Is melatonin ready to be used in preterm infants as a neuroprotectant? biran - 2014 - developmental medicine & child neurology - wiley online library

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Invited Review
Is melatonin ready to be used in preterm infants as a neuroprotectant?
First published:
27 February 2014 Full publication history
DOI:
10.1111/dmcn.12415 View/save citation
Cited by (CrossRef):
17 articles Check for updates
Valérie Biran , An Phan Duy, Fabrice Decobert, Nathalie Bednarek, Corinne Alberti, Olivier Baud
View issue TOC
Volume 56, Issue 8
August 2014
Pages 717–723
Abstract
The prevention of neurological disabilities following preterm birth remains a major public health challenge
and efforts are still needed to test the neuroprotective properties of candidate molecules. Melatonin serves
as a neuroprotectant in adult models of cerebral ischemia through its potent antioxidant and anti-
inflammatory effects. An increasing number of preclinical studies have consistently demonstrated that
melatonin protects the damaged developing brain by preventing abnormal myelination and an
inflammatory glial reaction, a major cause of white matter injury. The main questions asked in this review
are whether preclinical data on the neuroprotective properties of melatonin are sufficient to translate this
concept into the clinical setting, and whether melatonin can reduce white matter damage in preterm
infants. This review provides support for our view that melatonin is now ready to be tested in human
preterm neonates, and discusses ongoing and planned clinical trials.
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Abbreviations
CYP1A
Cytochrome P450
Brain injury and the related neurodevelopmental disabilities resulting from preterm birth are a major public
health concern. Preterm birth survivors often suffer from long-term clinical, educational, and social problems;
10% to 15% of very preterm infants who survive develop cerebral palsy and more than 40% have associated
motor and cognitive deficiencies at 8 years.[1] Because of the dramatic improvements in the perinatal
management of high-risk preterm neonates, the pathological conditions associated with neurological
impairment have changed over the past 10 years. Major destructive focal lesions remain a serious problem,
but have become less common. In contrast, the most predominant neuropathological lesion at present is
diffuse white matter damage, in which glial injury is associated with microglial activation and, ultimately,
myelination defects. Many factors are associated with white matter damage, including infection/inflammation,
hypoxia-ischemia, the excitotoxic cascade, endocrine imbalances, genetic factors, and growth restriction.[2-
6] Based on these potential targets, a number of treatments for neonatal brain injury have been investigated
in preclinical models of perinatal brain injury that mimic the lesions observed in preterm infants.[7, 8] Apart
from magnesium sulphate, however, none of the neuroprotective treatments have been translated to the
clinical setting.[9]
Among the most promising molecules, melatonin could be considered a prime candidate for preclinical
studies and clinical trials of neuroprotection in preterm infants.[10] The effects of melatonin are pleiotropic
and include the blocking of oxidative, excitotoxic, and inflammatory pathways, which are all involved in the
pathogenesis of perinatal brain damage in preterm neonates. Furthermore, because of its lipophilic
properties, melatonin easily crosses most biological barriers, including the placenta[11] and the blood–brain
barrier.[12] Melatonin has a good safety profile with no known adverse effects.[13, 14] The main aims of this
review are to recapitulate the results of preclinical studies and to provide a balanced analysis of each line of
evidence suggesting that melatonin may be an effective neuroprotectant in preterm infants.
A systematic PubMed search up to May 2013 was undertaken to identify the neuroprotective properties of
melatonin in preclinical studies and in preterm infants. Melatonin was given either antenatally or postnatally in
different animal models of brain lesions mimicking the lesions observed in human neonates.
Melatonin: Its Synthesis and Functions
Melatonin is the principal hormone secreted by the pineal gland, and its synthesis involves the transformation
of tryptophan to serotonin. Its rhythmic secretion is induced by the light/dark cycle, with maximum secretion
during the night, including a peak at around 3 to 4 a.m.; its secretion is also inhibited by exposure to relatively
high levels of artificial light.[15, 16]
The transmission of photoperiodic information from the retina to the pineal gland takes place through a
polysynaptic neural pathway that includes the suprachiasmatic nuclei of the hypothalamus, which represent
the principal circadian clock of the organism, and the sympathetic nervous system through the involvement of
the superior cervical ganglia.[17, 18] The role of melatonin is to provide the organism with information
regarding the dark period. It constitutes an endogenous synchronizer that is capable of reinforcing certain

