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Hydrogen and therapeutic gases for neonatal hypoxic–ischemic encephalopathy: potential neuroprotective adjuncts in translational research


Numerous studies have examined the potential use of therapeutic gases for the treatment of various neurological disorders. Hydrogen gas, a promising neuroprotective agent, has been a focus of study due to its potent antioxidative properties. In translational research into adult diseases, hydrogen has been shown to be neuroprotective in disorders such as cerebral ischemia and traumatic brain injury, and in neurodegenerative diseases such as Alzheimer’s disease. Animal and human studies have verified the safety and feasibility of molecular hydrogen. However, despite extensive research on its efficacy in adults, only a few studies have investigated its application in pediatric and neonatal medicine. Neonatal hypoxic–ischemic encephalopathy (HIE) is characterized by damage to neurons and other cells of the nervous system. One of the major contributing factors is excessive exposure to oxidative stress. Current research interest in HIE is shifting toward new neuroprotective agents, as single agents or as adjuncts to therapeutic hypothermia. Here, we review therapeutic gases, particularly hydrogen, and their potentials and limitations in the treatment of HIE in newborns.


  • Translational animal models of neonatal HIE are a current focus of research into the therapeutic usefulness of various gases.

  • Hydrogen ventilation as a single agent or in combination with therapeutic hypothermia shows short- and long-term neuroprotection in neonatal translational HIE models.

  • The optimal target severity for therapeutic interventions should be well established to improve outcomes.

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This study was financially supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (number 16K10092 to T.K., and numbers 19K08253, 16H06276, 16K19685, and 15KK0311 to S.N.), grants from the Kagawa University Faculty of Medicine School of Medicine Alumni Association Sanjukai Research Aid (numbers R1-1 and 25-2), and a scholarship from the Honjo International Scholarship Foundation (to Y.H.).

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Y.H. and T.K. designed the study and drafted the article. Y.H., S.N., and T.K. revised it critically and contributed to the final approval of the version to be published.

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Correspondence to Takashi Kusaka.

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Htun, Y., Nakamura, S. & Kusaka, T. Hydrogen and therapeutic gases for neonatal hypoxic–ischemic encephalopathy: potential neuroprotective adjuncts in translational research. Pediatr Res 89, 753–759 (2021).

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