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Pluta, R.;  Furmaga-Jabłońska, W.;  Januszewski, S.;  Tarkowska, A. Melatonin in the Treatment of Clinical Perinatal Asphyxia. Encyclopedia. Available online: https://encyclopedia.pub/entry/40978 (accessed on 14 December 2025).
Pluta R,  Furmaga-Jabłońska W,  Januszewski S,  Tarkowska A. Melatonin in the Treatment of Clinical Perinatal Asphyxia. Encyclopedia. Available at: https://encyclopedia.pub/entry/40978. Accessed December 14, 2025.
Pluta, Ryszard, Wanda Furmaga-Jabłońska, Sławomir Januszewski, Agata Tarkowska. "Melatonin in the Treatment of Clinical Perinatal Asphyxia" Encyclopedia, https://encyclopedia.pub/entry/40978 (accessed December 14, 2025).
Pluta, R.,  Furmaga-Jabłońska, W.,  Januszewski, S., & Tarkowska, A. (2023, February 08). Melatonin in the Treatment of Clinical Perinatal Asphyxia. In Encyclopedia. https://encyclopedia.pub/entry/40978
Pluta, Ryszard, et al. "Melatonin in the Treatment of Clinical Perinatal Asphyxia." Encyclopedia. Web. 08 February, 2023.
Melatonin in the Treatment of Clinical Perinatal Asphyxia
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This entry is adapted from the peer-reviewed paper 10.3390/molecules28031105

Melatonin is synthesized from serotonin, which, in turn, is synthesized from the amino acid tryptophan. In the pineal gland, tryptophan is taken from the blood and hydroxylated to 5-hydroxytryptophan, which is then decarboxylated to serotonin. Key functions of melatonin include regulating circadian patterns, such as fluctuations in body temperature and sleep–wake cycles, seasonal reproduction, boosting the immune system and regulating glucose levels. Melatonin has several hormonal functions, but this unique substance also has paracrine and autocrine effects and exhibits antioxidant and free radical scavenger properties.

perinatal asphyxia melatonin brain

1. Introduction

Melatonin has broad antioxidant, anti-inflammatory and anti-apoptotic properties, and it prevents amyloid and tau protein toxicity. As an antioxidant, it acts as a reactive oxygen species scavenger and also enhances the enzymatic activity of superoxide dismutase, glutathione peroxidase and glutathione reductase [1][2], and by reducing the expression of NOS, it contributes to reductions in peroxide nitrite formation [1][3]. Due to its lipophilic nature, it easily crosses the placenta and the blood–brain barrier, which has incredibly useful therapeutic implications [4][5][6]. The antioxidant benefits of melatonin in hypoxic-ischemic encephalopathy are largely documented through preclinical studies, indicating lower levels of reactive oxygen species, products of lipid and protein peroxidation in the brain, free iron and NO, increased levels of glutathione in periventricular white matter, reduced neuronal apoptosis and better long-term development outcomes [7][8][9][10][11]. Melatonin in combination with hypothermia significantly increases hypothermic neuroprotection in neonates after asphyxia, especially in deep gray matter, improving the energy metabolism of the brain and reducing the severity of apoptosis in the basal ganglia and inner capsule [12].