circadian rhythms (e.g. temperature) while maintaining the phase of other rhythms (internal synchronization);
the antioxidant defence system of the body is also organized around circadian rhythms, with the involvement
of melatonin.
The actions of melatonin are mediated through specific receptors (MT1, MT2),[19] but it can also function as
a direct antioxidant[20] and has antiapoptotic effects.[21] The MT1 receptor is commonly found in the
suprachiasmatic nuclei, hippocampus, cerebellum, and in the pars tuberalis of the pituitary.[22] The MT2
receptor is most strongly expressed in the retina and at considerably lower levels in the suprachiasmatic
nuclei, hippocampus, and cerebellum. Melatonin receptor expression in peripheral human tissues is also well
documented (particularly in the uterine myometrium and the breast epithelium).[23]
Ontogeny of Melatonin Synthesis During Pregnancy and
the Perinatal Period
The pineal production of melatonin starts postnatally in humans, sheep, and rats;[24, 25] nevertheless, the
passage of maternal melatonin into the fetal circulation exposes the fetus to a daily melatonin rhythm of low
concentrations during the day and high concentrations at night.[26]
During a normal pregnancy, nocturnal maternal blood levels of melatonin increase progressively and
significantly from 26 to 32 weeks gestational age until term, and are normalized 48 hours after delivery.[27,
28] Daytime levels increase from 34 weeks gestational age, although not significantly. The mechanisms
underlying this increase are unknown; an increase in maternal production by the pineal gland, synthesis of
melatonin by the placenta, and the expression of its receptors, MT1, MT2 and the orphan receptor RORα1 by
the trophoblast have been proposed.[26, 29]
Nocturnal levels of melatonin are significantly higher in twin pregnancies after 28 weeks gestational age
compared with singleton pregnancies; conversely, they are lower in pregnancies complicated by pre-
eclampsia.[30]
Previous studies have confirmed a circadian rhythm in melatonin levels in the umbilical circulation of term
neonates. There is no significant difference between melatonin levels in the umbilical artery and umbilical
vein at birth, although these are lower than levels in the maternal circulation.[30] Recently, Bagci et al.[31]
have reported that melatonin concentrations in the umbilical artery and vein are higher after spontaneous
vaginal deliveries than after Caesarean sections.
Specific Features of Melatonin Secretion in the Newborn
Several studies have explored melatonin secretion in children, but only a few have addressed the synthesis
of melatonin in preterm and term neonates,[25] showing a reduced urinary concentration of melatonin during
the first 3 months after birth in preterm infants.
Factors responsible for the variability in melatonin concentration estimations
The variability observed in the synthesis of melatonin by the pineal gland depends mainly on three factors: (1)
The measurement techniques used.[15, 27] Studies carried out in preterm infants have yielded contradictory
results, with a decrease in urinary levels of melatonin or an increase in its plasma levels in term neonates

when compared with preterm neonates.[28, 32, 33] Commentz et al.[28] also demonstrated a greater
increase in urinary levels of 6-sulfatoxymelatonin in preterm infants at 26 to 32 weeks gestational age ( n =26)
compared with those at 33 to 42 weeks gestational age ( n =38) between the second and seventh day of life,
perhaps related to the immaturity of neuronal connections between the retina and the pineal gland. The
absence of maternal and fetal/neonatal levels of melatonin as well as of measurements of luminosity,
however, does not allow us to draw any conclusions as to a decrease in the synthesis of melatonin in preterm
infants when compared with term infants in this study.[28, 34, 35] A longitudinal study currently underway in
200 mothers and their term or preterm neonates regarding the ontogeny of the synthesis of melatonin found
in the plasma, urine, and maternal milk (ClinicalTrials.gov Identifier NCT01340417) could clarify this issue. (2)
The luminosity of the environment. (3) Drug interactions. As the metabolism of melatonin is principally
mediated by cytochrome P450 (CYP1A) enzymes, interactions between melatonin and other substances
(e.g. caffeine, beta blockers, or quinolones) are possible.[26]
Other factors such as intrauterine growth retardation, pre-eclampsia, and premature rupture of membranes
(>6h), are most often associated with a delay in the appearance of a circadian rhythm in the production of
melatonin.[30] In contrast, sex, route of delivery, and breastfeeding[28] are not significantly associated with
modifications in melatonin secretion.
Melatonin during early infancy
The secretion of melatonin is extremely weak at less than 2 to 3 months of life, but increases rapidly to reach
50% of adult values at the age of 1 year in preterm and term infants.[26, 36] The rhythm seen in infants from
birth up to 3 to 4 months of age is not circadian but ultradian. The rhythmic secretion of melatonin appears
around the age of 3 months in term neonates.[28] Preterm neonates display a delayed secretion of melatonin
when compared with term neonates, which persists after correction for gestational age up to 8 to 9 months of
age. In the absence of maternal melatonin, the appearance of circadian rhythms depends principally on
neurological maturation, and very little on the environment.[37]
Circadian rhythm and neuroprotection
Melatonin is secreted according to a circadian rhythm, as previously mentioned.[38] It influences the sleep–
wake cycle, changing from daytime physiology to night-time physiology in a well-coordinated manner. It also
influences the circadian rhythm of other organs of the body. The circadian rhythm is important for normal
neurodevelopment, and its absence suppresses neurogenesis in animal models.[39] There is also increasing
evidence that circadian gene regulation is important for normal embryonic development.[40] In vitro
experiments with human tissues have shown that cell proliferation is controlled by the daily rise and fall of
melatonin levels.
Disturbed circadian rhythms are not only associated with sleep disorders, but also with impaired health.[41]
Children with multiple developmental, neuropsychiatric, and health difficulties often have an associated
melatonin deficiency.[42] When circadian rhythms are restored, behaviour, mood, development, intellectual
function, health, and even seizure control may improve.[43, 44]
Preclinical Data Regarding the Neuroprotective Effects

