Melatonin utility in neonates and children

Journal of the Formosan Medical Association (2012) 111, 57e66

Available online at www.sciencedirect.com

journal homepage: www.jfma-online.com

REVIEW ARTICLE

Melatonin utility in neonates and children Yu-Chieh Chen a, You-Lin Tain a, Jiunn-Ming Sheen a, Li-Tung Huang a,b,* a

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan b Chang Gung University, Linkow, Taoyuan, Taiwan Received 10 June 2011; received in revised form 20 November 2011; accepted 24 November 2011

KEYWORDS antioxidant; children; melatonin; neonates; sleep disorders

Melatonin (N-acetyl-5-methoxytryptamine) is an endogenously produced indoleamine secreted by the pineal gland and the secretion is suppressed by light. Melatonin is a highly effective antioxidant, free radical scavenger, and has anti-inflammatory effect. Plenty of evidence supports the utility of melatonin in adults for cancer, neurodegenerative disorders, and aging. In children and neonates, melatonin has been used widely, including for respiratory distress syndrome, bronchopulmonary dysplasia, periventricular leukomalacia (PVL), hypoxiae ischemia encephalopathy and sepsis. In addition, melatonin can be used in childhood sleep and seizure disorders, and in neonates and children receiving surgery. This review article discusses the utility of melatonin in neonates and children. Copyright ª 2012, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved.

Introduction Melatonin (N-acetyl-5-methoxytryptamine) (Fig. 1), an endogenously produced indoleamine, is a highly effective antioxidant, free radical scavenger, and primary circadian pacemaker.1,2 Melatonin was first identified during the late 1950s by Lerner et al in the pineal gland.3 Its name implies melatonin’s first identified functiondits skinlightening properties in fish and frog melanocytes. Melatonin is a lipophilic agent that crosses the bloodebrain

* Corresponding author. Department of Pediatrics, Chang Gung Memorial Hospital at Kaohsiung, 123 Ta-Pei Road, Niao Sung, Kaohsiung 833, Taiwan. E-mail address: [email protected] (L.-T. Huang).

barrier and enters cells rapidly. Melatonin acts as a free radical scavenger and protects DNA from the damage induced by free radicals.4 In addition, melatonin stimulates gene expression of antioxidative enzymes.5 Moreover, melatonin has an important stimulatory action in the immune system, protecting organisms against bacterial and viral infections.1,6 Melatonin has been used clinically in cancer, neurodegenerative diseases, sleep disorders, and ageing in adults;7,8 however, its utility in children has been rarely discussed.9e11

Melatonin synthesis and its receptor In mammals, the melatonin rhythm is generated by an endogenous circadian clock in the suprachiasmatic nucleus

0929-6646/$ - see front matter Copyright ª 2012, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved. doi:10.1016/j.jfma.2011.11.024

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H N H3C

CH3

a group of reductases that participate in the protection against oxidative stress by preventing electron transfer reactions of quinones.

O

O

Pleiotropy of melatonin

5

N H Figure 1 Structure tryptamine).

of melatonin

(N-acetyl-5-methoxy-

of the hypothalamus. The most important factor regulating the metabolism of the mammalian pineal gland is the light/ dark cycle. Circulating melatonin is synthesized primarily in the pineal gland, providing circadian and seasonal timing cues. Melatonin is locally found in various cells, tissues, and organs, including lymphocytes, bone marrow, the thymus, the gastrointestinal tract, the skin, the Harderian gland, and the retina.1,2,4 The production of melatonin also occurs in invertebrates, bacteria, and plants.12 Melatonin is synthesized from the amino acid precursor tryptophan, primarily in the pineal gland. At least four enzymes are known to be involved in this process. Among them, serotonin N-acetyltransferase is considered the ratelimiting enzyme in the regulation of melatonin biosynthesis (Fig. 2). The melatonin half-life in serum varies between less than 30 min and 60 min. It is metabolized primarily in the liver and secondarily in the kidney.12 There are two types of membrane-associated melatonin receptors, MT1 and MT2, which belong to the G-proteincoupled receptor superfamily, and have been cloned in mammals. The melatonin MT1 and MT2 membrane-bound receptors show 60% homology at the amino acid level. A third membrane-associated receptor, named MT3, has been described pharmacologically and characterized as the enzyme quinine reductase 2. This enzyme belongs to

