Melatonin as a Therapy for Preterm Brain Injury: What Is the Evidence?

Abstract

Despite significant improvements in survival following preterm birth in recent years, the neurodevelopmental burden of prematurity, with its long-term cognitive and behavioral consequences, remains a significant challenge in neonatology. Neuroprotective treatment options to improve neurodevelopmental outcomes in preterm infants are therefore urgently needed. Alleviating inflammatory and oxidative stress (OS), melatonin might modify important triggers of preterm brain injury, a complex combination of destructive and developmental abnormalities termed encephalopathy of prematurity (EoP). Preliminary data also suggests that melatonin has a direct neurotrophic impact, emphasizing its therapeutic potential with a favorable safety profile in the preterm setting. The current review outlines the most important pathomechanisms underlying preterm brain injury and correlates them with melatonin's neuroprotective potential, while underlining significant pharmacokinetic/pharmacodynamic uncertainties that need to be addressed in future studies.

Keywords: encephalopathy of prematurity; inflammation; melatonin; neuroprotection; oligodendrocyte dysmaturation; oxidative stress; preterm infants.

Figure 1

Melatonin signaling mechanisms: Melatonin shows receptor-mediated and receptor-independent activity and interacts with a variety of cellular signaling pathways. Both MT1 and MT2 are members of the GPCR receptor family. Melatonin binding and signaling involve several effectors, including PKC, PLC, and PKA, as well as downstream signaling pathways. Melatonin can also enter the cell through passive diffusion and transporters, where it activates mitochondrial receptors or cytosolic quinone reductase 2 (MT3), which in turn activates nuclear receptors ROR/RZR. Melatonin causes a shift towards an anti-inflammatory and antioxidant response and the preservation of mitochondrial and neuronal integrity. (Abbreviations: 5-OH-Trp, 5-Hydroxytryptophan; AMK, N¹-acetyl-5-methoxykynuramine; AFMK, N¹-acetyl-N²-formyl-5-methoxykynuramine; Akt, protein kinase B; COX, cyclooxygenase; CREB, cAMP response element-binding protein; Cyt, cytochrome c; ETC, electron transport chain; GPX, glutathione peroxidase; HO, heme oxygenase; IκB, Inhibitory-kappa B; iNOS, inducible nitric oxide synthase; KEAP1, Kelch-like ECH-associated protein 1; LOX, lipoxygenase; MAPK, mitogen-activated protein kinase; MPO, myeloperoxidase; mPTP, mitochondrial permeability transition pore; MT1/2/3, melatonin receptors 1/2/3; mtDNA, mitochondrial DNA; NF-κB, nuclear factor- kappa B; Nrf2, nuclear factor erythroid 2-related factor 2; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PKC, protein kinase C; PLC, phospholipase C; RNS, reactive nitrogen species; ROR/RZR, retinoid acid receptor-related orphan receptor/retinoid Z receptor (RZR); ROS, reactive oxygen species SIRT1, sirtuin-1; SOD, superoxide dismutase; Trp, tryptophan).

Figure 2

Neuroprotective and neurorestorative effects of melatonin: Prenatal and postnatal risk factors are associated with increased inflammation, which causes injury to the developing brain. Melatonin exerts its neuroprotective effects by reducing excitotoxicity, oxidative stress, and inflammation (acute and chronic), as well as by promoting oligodendroglial maturation and myelination. (Abbreviations: GMD, gestational diabetes mellitus; RDS, respiratory distress syndrome; PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; PHVD, posthemorrhagic ventricular dilatation).