Melatonin and circadian regulation of inflammatory-oxidative pathways in pediatric neurological disorders

Circadian rhythms are intrinsic 24-hour cycles that regulate nearly all aspects of human physiology and play essential roles in brain development, immune regulation, and redox balance. Adult studies have explored the links between circadian rhythms and neurological or metabolic diseases, but research in pediatric populations remains limited. In infants and children, circadian systems undergo rapid maturation, and this developmental window is particularly vulnerable to disruption from maternal, environmental, or endogenous factors. The aim of this review is to examine how circadian mechanisms intersect with inflammatory and oxidative pathways in pediatric neurological disorders, highlighting both mechanistic insights and therapeutic potential. We conducted a narrative review of PubMed/MEDLINE and complementary sources, covering studies published between January 2016 and March 2025, with relevant studies selected for detailed synthesis. Evidence shows that oxidative stress and inflammation are exacerbated by immature circadian control, with glial circadian clocks, clock genes, and cytokine-melatonin interactions playing important roles. Melatonin is frequently identified as a key circadian-regulated mediator in pediatric conditions, including hypoxic-ischaemic encephalopathy, autism spectrum disorder, metabolic encephalopathies, and sepsis. Preclinical and translational studies demonstrate that melatonin reduces oxidative damage, maintains mitochondrial function, and modulates immune responses, while early clinical data indicate that it is safe and holds promise as an adjunctive therapy. The review further emphasizes that circadian regulation of oxidative stress is shaped by maternal signals, melatonin in breast milk, and environmental exposures in neonates, particularly in preterm infants. Despite growing evidence, major gaps remain, including the lack of pediatric-specific chronotherapy trials, standardized dosing protocols, and time-stamped biospecimen studies. We suggest a feasible roadmap for future melatonin-based pediatric chronotherapy trials, linking mechanistic insights to clinical application. Overall, advancing circadian biology, particularly through melatonin, offers a promising avenue for pediatric neuroprotection and opens new directions for chronotherapy in vulnerable populations.