Figure 2 Synthesis tryptamine).

of

melatonin

(N-acetyl-5-methoxy-

Melatonin has pleiotropic bioactivities, including regulation of the circadian rhythms, reproductive physiology, and body temperature.1,2 Subsequently, melatonin and its metabolites were found to have important antioxidant properties owing to their direct and indirect antioxidant actions.1,2 Oxygen-derived metabolites, collectively termed reactive oxygen species (ROS), are normally produced in aerobic organisms. Oxidative stress is defined as an imbalance between prooxidant and antioxidant forces leading to an overall prooxidant insult. Melatonin and its byproducts are capable of scavenging both ROS and reactive nitrogen species (RNS), including the hydroxyl radical (
OH), hydrogen peroxide (H2O2), singlet oxygen (1O2), hypochlorous acid (HClO), peroxynitrite anion (ONOOe), and/or peroxynitrous acid (ONOOH).8 Melatonin also acts as a potent endogenous antioxidant by scavenging free radicals and upregulating antioxidant pathways. The activity and expression of antioxidant enzymes such as superoxide dismutase, glutathione, catalase, glutathione peroxidase, and glutathione reductase have been shown to be increased by melatonin, supporting its indirect antioxidant action. Further evidence of the antioxidant effect of melatonin is provided by its ability to reduce lipid peroxidation, a degradative phenomenon involved in the pathogenesis of many diseases.8 Melatonin may be metabolized not only to kynurenic acid but also to N1-acetyl-N2-formyl-5-methoxykynuramine and N1-acetyl-5-methoxykynuramine. These metabolites are very powerful antioxidants and cyclooxygenase-2 inhibitors. Therefore, they are considered as potential selective anti-inflammatory agents.1,2,6 Mitochondria are surrounded by outer and inner membranes, and contain two compartments, the intermembrane space and the matrix. Mitochondria play a critical role in generating energy within the cell through the electron transport chain. During the process of biogenesis, mitochondria produce high amounts of ROS and RNS. In this context, melatonin can stimulate mitochondrial biogenesis and increase the efficiency of the electron transport chain, thereby limiting electron leakage and free radical generation. In addition, the antioxidant effect of melatonin and its ability to increase mitochondrial glutathione levels is of great importance for mitochondrial physiology.13 Melatonin is formed by various leukocytes, including monocytes, eosinophils, mast cells, T-lymphocytes, NK cells, and bone marrow cells.14 Leukocytes possess both MT1/MT2 and nuclear receptors, and this provides the molecular basis for leukocytes to respond to melatonin. Melatonin has the capability to regulate inflammatory and immune processes, thus acting as both an activator and inhibitor of these responses.1 Melatonin has been suggested to act as an immunomodulator by preventing the

Melatonin and pediatrics translocation of nuclear factor-kappa B to the nucleus, thereby reducing the upregulation of pro-inflammatory cytokines.6 In addition, melatonin prevents or reduces the inflammatory-derived activation of phospholipase A2, lipoxygenase, and cyclooxygenases.1

Ontogeny of melatonin function Melatonin is important in pregnancy and parturition.15 Maternal plasma melatonin levels are elevated during pregnancy, reaching a maximum at term, and then returning to basal levels soon after delivery.15 The placenta expresses melatonin receptors. Melatonin readily crosses the placenta and the fetal bloodebrain barrier.16 After birth, the circadian rhythm of melatonin biosynthesis develops between the sixth and eighth week of life.17 Detectable circadian variations in melatonin level are observed from the third to sixth month of life, which coincides chronologically with the development of normal sleep rhythm. The maximal rise of the amplitude of this nocturnal melatonin secretion occurs between the fourth and seventh year of life.18 A role of melatonin in infant development has also been suggested. Pineal dysfunction may be associated with deleterious outcomes in infants and may contribute to an increased prevalence of sudden infant death syndrome.19 Delayed melatonin production is evident in infants who had experienced an apparent lifethreatening event. At puberty, there is a drop in melatonin concentrations, and thereafter plasma concentrations of melatonin diminish gradually. In adulthood, melatonin production in the pineal gland declines progressively with age.

