Magnesium Sulfate in Neonatal Hypoxic–Ischemic Encephalopathy: Bridging the Gap Between Molecular Neuroprotection and Clinical Outcomes
Year: 2026
Type: article
Abstract: ) has emerged as one of the most biologically plausible neuroprotective agents because of its ability to modulate glutamate-mediated excitotoxicity, intracellular calcium influx, oxidative stress, neuroinflammation, and apoptotic pathways. Nevertheless, encouraging molecular and preclinical findings have not translated into consistent clinical benefit. This narrative review critically examines the translational gap between the molecular mechanisms of magnesium sulfate and its clinical performance in neonatal HIE. Evidence from experimental models, clinical studies and recent meta-analyses was integrated to identify the biological and methodological factors potentially responsible for this discrepancy. We discuss the evolving pathophysiology of HIE across the primary, latent, secondary and tertiary phases of brain injury and analyze how the timing of intervention, lesion heterogeneity and inadequate biological stratification may influence therapeutic responsiveness. Current clinical research has largely evaluated broad neurological outcomes, particularly cerebral palsy, despite the heterogeneous neuropathological substrates underlying neonatal brain injury. We argue that this strategy may dilute genuine treatment effects by grouping together distinct lesion phenotypes with different biological mechanisms. Accordingly, we propose the "Neuroprotection per Effective Therapy (NET)" framework, a conceptual translational model integrating molecular targets, experimental evidence, MRI-defined lesion phenotypes, methodological quality, and advanced statistical approaches to improve patient stratification and outcome selection. Rather than questioning the biological efficacy of magnesium sulfate itself, this review suggests that future progress will depend on aligning molecular mechanisms with clinically meaningful phenotypes. Precision-based translational strategies may ultimately allow magnesium sulfate and other neuroprotective therapies to better reveal their therapeutic effects in biologically appropriate patient subgroups.
DOI: 10.3390/cimb48080844
Institutions: University of Genoa, Istituto Giannina Gaslini
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,654
OpenAlex ID: W7203820657