardation in mice. J Pineal Res 2006; 40:4047.
  • 54
    Kilic E, Hermann DM, Isenmann S et al. Effects of pinealectomy and melatonin on the retrograde degeneration of retinal ganglion cells in a novel model of intraorbital optic nerve transection in mice. J Pineal Res 2002; 32:106111.
  • 55
    Beni SM, Kohen R, Reiter RJ et al. Melatonin-induced neuroprotection after closed head injury is associated with increased brain antioxidants and attenuated late-phase activation of NF-kappaB and AP-1. FASEB J 2004; 18:149151.
  • 56
    Ozdemir D, Tugyan K, Uysal N et al. Protective effect of melatonin against head trauma-induced hippocampal damage and spatial memory deficits in immature rats. Neurosci Lett 2005; 385:234239.
  • 57
    Baydas G, Tuzcu M. Protective effects of melatonin against ethanol-induced reactive gliosis in hippocampus and cortex of young and aged rats. Exp Neurol 2005; 194:175181.
  • 58
    Martinez-Cruz F, Pozo D, Osuna C et al. Oxidative stress induced by phenylketonuria in the rat: prevention by melatonin, vitamin E, and vitamin C. J Neurosci Res 2002; 69:550558.
  • 59
    Miller SL, Yan EB, Castillo-Melendez M et al. Melatonin provides neuroprotection in the late-gestation fetal sheep brain in response to umbilical cord occlusion. Dev Neurosci 2005; 27:200210.
  • 60
    Turgut M, Uyanikgil Y, Ats U et al. Pinealectomy stimulates and exogenous melatonin inhibits harmful effects of epileptiform activity during pregnancy in the hippocampus of newborn rats: an immunohistochemical study. Childs Nerv Syst 2005; 25:481488.
  • 61
    Machida M, Dubousset J, Imamura Y et al. Role of melatonin deficiency in the development of scoliosis in pinealectomised chickens. J Bone Joint Surg Br 1995; 77:134138.
  • 62
    Nishida S, Sato R, Murai I et al. Effect of pinealectomy on plasma levels of insulin and leptin and on hepatic lipids in type 2 diabetic rats. J Pineal Res 2003; 35:251256.
  • 63
    Fjelldal PG, Grotmol S, Kryvi H et al. Pinealectomy induces malformation of the spine and reduces the mechanical strength of the vertebrae in Atlantic salmon, Salmo salar. J Pineal Res 2004; 36:132139.
  • 64
    Uysal N, Ozdemir D, Dayi A et al. Effects of maternal deprivation on melatonin production and cognition in adolescent male and female rats. Neuro Endocrinol Lett 2005; 26:555560.
  • 65
    Tunc AT, Turgut M, Aslan H et al. Neonatal pinealectomy induces Purkinje cell loss in the cerebellum of the chick: a stereological study. Brain Res 2006; 1067:95102.
  • 66
    Thomas L, Purvis CC, Drew JE et al. Melatonin receptors in human fetal brain: 2-[(125)I]iodomelatonin binding and MT1 gene expression. J Pineal Res 2002; 33:218224.
  • 67
    Williams LM, Hannah LT, Adam CL et al. Melatonin receptors in red deer fetuses (Cervus elaphus). J Reprod Fertil 1997; 110:145151.
  • 68
    Fujieda H, Scher J, Lukita-Atmadja W et al. Gene regulation of melatonin and dopamine receptors during eye development. Neuroscience 2003; 120:301307.
  • 69
    Tosini G. Melatonin circadian rhythm in the retina of mammals. Chronobiol Int 2000; 17:599612.
  • 70
    Niles LP, Armstrong KJ, Rincon Castro LM et al. Neural stem cells express melatonin receptors and neurotrophic factors: colocalization of the MT1 receptor with neuronal and glial markers. BMC Neurosci 2004; 5:41.
  • 71
    Peters JL, Earnest BJ, Tjalkens RB et al. Modulation of intercellular calcium signaling by melatonin in avian and mammalian astrocytes is brain region-specific. J Comp Neurol 2005; 493:370380.
  • 72
    Turgut M, Uyanikgil Y, Baka M et al. Pinealectomy exaggerates and melatonin treatment suppresses neuroma formation of transected sciatic nerve in rats: gross morphological, histological and stereological analysis. J Pineal Res 2005; 38:284291.
  • 73
    Diaz B, Diaz E, Colmenero MM et al. Maternal melatonin influences rates of somatic and reproductive organs postnatal development of male rat offspring. Neuroendocrinol Lett 1999; 20:6976.