Safety profiles and possible side effects of melatonin It is worth mentioning that, in pregnant rats, high doses of melatonin (200 mg/kg/day) from gestational days 6e19 do not adversely influence the development of rat pups.20 In the study of Sadowsky et al, a high dose was apparently without effect on fetal or maternal well-being, and it did not affect myometrial activity in late gestation.16 Human studies have shown melatonin toxicity to be remarkably low with no serious negative side effects even at high doses.21 Safety data are also available from use in children with various neurologically disabling disorders to improve sleep patterns and learning disabilities22 and recently from administration to neonates with sepsis.23 There is general agreement that melatonin therapy has a remarkably benign safety profile, even when children are treated with pharmacological doses. However, melatonin is known to inhibit prostaglandin synthases because prostaglandins have important circulatory and endocrine functions in the fetus.24 Few significant adverse events have been reported in children under melatonin treatment.25,26 There was only one report of increasing seizure activity in four children with neurologic disabilities treated with melatonin.27 Table 123,27,36,37,55,62,63,66e69,71,82,83,88e90 summarizes the main clinical utilities of melatonin for pediatric patients.

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Melatonin in compromised pregnancy Pregnancy is a physiological state accompanied by a high metabolic demand and elevated requirements for oxygen and hence prone to oxidative stress-induced organ damages. Furthermore, the placenta is a major source of oxidative stress because it is rich in polyunsaturated fatty acids. With advancing human gestation, there is a gradual favoring of antioxidant activity over oxidant activity. Preeclampsia and fetal undernutrition are two common entities of compromised pregnancy.

Melatonin and preeclampsia Preeclampsia is a multisystem disorder that is unique to human pregnancy. It happens in 5e10% of pregnancies and remains a leading cause of maternal and neonatal mortality and morbidity. In this disorder, lipid peroxide levels in maternal blood and placental tissue are significantly increased. In addition, total antioxidant activities are lowered. Hence, preeclampsia might be considered as a disorder of oxidative stress in pregnancy.28 Melatonin easily crosses the placenta without being altered. Also, it can be a desirable component of antioxidant system in human placental mitochondria, significantly improving its efficiency.29 During normal pregnancy, melatonin works in a variety of ways to serve as a direct free radical scavenger and an indirect antioxidant, and it appears to be essential for successful pregnancy. Endogenous melatonin level is significantly decreased in severe preeclampsia.30 Although most studies for supplement of melatonin in pregnancy are from animals, recent evidence has suggested supplements of melatonin as a way of prevention of preeclampsia in humans.31

Melatonin and fetal undernutrition Fetal undernutrition resulting in growth restriction in complicated pregnancy is common in obstetric practice. Maternal undernutrition during pregnancy can result in asymmetric growth retardation, and it is associated with increased oxidative stress. There is growing evidence linking slow fetal growth with the developmental programming of cardiovascular, metabolic diseases, and neuropsychiatric disorders.32 In humans, fetal undernutrition is associated with significant oxidative stress in small-for-gestational-age neonates born at term to malnourished mothers.33 Melatonin can increase glutathione peroxidase activity in human chorion.34 In rats, maternal treatment with melatonin in undernourished pregnancy improved placental efficiency, restored birth weight, and increased the expression of placental manganese superoxide dismutases and catalase.35

Melatonin and clinical conditions related to premature neonates Preterm labor itself is a condition susceptible to oxidative stress injury. Preterm delivery, oxygen use at initial resuscitation setting, and immature fetal organ development all make the condition vulnerable to oxidative stress and thus

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Table 1

Major applications of melatonin in infant and child disorders.