of Melatonin
Various experimental studies have tested the neuroprotective effects of antenatal and postnatal melatonin
administration in different animal models (e.g. rat, mouse, sheep, and pig) of brain lesions mimicking the
lesions observed in human neonates (Table 1). These data strongly emphasize the ability of melatonin to be
systematically neuroprotective, whatever the animal species used, in several types of brain damage
reproduced at various developmental stages.
Table 1. Preclinical trials with melatonin
Study
Antenatal
melatonin
Postnatal
melatonin
Animal
model/injury
Antioxidant
effect
Anti-
excitotoxic
effect
Anti-
inflammatory
effect
EC, excitotoxic cascade; POS, perinatal oxidative stress; +, yes; −, no.
Husson et al.
[46]
No Yes Mice/EC − + –
Gressens et
al.[47]
No Yes Mice/EC − + −
Carloni et al.
[49]
No Yes Rat/POS + − +
Olivier et al.
[51]
Kaur et al.
[59]
Olivier et al.
[61]
Welin et al.
[53]
No Yes Sheep/POS − − +
Miller et al.
[54]
No Yes Sheep/POS + − −
Watanabe et
al.[55]
Yes No Rat/POS + − −
Okatani et al.
[57]
Yes No Rat/POS + − −
Villapol et al.
[52]
No Yes Rat/stroke − − +

Protective effects of melatonin against excitotoxic brain injury
In a mouse model of excitotoxic white matter lesions (P5 pups),[45] melatonin had a dose-dependent
protective effect on the developing white matter. Mice that received intraperitoneal melatonin had an 82%
reduction in the size of ibotenate-induced white matter cysts when compared with controls.[46] Although
melatonin did not prevent the initial appearance of white matter lesions, it did promote secondary lesion
repair by inducing axonal regrowth or sprouting, as shown by axonal markers. Three lines of evidence
suggest that the neuroprotective effects of melatonin are largely mediated by specific melatonin receptors,
rather than its intrinsic antioxidant properties: (1) the selective melatonin receptor antagonist luzindole
abolishes melatonin-induced neuroprotection; (2) the doses at which the neuroprotective effects of melatonin
are observed are lower than those generally used to obtain a significant antioxidant effect; and (3) melatonin
protects against white matter lesions but not cortical plate lesions, whereas N-acetylcysteine, a typical
antioxidant molecule, protects against both.
Agomelatine (S 20098), a melatonin derivative, is a potent neuroprotectant against ibotenate-induced injury in
the developing brain.[47] Although agomelatine is slightly less effective than melatonin, the window of
opportunity for treatment is much broader than for melatonin.
Furthermore, Bouslama et al.[48] have assessed the effectiveness of melatonin in preventing learning
disabilities in newborn mice with ibotenate-induced brain injury, and shown that melatonin protects the ability
to develop conditioning.
Protective effects of melatonin against oxidative stress-induced brain injury
Melatonin protects the brain of newborn rat pups subjected to neonatal hypoxia-ischemia.[49] Melatonin
administration is associated with a dramatic decrease in microglial and astrocytic activation in a model of
intrauterine growth retardation induced by unilateral uterine artery ligation[50] and in a model of cerebral
hypoxia-ischemia.[51] In a neonatal stroke model, melatonin does not reduce cortical infarct volume, but
strongly reduces inflammation and promotes subsequent myelination within the underlying white matter.[52]
Confirming these results obtained in rodents and reproducing them in a large-animal model, melatonin
administered to fetal sheep subjected to cerebral ischemia significantly protects the white matter by
attenuating cell death in association with a reduced inflammatory response in the blood and brain.[53]
Melatonin is also a potent antioxidant, both directly as a scavenger of free oxygen radicals, particularly the
highly destructive hydroxyl radical, and indirectly via the upregulation of the antioxidant enzymes glutathione
peroxidase, glutathione reductase, superoxide dismutase, and catalase.[16]
Acute in utero asphyxia in late-gestation fetal sheep results in a significant biphasic increase in hydroxyl
radical formation within the cerebral grey matter, consistent with the primary and secondary phases of
oxidative stress. When melatonin is administered as prophylaxis to the ewe, both the primary and secondary
increases in hydroxyl radicals are abolished. The rise in lipid peroxidation products and cerebral injury are
also prevented by the preinsult administration of melatonin.[53-56] The administration of melatonin to
pregnant rats increases the activities of superoxide dismutase and glutathione peroxidase in preterm[55] and
near-term fetal rat brains.[57] The modulatory and neuroprotective actions of melatonin may not be solely
due to the scavenging of hydroxyl radicals[54] and the increase in intracerebral antioxidant enzyme activity.

