Abstract: Neonatal hypoxic-ischemic encephalopathy is the leading cause of brain injury in term infants worldwide and disproportionately affects low- and middle-income communities. Therapeutic hypothermia, the standard of care for hypoxic-ischemic encephalopathy in high-resourced settings, has no effect on morbidity and increases mortality after hypoxic-ischemic encephalopathy in low- and middle-income settings. Intranasal administration offers the opportunity to deliver more accessible treatments for all babies with neonatal hypoxic-ischemic encephalopathy due to lower resource needs, ease of administration, and the capacity to directly target the brain. We reviewed preclinical literature concerning intranasal treatments for hypoxic-ischemic encephalopathy and developed a novel semi-quantitative index ranking intranasal therapies for their potential for further development as biologically plausible, effective, and accessible treatments for hypoxic-ischemic encephalopathy. We searched PubMed and Google Scholar for peer-reviewed articles on intranasal therapies for hypoxic-ischemic encephalopathy using the mesh phrases “Neonatal hypoxic-ischemic encephalopathy intranasal” and “Neonatal brain intranasal.” Sixty-two studies were included that described thirty-four unique intranasal therapies. Neonatal intranasal therapies have been widely studied in small animal models, infrequently in large animals, and only recently in human clinical trials. Our semi-quantitative ranking revealed cell-based therapies as potentially the most effective and developed intranasal therapy in animal models of hypoxic-ischemic encephalopathy, though the pharmaceutical support compulsory to current cell-based treatments limits their accessibility in low-resourced settings. Intranasal therapies for neonatal hypoxic-ischemic encephalopathy have both feasibility and neuroprotective potential for safe, effective, and accessible treatment of hypoxic-ischemic encephalopathy. Additional research is needed for translation to humans. Future investigation should emphasize appropriate animal modeling with pharmaceutics and cells, combined with an evaluation of the brain connectome and neurobehavioral outcomes.

Key words: anti-inflammatory drugs, cell therapies, cellular stress, drug development, global health, growth factors, hypoxia-ischemia, intranasal therapies, neonatal brain injury, systematic review