Condition

Study

Main results

References 36

Melatonin treatment in 110 newborns with RDS Melatonin treatment in 120 newborns with RDS

Reduce proinflammatory cytokines and nitrite/nitrate level and improve clinical outcome Clearly had anti-inflammatory effects No clear beneficial result in hastening the development of BPD

Melatonin administration in 10 septic newborns with sepsis

Significant reduction of the levels of lipid peroxidation products

55

80% reported improvement of sleep

62

Reduce sleep latency in the studied children 47 reported improvement of sleep and reduction of family stress

63

Effective in improving sleep

66

Effective in improving sleep

67

Effective in decreasing sleep-onset latency time Efficacy and tolerability of melatonin treatment

68

Six children treated with melatonin and their anticonvulsants Randomized, double-blind, placebocontrolled study in 31 children receiving carbamazepine monotherapy Six children, of whom five had a seizure disorder and one had none

Five reported improvement of seizure control Exert antioxidative effect in children receiving carbamazepine treatment

82

Five reported sleep improvement but four were found to have increased seizure frequency

27

Ten neonates undergoing surgical procedure received melatonin within 3 h after the operation Double-blind, placebo-controlled study in 105 children receiving surgery Melatonin for sedation in 40 children receiving MRI exam

Exerts antioxidative activity

88

As effective as midazolam, with lower incidence of sleep disturbance Effective in sedation for MRI exam

89

Conditions related to prematurity RDS Melatonin treatment in 24 newborns with grade III/IV RDS

BPD Neonatal events Neonatal sepsis Childhood disorders Children with sleep disorders Children with sleep disorders

Melatonin in 100 children with sleep disorders Neurodevelopmentally disabled Melatonin in 20 children children with sleep disorders Neurodevelopmentally disabled Randomized, placebo-controlled trial children with sleep disorders of controlled-release melatonin in 50 children Children with autism Controlled-release melatonin in 25 autistic children, an open-labeled study Children with autism Randomized, placebo-controlled study in 11 children Asperger syndrome Open clinical trial in 15 children Autistic spectrum disorder and fragile X syndrome Children with seizure disorders Intractable seizure Children with epilepsy receiving carbamazepine Melatonin in neurologically disabled children Surgical neonates and children Melatonin in surgical neonates

Melatonin as a premedication for anesthesia Melatonin as an alternative sedative drug

Randomized, double-blind, placebocontrolled study in 12 children

37

23

69

71

83

90

BPD Z bronchopulmonary dysplasia; MRI Z magnetic resonance imaging; RDS Z respiratory distress syndrome.

prone to further tissue injury. Among the organs, the lung and brain are the two organs most affected.

Melatonin and respiratory distress syndrome and bronchopulmonary dysplasia Although hyperoxia is essential for promoting survival of infants with respiratory distress syndrome (RDS), it unavoidably leads to excessive production of ROS in the

respiratory system. The high concentration of pulmonary arterial oxygenation, prooxidant drugs, concomitant infections, or extrapulmonary inflammation can all promote ROS accumulation and depletion of antioxidants. Improved survival because of advances in neonatal care has resulted in an increased number of infants at risk for chronic lung disease (CLD). Gitto et al measured the levels of melatonin in 120 newborns diagnosed with RDS and examined whether

Melatonin and pediatrics melatonin treatment may delay the development of bronchopneumonic dysplasia (BPD). Although no clear beneficial result was found, they concluded that newborns with CLD and without melatonin treatment had higher levels of proinflammatory cytokines than those treated with melatonin.23 Similarly, Gitto et al examined whether melatonin treatment would lower proinflammatory cytokines [interleukin-6, interleukin-8, and tumor necrosis factora (TNF-a)] and nitrite/nitrate levels in 24 newborns with respiratory distress syndrome grade III or IV diagnosed within the first 6 hours of life and concluded that melatonin treatment reduced the proinflammatory cytokines and improved the clinical outcome.36 In their later work, Gitto et al examined the proinflammatory cytokines (interleukin-6, interleukin-8, and TNF-a) and the clinical status in 110 preterm newborns with RDS ventilated before and after treatment with melatonin and concluded that melatonin treatment clearly had antiinflammatory effects.37 In the above studies, the beneficial actions of melatonin were presumably related to melatonin’s antioxidative action.