[57] Melatonin directly inhibits noradrenalin-stimulated fetal cerebral artery constriction,[58] and decreases
cerebral vascular permeability following hypoxia.[59] Systemically, melatonin induces umbilical vasodilatation
via the stimulation of nitric oxide synthase,[60] a property that may prove to be particularly useful in
pregnancies complicated by placental insufficiency.
In a recently developed model of perinatal oxidative stress based on unilateral uterine artery ligation, which
induces fetal growth restriction and a specific pattern of diffuse white matter damage,[61] melatonin
significantly improved the myelin content of rat pup brains. This effect on white matter integrity was
associated with a potent impact on brain inflammation during the first week of life.[62]
Effects of melatonin on brain injury-induced inflammation and oligodendroglial
cell maturation
Melatonin has both proinflammatory and anti-inflammatory effects, including the activation of proinflammatory
cytokines in the early phase response and the mediation of leukocyte recruitment.[63, 64] The anti-
inflammatory property of melatonin arises from the fact that it prevents the translocation of NFκB to the
nucleus, thus reducing the upregulation of proinflammatory cytokines.[16] Postasphyxial melatonin treatment
attenuates inflammatory markers, such as the increase in activated microglia and 8-isoprostane production,
while reducing apoptotic cell death in the cerebral white matter of mid-gestation fetal sheep in response to
acute in utero asphyxia.[53]
Thus, melatonin appears to be systematically and powerfully effective in all the preclinical models of preterm
brain damage tested, regardless of the factor(s) responsible for brain damage and the animal species used.
Similarly, in models of hypoxia-ischemia that mimic brain damage in term neonates (hypoxic-ischemic
encephalopathy and stroke), melatonin has a significant neuroprotective effect.[49, 52, 65]
Melatonin as a Neuroprotectant: What is the Status of its
Translation to the Clinic?
Safety profile of melatonin
There is general agreement that short-term melatonin therapy has a remarkably benign safety profile in both
animals and humans. None of the animal studies of maternal or postnatal melatonin treatment have shown
treatment-related side effects,[66] nor have there been any reports of significant complications with long-term
melatonin therapy in human children and adults, although these studies are few in number.[42, 67-74]
Fortunately, melatonin improves the survival of neonates with septic shock[67] and may reduce ventilator-
associated lung injury in preterm infants[70] (Table 2). A previous dose-response study (MIND study,
ClinicalTrials.gov Identifier NCT00649961) did not reveal any problems after the administration of a single
dose of melatonin to preterm infants. Melatonin supplementation does not suppress the endogenous
secretion of melatonin, but is known to aid the establishment of appropriate circadian rhythms.[42]
Table 2. Neonatal clinical trials with melatonin
Non-