1.1. Neuroprotective Effects of Melatonin in Experimental Hypoxic-Ischemic Encephalopathy

It is now known that brain neurodegeneration after asphyxia is caused by numerous proteomic and genomic changes that lead to neuronal death by necrosis and apoptosis, with progressive neuroinflammation and brain atrophy, eventually leading to dementia in some cases [13][14][15][16][17][18]. Research indicates that perinatal asphyxia is associated with changes in amyloid and tau protein similar to alterations in Alzheimer’s disease [13][14][15][16][17][18]. The development of neuroinflammatory processes has been shown to play a key role in the progression of brain neurodegeneration after perinatal asphyxia [19]. Amyloid production and accumulation, tau protein modification and autophagy are involved in neurodegeneration after asphyxia in the same way as in Alzheimer’s disease [13][14][15][17][18]. Recirculation of blood in the brain after perinatal asphyxia and asphyxia alone provoke a violent reaction of reactive oxygen species, triggering a neuroinflammatory response and oxidative injury [19]. Reactive oxygen species destroy the membranes of neurons and glial cells, triggering lipid peroxidation, so antioxidants come into play as a therapeutic method [19]. Melatonin is recognized as an antioxidant that can buffer the destructive effects of oxidative stress in the brain following asphyxia by selectively reducing cytotoxic reactive oxygen species and reactive nitrogen species [19].
Melatonin reduces oxidative stress and inflammatory cell recruitment as well as activation of glial cells in the cortex of newborns caused by hypoxia-ischemia injury in rats (Table 1) [20]. Melatonin significantly improved postnatal neurological status and normalized brain markers of metabolism to control values in lambs (Table 1) [7]. At the cellular level, administration of melatonin caused a significant reduction in apoptosis, brain oxidative stress and neuroinflammation after asphyxia in lambs [7]. The data from this research support the ease of administering melatonin i.v. and strongly support clinical trials for the treatment of perinatal asphyxia with melatonin [7]. A simple melatonin skin patch, administered soon after birth, may improve outcome in lamb infants affected by asphyxia [7]. Other results suggest that melatonin mediates murine models of neonatal hypoxia-ischemia, in part, by restoring MT1 receptors, inhibiting the mitochondrial neuronal death pathways and suppressing astrocyte and microglia activation (Table 1) [21].
In addition, it was found that melatonin administered 5 min after the onset of hypoxia-ischemia injury in rats significantly reduced the necrotic neuronal death 1 h after its administration (Table 1) [22]. In parallel, decreased activation of the early phases of apoptosis has been shown [22]. These effects were accompanied by increased expression and activity of the silent information regulator 1, decreased expression and acetylation of p53 and increased activation of autophagy. Melatonin also reduced hypoxia-ischemia-induced neuroglial cell activation of the brain [22].
The volume of cerebral infarction was significantly reduced in rats receiving melatonin i.p. compared to the control group [23][24]. In addition, TUNEL staining showed a significantly reduced number of TUNEL-positive neurons in the CA1 and CA3 areas and in the dentate gyrus and cortex (Table 1) [23][24]. The number of surviving neurons with a well-preserved structure in the melatonin-treated group was identical to that in the control group of rats (Table 1) [25]. The results of this research indicate that treatment with melatonin after neonatal hypoxia-ischemia encephalopathy has a neuroprotective effect by reducing neuronal death, white matter demyelination and reactive neurogliosis (Table 1) [25].