Periventricular leukomalacia Periventricular leukomalacia (PVL) is a necrotic lesion of the periventricular white matter. The periventricular white matter, due to immaturity of blood vessels and a decrease in the vessel density, is highly susceptible to damage during hypoxic-ischemic episodes. In addition, the damage to the developing white matter is considered to be mediated by excess release of glutamate, free radical production, release of cytokines, and iron accumulation. PVL contributes significantly to neonatal mortality and long-term neurodevelopmental deficits in premature infants and is one of the main causes of cerebral palsy. Evidence of oxidative stress and lipid peroxidation in premyelinating oligodendrocytes has been shown in autopsy brains from premature children with PVL, suggesting that these are important factors in white matter injury.38 Likewise, an increase in free radical products in the cerebrospinal fluid in premature infants with white matter damage has also been demonstrated.39 Melatonin, as an antioxidant, may be an effective neuroprotective treatment for the fetus. Welin et al demonstrated that post-asphyxia melatonin treatment (20 mg/kg infusion) attenuated the increase in activated microglia and 8isoprostane (a marker of lipid peroxidation) production and, at the same time, reduced the number of apoptotic cells in the cerebral white matter in midgestation fetal sheep.40 Kaur et al found that the protective effects of melatonin on various parameters in the periventricular white matter of hypoxic neonatal brains were due to its antioxidant properties.41 Moreover, Hussen et al demonstrated that melatonin, acting on its receptors and through adenylate cyclase inhibition, is neuroprotective in a newborn mouse model of excitotoxic white matter lesions, mimicking human PVL.42

Melatonin utility in the neonatal period Newborns are especially susceptible to oxidative stress, which can be accounted for by the fact that neonates are

61 (1) easily exposed to high oxygen concentrations, (2) have infections or inflammation, (3) have reduced antioxidant defense mechanisms, and (4) have high levels of free iron that are required for the Fenton reaction and lead to the production of the highly toxic hydroxyl radical. In this context, Saugstad coined the phrase ‘oxygen radical diseases’ of neonatology.43

Melatonin and clinical conditions related to full-term neonates Neonatal hypoxiceischemic brain injury Hypoxiaeischemia (HI), an insult resulting from a lack of oxygen (hypoxia) or a reduced perfusion (ischemia) in various organs, is a common cause of brain injury in neonates. Neonatal HI is the major cause of neonatal brain injury, resulting in cerebral palsy, learning disabilities, visual field deficits, and epilepsy.44 Mechanistically, cerebral HI sets in motion a cascade of biochemical events and results in mitochondrial dysfunction, oxidative stress, inflammation, and cell death.45 Carloni et al examined whether melatonin administration before or after HI in immature rats has an excellent and long-lasting benefit on ischemic outcomes and found that melatonin could represent a potentially safe approach to perinatal brain damage in humans.46 Moreover, they found that melatonin has long-lasting beneficial effects on HI occurring during the substantial neurologic developmental process. Signorini et al demonstrated that HI induces an increase in desferrioxamine (DFO)-chelatable free iron in the cerebral cortex, which can induce cerebral oxidative stress, whereas the cerebral damage by the oxidative stress may be prevented by melatonin treatment.47 From the above studies, melatonin may be considered a treatment modality for reducing the oxidative stress injury at HI and further prevention of the ongoing neurological injury process, which may lead to developmental disabilities.

Neonatal sepsis Sepsis represents a serious problem in newborns, with an incidence of approximately 1e10 cases per 1000 live births. Reported mortality rates resulting from sepsis in newborns are between 30% and 50%.48 To date, many reports are consistent with the involvement of ROS/RNS in neonatal sepsis and its complications. Batra et al documented increased production of oxygenderived reactants in septic neonates.49 In addition, Seema et al found newborns with sepsis have significantly higher levels of TNF-a and increased activity of antioxidative enzymes such as superoxide dismutase and glutathione peroxidase.50 In line with the “oxygen radical diseases” of neonates, Kurt et al demonstrated that serum interleukin1b, interleukin-6, interleukin-8, and TNF-a are mediators of inflammation and can be used for the diagnosis and evaluation of the therapeutic efficiency of drugs in the setting of neonatal sepsis.51 Several clinical reports on melatonin demonstrated its role in the reduction of oxidative stress in neonates with