Study Trial
design
Population Melatonin
group
( n )
melatonin
group
( n )
Adverse events documents Dose, route
Gitto et
al.[71]
Open
comparative
Term
neonates with
surgical
malformations
10 10 surgical;
10 healthy
No mortality 10mg/kg/dose
as IV infusion
over 2h, 10
doses over
72h
Gitto et
al.[69]
Open
comparative
Term
neonates with
sepsis
10 10 septic;
10 healthy
No mortality in treated group; three
deaths in untreated group
10mg, two
doses orally
Gitto et
al.[70]
Randomized,
double-blind,
placebo-
controlled
Preterm
infants less
than or equal
to 32 weeks'
gestation
60 60 No difference in respiratory,
cardiovascular, septic, retinopathy of
prematurity complication in the study
group as compared with the control
group; three deaths in the control
group, none in the study group. No
untoward effect of melatonin
10mg/kg/dose
as IV infusion
over 2h, 10
doses over
72h
Fulia et
al.[14]
Randomized,
blind,
placebo-
controlled
Neonates
with perinatal
asphyxia
10 10 Three deaths in control group, none
in study group
10mg every
2h, eight
doses orally
Gitto et
al.[72]
Randomized Preterm
infants
40 34 None reported 10mg/kg/dose
as IV infusion
over 2h, 10
doses over
72h
Gitto et
al.[73]
Randomized,
double-blind,
placebo-
controlled
Preterm
infants less
than or equal
to 32 weeks'
gestation
55 55 Incidence of complication was higher
in the placebo group
10mg/kg/dose
as IV infusion
over 2h, 10
doses over
72h
Pharmacokinetics of melatonin in preterm infants
The pharmacokinetic profile of melatonin has been well defined in adults.[75] Secretion usually starts by 9
p.m., peaks at around 3 a.m., and plasma concentrations decline to negligible levels again by 9 a.m.[76] The
peak adult melatonin concentration is reported to be 44.3pg/mL but can range from 8 to 275pg/mL.[76] There
is no intrapineal storage of melatonin, and its turnover is very rapid (elimination half-life of 45-60min).[77]
Very recently, Merchant et al. provided the first report of the pharmacokinetic profile of melatonin in preterm
infants, which differs from that of adults.[78] Compared with adults and older children, in preterm infants the
half-life and clearance rate of melatonin are prolonged and its volume of distribution decreased. The dosage
of melatonin for use in preterm infants therefore, cannot be extrapolated from adult studies. This difference in

pharmacokinetics could be related to several factors. Melatonin is extremely lipophilic, and the low body fat
content of preterm infants (10%), as compared with adults and older children (20% to 25% and 15% to 20%
respectively) could affect its volume of distribution and contribute to higher-than-expected plasma
concentrations.[78] A 2-hour infusion of 0.1µg/kg/h increases blood melatonin concentrations from
undetectable levels to approximately peak adult levels;[78] these data can used to guide therapeutic clinical
trials of melatonin in preterm infants.
Clinical Studies
Experimental data obtained using several independent animal models of brain injury in neonates support the
plausibility of melatonin as a neuroprotectant in preterm neonates.
The fact that melatonin easily crosses the placental barrier and can, therefore, be administered antenatally is
a powerful argument for its use in the diminution, if not the prevention, of brain lesions in this population. A
multicentre therapeutic trial, ‘PREMELIP’, to test the neuroprotective properties of melatonin administration in
the immediate prepartum period in very preterm infants is under way in France. Its aim is to determine the
dose of melatonin to be administered prepartum by the parenteral route to mothers at risk of preterm delivery,
to decrease the extent of white matter damage detected by diffusion tensor imaging with spatial statistical
analysis (Tract-Based Spatial Statistics), at term equivalent age (40 weeks gestational age) in infants born
preterm.
Another phase II trial is currently underway in neonatal intensive care units in the United Kingdom. The
exploratory, multicentre, double-blinded, randomized, placebo-controlled trial is evaluating the use of
melatonin in addition to standard intensive care, in protecting preterm infants from brain injury
(ClinicalTrials.gov Identifier NCT00649961). Its primary objective is to prove that melatonin is capable of
reducing brain injury and white matter disease as defined by magnetic resonance imaging at term.
These two therapeutic trials of neuroprotection are complementary and will allow us to draw clear conclusions
as to the effect of the perinatal administration of melatonin in very preterm infants.
What Dosage of Melatonin can be used as a
Neuroprotectant?
The dosage of melatonin for use as a neuroprotectant in preterm infants remains speculative. The only
information on the clinical effects of melatonin available in the literature is reported in the treatment of sepsis
and chronic lung disease,[69, 70] two complications involving systems without biological barriers similar to
those observed in the central nervous system. Because of the blood–brain barrier, the efficient concentration
of melatonin in the developing brain is therefore unknown. However, serum concentration of melatonin used
to prevent/treat sepsis and chronic lung disease was higher than adult physiological levels. These scant data
already suggest that melatonin treatment should be more an additional treatment than a replacement
treatment to be neuroprotective.
Conclusion

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