Initial treatment with melatonin administered i.p. significantly reduced brain injury on day 7 after asphyxia in rats at a dose of 15 mg/kg melatonin compared to control animals (Table 1) [26]. Autophagy and apoptosis were significantly inhibited after treatment with melatonin in vivo and in vitro [26]. The administration of melatonin also significantly increased the amount of growth-related protein 43 in the cerebral cortex [26].
In vivo and in vitro studies have shown that the administration of melatonin reduces the permeability of the blood–brain barrier, the degradation of tight and adjacent junction proteins after hypoxic-ischemic encephalopathy, which was associated with the inhibition of microglial Toll-like receptor 4/nuclear factor-kappa B signaling pathway [27]. Additionally, administration of melatonin i.p. promoted white matter regeneration in experimental rats [27].
The intraperitoneal administration of melatonin reduced the neuropathological damage to the brain and peripheral organs caused by hypoxic-ischemic encephalopathy in rats [28]. In addition, melatonin reduced brain edema [28]. Cerebral hypoxia ischemia caused changes in the mRNA expression of proteins associated with brain edema, such as AQP-4, ZO-1 and occludin, and these changes after melatonin administration were partially reversible, indicating the mechanism of the protective action of melatonin in this case [28]. Moreover, administration of melatonin i.p. improved the behavior of mice after hypoxic-ischemic brain injury (Table 1) [29]. After administration of melatonin to rats, long-term protective effects were demonstrated through markedly improving behavioral and learning deficits following cerebral hypoxia ischemia (Table 1) [8]. Consequently, neuropathological changes in the brain were significantly reduced in the melatonin-treated group [8]. The study suggests that administration of melatonin before or after hypoxic-ischemic brain injury in rats has good and long-term benefits in terms of neuropathological changes and neurological outcomes, suggesting that melatonin may be safe for use after perinatal asphyxia in humans (Table 1) [8].
Table 1. Animal studies evaluating melatonin in the treatment of neonatal hypoxic-ischemic encephalopathy.
Animals Kind of Therapy Effects of Therapy References
Lamb Bolus 0.5 mg/kg 1 h before + 0.5 mg/kg/h infusion i.v. for 2 h Grey and white matter changes reduction. [30]
Rat 15 mg/kg i.p. 5 min after, next at 24 and 48 h Reduction loss of neurons in the CA1 area. Improvement behavioral impairment. [8]
Rat 20 mg/kg i.p. before, after and 24 h later Reduction TUNEL positive cells in cortex and hippocampus and caspase 3. [23][24]
Rat Single dose, 15 mg/kg i.p. 5 min after injury Oxidative stress, inflammatory cells, and activation of neuroglial cells in cortex reduction. [20]
Rat 15 mg/kg i.p. 5 min after, repeated at 24 and 48 h Reduced TUNEL positive cells, white matter demyelination and astrogliosis. [25]
Rat 15 mg/kg i.p. 5 min after, repeated at 24 and 48 h Reduction injury in cortex and
hippocampus.		 [31]
Rat Single dose 10 mg/kg i.p. after No improvement in metabolic activity in neurons and astrocytes. [32]
Rat 15 mg/kg i.p. 1 h before next daily for 6 days Reduced brain parenchyma loss, inhibition neuronal apoptosis in cortex. [26]
Rat Single dose 15 mg/kg i.p. 5 min after Reduction in necrosis, apoptosis and astrocytosis. [22]
Rat 10 mg/kg i.p. Reduction in brain tissue injury,
astrocytic and microglial cells
activation.		 [21]
Lamb 15 mg/kg i.v. after 30 min, next as 2 hourly 5 mg boluses over 24 h Reduction lipid peroxidation and
neuroinflammation. Improved suction, tone and standing.		 [7]
Rat 15 mg/kg i.p.
after, next 6 h and 25 h after		 Trend towards preventing brain tissue injury on day 1 but lost on days 7, 20 and 43. [33]
Mouse 10 mg/kg i.p.
after, next every 24 h for 1 month		 Reduction in brain tissue injury. Improvement performance in learning and memory, motor function and co-ordination and forelimb grip. [29]

