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.