  • 74
    Ishizuka B, Kuribayashi Y, Murai K et al. The effect of melatonin on in vitro fertilization and embryo development in mice. J Pineal Res 2000; 28:4851.
  • 75
    Kachi T, Tanaka D, Watanabe S et al. Physiological pineal effects on female reproductive function of laboratory rats: prenatal development of pups, litter size and estrous cycle in middle age. Chronobiol Int 2006; 23:289300.
  • 76
    Rada JA, Wiechmann AF. Melatonin receptors in chick ocular tissues: implications for a role of melatonin in ocular growth regulation. Invest Ophthalmol Vis Sci 2006; 47:2533.
  • 77
    Luciana M. Cognitive development in children born preterm: implications for theories of brain plasticity following early injury. Dev Psychopathol 2003; 15:10171047.
  • 78
    Mcquillen PS, Ferriero DM. Selective vulnerability in the developing central nervous system. Pediatr Neurol 2004; 30:227235.
  • 79
    Sweet MP, Hodgman JE, Pena I et al. Two-year outcome of infants weighing 600 grams or less at birth and born 1994 through 1998. Obstet Gynecol 2003; 101:1823.
  • 80
    Tolsa CB, Zimine S, Warfield SK et al. Early alteration of structural and functional brain development in premature infants born with intrauterine growth restriction. Pediatr Res 2004; 56:132138.
  • 81
    Bodensteiner JB, Johnsen SD. Cerebellar injury in the extremely premature infant: newly recognized but relatively common outcome. J Child Neurol 2005; 20:139142.
  • 82
    Limperopoulos C, Soul JS, Gauvreau K et al. Late gestation cerebellar growth is rapid and impeded by premature birth. Pediatrics 2005; 115:688695.
  • 83
    Messerschmidt A, Brugger PC, Boltshauser E et al. Disruption of cerebellar development: potential complication of extreme prematurity. AJNR Am J Neuroradiol 2005; 26:16591667.
  • 84
    Nosarti C, Rushe TM, Woodruff PW et al. Corpus callosum size and very preterm birth: relationship to neuropsychological outcome. Brain 2004; 127:20802089.
  • 85
    Anderson NG, Laurent I, Cook N et al. Growth rate of corpus callosum in very premature infants. AJNR Am J Neuroradiol 2005; 26:26852690.
  • 86
    Abernethy LJ, Cooke RW, Foulder-Hughes L. Caudate and hippocampal volumes, intelligence, and motor impairment in 7-year-old children who were born preterm. Pediatr Res 2004; 55:884893.
  • 87
    Kapellou O, Counsell SJ, Kennea N et al. Abnormal cortical development after premature birth shown by altered allometric scaling of brain growth. PLoS Med 2006; 3:13821390.
  • 88
    Lofqvist C, Engstrom E, Sigurdsson J et al. Postnatal head growth deficit among premature infants parallels retinopathy of prematurity and insulin-like growth factor-1 deficit. Pediatrics 2006; 117:19301938.
  • 89
    Ostrowska Z, Kos-Kudla B, Swietochowska E et al. Influence of pinealectomy and long-term melatonin administration on GH-IGF-I axis function in male rats. Neuro Endocrinol Lett 2001; 22:255262.
  • 90
    Schaeffer HJ, Sirotkin AV. Melatonin and serotonin regulate the release of insulin-like growth factor-I, oxytocin and progesterone by cultured human granulosa cells. Exp Clin Endocrinol Diabetes 1997; 105:109112.
  • 91
    Siu AW, Maldonado M, Sanchez-Hidalgo M et al. Protective effects of melatonin in experimental free radical-related ocular diseases. J Pineal Res 2006; 40:101109.
  • 92
    Gitto E, Reiter RJ, Amodio A et al. Early indicators of chronic lung disease in preterm infants with respiratory distress syndrome and their inhibition by melatonin. J Pineal Res 2004; 36:250255.
  • 93
    Gitto E, Karbownik M, Reiter RJ et al. Effects of melatonin treatment in septic newborns. Pediatr Res 2001; 50:756760.
  • 94
    Fulia F, Gitto E, Cuzzocrea S et al. Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: reduction by melatonin. J Pineal Res 2001; 31:343349.
  • 95
    Gitto E, Romeo C, Reiter RJ et al. Melatonin reduces oxidative stress in surgical neonates. J Pediatr Surg 2004; 39:184189.
