Molecular Hydrogen Affords Similar Neuroprotection to Therapeutic Hypothermia in a Porcine Model of Neonatal Hypoxic–Ischemic Encephalopathy

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a major cause of neonatal mortality and long-term disability, despite therapeutic hypothermia (TH) treatment, underscoring the need for further preclinical research. In the present study, we compared the neuroprotection afforded by TH and inhaled molecular hydrogen (H₂) treatment in a translational newborn pig HIE model. Following 20 min of asphyxia induced by a hypoxic/hypercapnic gas mixture, piglets were reoxygenated and monitored for 48 h. Animals were randomly assigned to normothermia, continuous H₂ ventilation (2.1%), or TH (33.5 °C for 37 h followed by slow rewarming) groups. Physiological parameters, electroencephalography (EEG), visual evoked potentials (VEPs), and neuropathology were assessed. TH eliminated post-asphyxia seizures and improved VEP latency, while H₂ delayed seizure onset and increased quantitative EEG markers of signal complexity. Neuropathology revealed severe thalamic injury in normothermic controls, which was significantly attenuated by both H₂ and TH, while neocortical, hippocampal, and basal ganglia injury was less extensive and not significantly altered by either of the neuroprotective interventions. These findings demonstrate that continuous H₂ inhalation provides neuroprotection in HIE comparable to TH, particularly in the thalamus. H₂ also exerts distinct electrophysiological effects, suggesting its therapeutic potential as a treatment for neonatal HIE.