2. Administration of Melatonin in Combination with Hypothermia

Currently, the only known treatment with greater or lesser clinical benefit after perinatal asphyxia is hypothermia. Thus, at present, the low effectiveness of hypothermia is the driving force behind the urgent search for adjuvants in the treatment of perinatal asphyxia. Melatonin, a hormone well known for its involvement in the circadian rhythm, has been tested in preclinical studies for perinatal asphyxia and has shown neuroprotective effects through pleiotropic and immunomodulatory mechanisms (Table 1).
Asphyxia induces abnormal brain metabolism in lambs with increased lactate levels and decreased choline content, triggers necrotic and apoptotic death of neuronal cells in the gray matter, damages white matter and stimulates neuroinflammation and oxidative stress [7]. Melatonin (i.v.) and hypothermia were independently associated with a site-specific reduction in oxidative stress, neuroinflammation and neuronal death compared to asphyxia alone [34]. There was a synergy between melatonin and hypothermia such that the ratio of choline did not differ in the combination therapy compared to the control group but was a greater overall reduction in neuropathology than either treatment alone [34]. This research shows that in newborn lambs, the combination therapy of neonatal hypoxic-ischemic encephalopathy provided significantly greater neuroprotection than either alone [34].
In another study, piglets showed faster EEG amplitude recovery between 25 and 30 h with melatonin (i.v.) plus hypothermia (Table 2) [35]. The lactate/aspartate peak ratio was lower after about 3 days with melatonin (i.v.) plus hypothermia [35]. Dual therapy reduced the number of TUNEL-positive neurons in the sensory cortex and improved the survival of oligodendrocytes in the hippocampus and periventricular white matter, and increased the immunoreactivity of astrocytes in the hippocampus and periventricular white matter (Table 2) [35]. In addition, melatonin (i.v.) significantly enhanced the protective effect of hypothermia by reducing the severity of neuropathological changes in the brain in piglets via increasing the lactate/N-acetyl aspartate and lactate/total creatine ratios in gray matter [12]. Dual therapy increased the whole-brain nucleotide triphosphate/replaceable phosphate pool [12]. Due to the improvement in brain metabolism, the number of TUNEL-positive cells was reduced in the dual treatment group compared to hypothermia alone in the inner capsule, thalamus, caudate and putamen, and there was a reduction in caspase 3 levels in the thalamus (Table 2) [12]. Although the total number of microglial cells did not decrease in gray and white matter, expression of the cytotoxic microglial activation marker CD86 was decreased in the cortex two days after hypoxia ischemia [12]. The protective effect was dose-dependent, starting from a dose of 15 mg/kg melatonin, administered 2 h after the pathological episode and continued for 6 h, and was well tolerated and clearly enhanced protection by hypothermia, especially in the sensorimotor cortex (Table 2) [36]. Assessment of high-dose melatonin (i.v.) 18 mg/kg in combination with hypothermia was also safe and showed neuroprotective effects in hypoxic-ischemic encephalopathy [37]. Compared to the melatonin–hypothermic group with the hypothermic group, the EEG recovered faster after 19 h of double treatment (Table 2) [37]. For melatonin–hypothermia compared with hypothermia brain phosphatecreatine/inorganic phosphate and nucleotide triphosphate/exchangeable phosphate, levels were higher after 48 h [37]. Melatonin–hypothermia treatment showed a reduction in the total number of TUNEL-positive cells compared to hypothermia alone (Table 2) [37]. A localized effect of protection in the white matter and internal capsule has been reported in melatonin–hypothermia treatment compared to hypothermia alone [37].
Table 2. Experimental studies evaluating melatonin neuroprotection in combination with hypothermia of neonatal hypoxic-ischemic encephalopathy.
Animals Kind of Therapy Effects of Therapy References
Piglet 30 mg/kg over 6 h
at 10 min and 24 h
after		 Reduction in TUNEL positive cells in hippocampus, internal capsule, caudate and putamen. [12]
In vitro cultures of hippocampal slices 100 µM (~25 mg/L) Dose-dependent
reduction in neuronal cells death.		 [22]
Piglet 15 mg/kg/24, 2 and 26 h after Augmented protection in sensorimotor cortex. [36]
Piglet 18 mg/kg over 2 h at 1 and 25 h after Improvement EEG
from 19–24 h. Reduction TUNEL positive cells.		 [37]
Piglet 20 mg/kg over 2 h
at 1, 24 and 48 h
after		 Improvement EEG
from 25–30 h. Reduction TUNEL positive cells in sensorimotor cortex.		 [35]