  • 96
    Gerber J, Lotz M, Ebert S et al. Melatonin is neuroprotective in experimental Streptococcus pneumoniae meningitis. J Infect Dis 2005; 191:783790.
  • 97
    Imamoglu M, Cay A, Cobanoglu U et al. Effects of melatonin on suppression of renal scarring in experimental model of pyelonephritis. Urology 2006; 67:13151319.
  • 98
    Kaur C, Ling EA. Effects of melatonin on macrophages/microglia in postnatal rat brain. J Pineal Res 1999; 26:158168.
  • 99
    Baydas G, Reiter RJ, Nedzvetskii VS et al. Altered glial fibrillary acidic protein content and its degradation in the hippocampus, cortex and cerebellum of rats exposed to constant light: reversal by melatonin. J Pineal Res 2002; 33:134139.
  • 100
    Baydas G, Ozveren F, Akdemir I et al. Learning and memory deficits in rats induced by chronic thinner exposure are reversed by melatonin. J Pineal Res 2005; 39:5056.
  • 101
    Hayter CL, Bishop GM, Robinson SR. Pharmacological but not physiological concentrations of melatonin reduce iron-induced neuronal death in rat cerebral cortex. Neurosci Lett 2004; 362:182184.
  • 102
    Reiter RJ, Sainz RM, Lopez-Burillo S et al. Melatonin amelisrates neurologic damage and neurophysiologic benefits in experimental models of Stoke. Ann NY Acad Sci 2003; 993:3547.
  • 103
    Torii K, Uneyama H, Nishino H et al. Melatonin suppresses cerebral edema caused by middle cerebral artery occlusion/reperfusion in rats assessed by magnetic resonance imaging. J Pineal Res 2004; 36:1824.
  • 104
    Er H, Turkoz Y, Mizrak B et al. Inhibition of experimental proliferative vitreoretinopathy with protein kinase C inhibitor (chelerythrine chloride) and melatonin. Ophthalmologica 2006; 220:1722.
  • 105
    Bardak Y, Ozerturk Y, Ozguner F et al. Effect of melatonin against oxidative stress in ultraviolet-B exposed rat lens. Curr Eye Res 2000; 20:225230.
  • 106
    Genovese T, Mazzon E, Muia C et al. Attenuation in the evolution of experimental spinal cord trauma by treatment with melatonin. J Pineal Res 2005; 38:198208.
  • 107
    Gul S, Celik SE, Kalayci M et al. Dose-dependent neuroprotective effects of melatonin on experimental spinal cord injury in rats. Surg Neurol 2005; 64:355361.
  • 108
    Reiter RJ, Tan DX, Sainz RM et al. Melatonin: reducing the toxicity and increasing the efficacy of drugs. J Pharm Pharmacol 2002; 54:12991321.
  • 109
    Mirmiran M, Baldwin RB, Ariagno RL. Circadian and sleep development in preterm infants occurs independently from the influences of environmental lighting. Pediatr Res 2003; 53:933938.
  • 110
    Meredith S, Jackson K, Dudenhoeffer G et al. Long-term supplementation with melatonin delays reproductive senescence in rats, without an effect on number of primordial follicles. Exp Gerontol 2000; 35:343352.
  • 111
    Demuro RL, Nafziger AN, Blask DE et al. The absolute bioavailability of oral melatonin. J Clin Pharmacol 2000; 40:781784.
  • 112
    Rodenbeck A, Huether G, Ruther E et al. Altered circadian melatonin secretion patterns in relation to sleep in patients with chronic sleep-wake rhythm disorders. J Pineal Res 1998; 25:201210.
  • 113
    Palm L, Blennow G, Wetterberg L. Long-term melatonin treatment in blind children and young adults with circadian sleep-wake disturbances. Dev Med Child Neurol 1997; 39:319325.
  • 114
    Siegrist C, Benedetti C, Orlando A et al. Lack of changes in serum prolactin, FSH, TSH, and estradiol after melatonin treatment in doses that improve sleep and reduce benzodiazepine consumption in sleep-disturbed, middle-aged, and elderly patients. J Pineal Res 2001; 30:3442.
  • 115
    Chan WY, Ng TB. Development of pre-implantation mouse embryos under the influence of pineal indoles. J Neural Transm Gen Sect 1994; 96:1929.
  • 116
    Jahnke G, Marr M, Myers C et al. Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats. Toxicol Sci 1999; 50:271279.