62 sepsis, asphyxia, or conditions associated with excessive ROS production.52e54 Gitto et al had demonstrated that melatonin was effective in neonates with septicemia by reducing the levels of lipid peroxidation products, thereby improving neonates’ clinical status. 55

Neonatal stress Neonatal stress has been demonstrated as one of the most important factors affecting lifelong health.56 Neonatal stress in humans can originate from maternal postpartum depression, family conflict, or physical abuse. In a rodent study, Rasmussen et al showed that daily melatonin supplementation suppressed hypothalamic gene expression of proopiomelanocortin that encodes adrenocorticotropic hormone.57 Munoz et al studied 112 newborns, including normal term babies, preterm infants born before the 38th week, and babies with fetal distress. They found that neonatal stress can increase nocturnal melatonin production compared with normal term and preterm neonates.58 In their subsequent study, MunozHoyos et al studied 35 neonates admitted to the Neonatal Unit with RDS and postulated that the high melatonin concentrations they observed may serve as a mechanism to protect against oxidative stress.59 Saito et al showed that melatonin could modulate the activity of the hypothalamopituitary-adrenal (HPA) axis in chicks.60 Melatonin blocked the enhanced corticosterone concentrations observed after layers were either exposed to a novel, open field or injected intracerebroventricularly with corticotropin-releasing factor. This study provides direct evidence that melatonin plays a role in the regulation of the stress response in neonatal chicks. 60

Melatonin in infants and children Children with sleep disorder Aside from treatment of insomnia associated with shift work and jet lag, melatonin has been used to treat various sleep disorders. Sleep disorders are a common problem in childhood, with a prevalence of about 25% in typical preschool and school-aged children.61 Children with neurodevelopmental disabilities are at increased risk of having a sleep disorder. Melatonin may induce sleep during the day, when the endogenous levels of melatonin are low; however, it does not produce additional sleep-promoting effect when the melatonin levels are adequate. Melatonin has been administered to neurologically disabled children to improve their sleep pattern.62,63 The average dose of melatonin used for disabled children with sleep disorders ranges from 2 mg to 10 mg.64 Sleep disturbance is common in patients with autistic spectrum disorders, and melatonin has a specific role for sleep problems in children with autistic spectrum disorder.65 One open-label study of controlled-release melatonin in children with autistic spectrum disorders documented an improvement in sleep patterns measured with the Children’s Sleep Habits Questionnaire.66 Garstang and Wallis found melatonin to be effective for the treatment of sleep difficulties in seven children with autistic

Y.-C. Chen et al. spectrum disorders who participated in a randomized, double-blind, crossover trial.67 With regard to Asperger syndrome, Paavonen et al reported the effectiveness of melatonin in decreasing sleeponset latency times and improving associated behavioral problems in children.68 They found no improvement in sleep duration; however, they did report a slight increase in the number of nighttime awakenings. In a study by Wasdell et al, melatonin was used in 50 children with neurodevelopmental disabilities, including autistic spectrum disorders. Overall, the therapy improved the sleep of 47 children and was effective in reducing family stress.69 Children with neurodevelopmental disabilities who had treatment-resistant, chronic, delayed sleep phase syndrome and impaired sleep maintenance showed improvement in melatonin therapy. 69 Sleep problems are reported in up to 77% of children with fragile X syndrome.70 In this regard, Wirojanan et al demonstrated for the first time, a beneficial effect of melatonin in fragile X syndrome patients.71

