Inhalation of hydrogen gas mitigates sevoflurane‐induced neuronal apoptosis in the neonatal cortex and is associated with changes in protein phosphorylation

Abstract Inhalation of hydrogen (H 2 ) gas is therapeutically effective for cerebrovascular diseases, neurodegenerative disorders, and neonatal brain disorders including pathologies induced by anesthetic gases. To understand the mechanisms underlying the protective effects of H 2 on the brain, we investigated the molecular signals affected by H 2 in sevoflurane‐induced neuronal cell death. We confirmed that neural progenitor cells are susceptible to sevoflurane and undergo apoptosis in the retrosplenial cortex of neonatal mice. Co‐administration of 1–8% H 2 gas for 3 h to sevoflurane‐exposed pups suppressed elevated caspase‐3‐mediated apoptotic cell death and concomitantly decreased c‐Jun phosphorylation and activation of the c‐Jun pathway, all of which are induced by oxidative stress. Anesthesia‐induced increases in lipid peroxidation and oxidative DNA damage were alleviated by H 2 inhalation. Phosphoproteome analysis revealed enriched clusters of differentially phosphorylated proteins in the sevoflurane‐exposed neonatal brain that included proteins involved in neuronal development and synaptic signaling. H 2 inhalation modified cellular transport pathways that depend on hyperphosphorylated proteins including microtubule‐associated protein family. These modifications may be involved in the protective mechanisms of H 2 against sevoflurane‐induced neuronal cell death. image