3. Clinical Use of Melatonin Alone and as an Adjunct to Other Therapies

Despite the hard experimental data supporting the role of the neuroprotective properties of melatonin after perinatal asphyxia, both alone and in combination with hypothermia, clinical trials supporting the neuroprotective effect in asphyxiated neonates are very limited. In one small clinical cohort study of neonates given melatonin, lower levels of malondialdehyde, nitrosative markers and reduced mortality were observed without presenting clinical results (Table 3) [38]. Another study with melatonin administration showed reduced mortality in cases of moderate to severe perinatal asphyxia, excluding mild cases (Table 3) [39]. The data from this research should be interpreted very carefully due to the high risk of bias, and the case registration was based solely on a clinical study. In another study, the combination of melatonin with hypothermia resulted in lower blood NO levels, fewer seizures, reduced white matter damage and improved survival without affecting neurodevelopmental changes only at 6 months of follow-up (Table 3) [40]. These results may have distorted the heterogeneous study groups with varying degrees of severe hypoxic-ischemic encephalopathy in the study groups. Aly et al. [40] found no difference in gray matter changes, while white matter alterations were significantly reduced (Table 3). On the other hand, the EEGs in treated and control cases did not differ from each other after two weeks. Further, another study with the administration of melatonin plus hypothermia presented very few cases and showed development at 18 months, but cerebral palsy and neurosensory disorders have not been described [41]. Only the above study reported development at 18 months of age, showing a composite score on the cognitive component of the Bayley III test at 18 months of age, significantly higher in the melatonin with hypothermia group [41]. Note that there were no statistical differences in the composite score for the Bayley III cognitive component test at six months or in other neurological components, such as language and motor skills, at six and eighteen months of follow-up [41]. On the other hand, no differences in MRI or EEG were found between the groups (Table 3) [41].
Table 3. Melatonin alone and as adjunct to other therapies in treatment of perinatal asphyxia in human clinical studies.
Clinical Study Time of Born Number of Neonates Kind of Therapy Effects of Therapy References
Small cohort study. Term 20 Melatonin p.o. 10 mg, 8 times Malondialdehyde and nitrite/nitrate in serum reduction. Reduction mortality. [38]
Randomized controlled trial. Term and late preterm 80 Melatonin p.o. 10 mg single dose Mortality was reduced in moderate and severe cases [39]
Randomized controlled pilot study. Term 30 Melatonin p.o. 10 mg/kg for five days plus manual cooling with ice packs After 6 months significant improvement of survival without disability, normal neurological
examination, fewer clinical seizures and less white matter changes in melatonin with hypothermia group.		 [40]
Randomized-controlled pilot study. Term and late
preterm		 25 Melatonin i.v. 5 mg/kg for 3 days plus hypothermia After 18 months composite score for the cognitive section of the Bayley III test
significantly higher in the melatonin+ hypothermia group. No difference in MRI, integrated EEG and mortality between treatment groups.		 [41]
Randomized controlled trial. Term and late
preterm		 60 Melatonin 10 mg/kg p.o.
for 5 days plus magnesium sulfate.		 Observed lower concentration in blood of S100 on 2nd and 6th day from baseline. [42]
Only one study used a combination of melatonin with magnesium. Although a reduction in markers of neuronal damage was found, no clinical data were presented, which severely limit its clinical usefulness [42]. In the above study, it was found that the blood neuronal injury biomarker S100, which correlates with the severity of hypoxic-ischemic encephalopathy, was significantly decreased on days 2 and 6 in the dual treatment group (Table 3) [42]. No study has looked at the long-term clinical sequelae of cerebral palsy, impaired neurodevelopment, deafness and blindness. One mortality meta-analysis study found no significant difference between the melatonin plus hypothermic and hypothermic groups [43].

4. Melatonin versus Amyloid, Tau Protein and Neurotransmitters

4.1. Melatonin versus Amyloid

Melatonin has been shown to break the histamine–aspartate salt bridges in beta-amyloid peptides, which destabilizes the beta-sheet structure and causes large differences in beta-sheet content between amyloid plaques incubated with and without melatonin and inhibit the formation of amyloid plaques [44]. Studies in transgenic mice showed that melatonin was able to reduce the amount of amyloid plaques in the frontal cortex and hippocampus, accompanied by better spatial learning and memory [45][46]. In addition, melatonin has been shown to inhibit the expected time-dependent development of amyloid plaques and increases survival in transgenic mice [47]. Melatonin has also been found to increase the removal of amyloid from the brain by supporting the glymphatic system [48]. Clinical trials have shown that clearance of amyloid from the sleeping brain is significantly enhanced compared to the waking brain [48]. This was supported by studies in transgenic mice where melatonin treatment increased brain amyloid clearance [44].