Childhood seizure disorders Melatonin has been shown to have antiepileptic activity in animal studies using different seizure models as well as in cases of childhood epilepsy.72 Melatonin may specifically inhibit the N-methyl-D-aspartate subtype of excitatory glutamatergic receptors in rat striatum.73 Moreover, melatonin increases brain g-aminobutyric acid concentrations and receptor affinity74 and potentiates brain inhibitory transmission via g-aminobutyric acid synapses.75 In animal models, melatonin can inhibit audiogenic76 and electrical seizures77 as well as reduce convulsions induced by pentetrazole,78 pilocarpine,79 L-cysteine,80 and kainate.81 Peled et al showed improvement in seizure activity in five of six children with intractable seizures when melatonin was combined with an antiepileptic drug. In addition, sleep studies showed a decrease in epileptic activity in two of the three patients who were monitored during treatment.82 Furthermore, Gupta et al observed that the association of melatonin in the treatment of children with epilepsy on carbamazepine monotherapy improved their quality of life.83 Paprocka et al assessed diurnal melatonin secretion in children with refractory epilepsy as compared to children without epileptic seizures.84 Analysis of diurnal melatonin secretion indicated a lower level of the hormone in patients with refractory epilepsy. They concluded that a lowered level of melatonin in children with refractory epilepsy in relation to the control group is the consequence of the intractable epilepsy or is influenced by antiepileptic drugs. Only a few studies have shown direct or indirect proconvulsant effects of melatonin. Experimentally, melatonin enhanced low Mg2þ-induced epileptiform activity in the hippocampus,85 whereas melatonin antagonists delayed the onset of pilocarpine-induced seizures.86 Clinically, melatonin has been shown to induce electroencephalographic abnormalities in patients with temporal lobe epilepsy87 and increase seizure activity in neurologically disabled children.27

Melatonin and pediatrics

63

Surgical neonates and children

Conclusions

Gitto et al reported 10 neonates who received lung or abdomen operations and showed a significant clinical improvement after administration of melatonin and were associated with lower levels of interleukin-6 and interleukin-8.88 In the context of pediatric surgery, two clinical trials involving children reported that melatonin was as effective as midazolam in reducing preoperative anxiety.89,90 In addition, melatonin was associated with a more rapid recovery, a reduced incidence of postoperative delirium, and a lower incidence of sleep disturbances 2 weeks after surgery when compared with midazolam.

Melatonin is both a potent free radical scavenger and a broad-spectrum antioxidant. Melatonin also possesses the capability to modulate inflammation and increase mitochondrial biogenesis. It seems likely that melatonin treatment might give useful results in a wide range of childhood disorders as has been shown for adults. Altogether, these features make melatonin a potential therapeutic tool to improve child health.

Potential other applications of melatonin from evidence of recent animal studies During the past two decades, numerous animal and human studies have examined the therapeutic usefulness of melatonin in different fields of medicine and found that melatonin has potential therapeutic effects in ocular, blood, cardiovascular, gastrointestinal, and rheumatic diseases as an adjuvant agent.91 Of these, cardiovascular protective effect is the most widely studied, and prior studies concluded that melatonin may exert its cardioprotective effect through various mechanisms such as scavenging free radicals, increasing nitric oxide availability, activation of the melatonin receptor in vascular and endothelial smooth muscle cells to restore normal vascular tone, and lowering the serum lipids.92,93 Apart from the utility of melatonin mentioned above, our previous study demonstrated that melatonin has antihypertensive effects in 4-week-old young rats by addition of 0.01% melatonin in drinking water for 8 weeks in the study group.94 The antihypertensive effect of melatonin is presumed to be through the restoration of the nitric oxide pathway by reduction of plasma asymmetric dimethylarginine, restoration of plasma L-arginine to asymmetric dimethylarginine ratio, preservation of renal L-arginine availability, and attenuation of oxidative stress.94,95 Furthermore, we examined the effect of melatonin treatment in young rats with hepatic encephalopathy by using the bile duct ligation model, which found that cholestasis in developing rats may increase oxidative stress and cause spatial memory deficits and could be prevented by melatonin treatment.96 Melatonin belongs to the group of over-the-counter medications in the United States and many European countries. Taking melatonin pills for jet lag or sleep disorders in the United States does not require a physician’s prescription. However, approval from the Food and Drug Association is mandatory before clinical use of melatonin in Taiwanese children. Therefore, more clinical studies to test the safety in children are needed. Although our previous studies indicate that melatonin treatment may be considered in various pediatric disorders for its antioxidative effect, large-scale, double-blind, randomized, controlled studies in children are needed before its wide use in pediatric disorders.

Acknowledgments This work was supported by grants 99-2314-B-182A-003-MY3 from National Science Council, Taiwan, and CMRPG890191 from Kaohsiung Chang Gung Memorial Hospital to Dr. LiTung Huang.

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