4.2. Melatonin versus Tau Protein

The ability of melatonin to inhibit the hyperphosphorylation of the tau protein has been documented in numerous in vivo and in vitro studies [44][49]. Studies on N2a neuroblastoma cells with hyperphosphorylated tau protein triggered by wortmannin [49] or calyculin-A [44] have shown that melatonin influences the viability of cells via inhibiting tau protein hyperphosphorylation. In a study in transgenic mice, melatonin has been shown to lower tau protein hyperphosphorylation, and along with exercise, it also lowers the levels of amyloid oligomers in the brain [50]. In addition, in the above study, melatonin had a positive effect on impaired cognitive functions, oxidative stress and reductions in mitochondrial DNA in the brain. In a study in mice given β-amyloid peptides to the brain to induce Alzheimer’s disease, decreased hyperphosphorylated tau protein was observed, resulting in improved neuronal viability and reduced cognitive deficits [51]. In addition, inhibition of the melatonin-synthesizing enzyme has been shown to trigger tau protein hyperphosphorylation and impairments in spatial memory, which were reversible after melatonin administration for 1 week [44]. Data indicate that melatonin may alleviate the specific hallmarks of Alzheimer’s disease by inhibiting the hyperphosphorylation of the tau protein.

4.3. Melatonin versus Changes in Neurotransmission

The effect of melatonin on neurotransmission is mainly related to improvements in the functioning of the cholinergic and glutamatergic systems [44]. As previously noted, amyloid impairs the function of glutamatergic neuronal cells and triggers an excessive influx of calcium into the cytoplasm, leading to overstimulation and release of acetylcholine esterase, resulting in decreased levels of choline acetyltransferase and acetylocholine. The above is supported by studies in the Alzheimer’s disease model where it has been shown that melatonin administration significantly reduces neuroinflammation and oxidation and also inhibits acetylcholine esterase activity [52]. It has been presented that with age, the synthesis of choline acetyltransferase and acetylcholine esterase slowly decreases, which positively correlates with the progression of dementia [53]. It has also been documented that melatonin enhances choline transport, which significantly improves the synthesis of acetylcholine [44]. In transgenic mice, melatonin significantly increased the activity of choline acetyltransferase in the hippocampus and frontal cortex and promoted neuroprotection [54][55]. It has also been presented that by inhibiting the activity of NMDA receptors, melatonin reduces changes in the glutamatergic system and prevents excessive calcium influx into the cytoplasm [44][56]. This was supported by a rat study in which administration of melatonin was shown to attenuate the glutamatergic excitatory response in striatal neurons by reducing calcium influx through voltage-gated calcium channels and NMDA-gated calcium channels, resulting in anti-excitotoxicity effects [44].

5. Safety and Side Effects of Melatonin

Melatonin is considered safe and non-addictive. The data from animal studies are interesting; namely, the administration of exogenous melatonin in doses up to 800 mg/kg did not cause any acute toxic symptoms [57]. Additionally, due to the upper limit of the solubility of the drug, the median lethal dose of melatonin cannot be calculated [57]. In the clinic, patients subjected to large sections of the liver received a single dose of melatonin (50 mg/kg) before surgery, showing no serious adverse events [57]. The most common side effects of melatonin are diarrhea, headache, fatigue, dizziness, fever, nausea and sleepiness [4][58]. Research data have shown that high intravenous doses of melatonin or 5 mg of melatonin in the diet of healthy people did not affect attention, concentration, reaction time or ability to drive [57]. However, melatonin can interact with a variety of medications, including anticoagulants, anticonvulsants, antidepressants and diabetes medications. It should be added that children should avoid melatonin therapy, unless advised by a pediatrician, because exogenous melatonin may interfere with the proper development of children. The action of melatonin is non-specific because melatonin’s targets are numerous and melatonin receptors are widely distributed throughout the body.

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