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Nitric oxide and the brain. Part 2: Effects following neonatal brain injury—friend or foe?


Nitric oxide (NO) has critical roles in a wide variety of key biologic functions and has intricate transport mechanisms for delivery to key distal tissues under normal conditions. However, NO also plays important roles during disease processes, such as hypoxia–ischemia, asphyxia, neuro-inflammation, and retinopathy of prematurity. The effects of exogenous NO on the developing neonatal brain remain controversial. Inhaled NO (iNO) can be neuroprotective or toxic depending on a variety of factors, including cellular redox state, underlying disease processes, duration of treatment, and dose. This review identifies key gaps in knowledge that should prompt further investigation into the possible role of iNO as a therapeutic agent after injury to the brain.


  • NO is a key signal mediator in the neonatal brain with neuroprotective and neurotoxic properties.

  • iNO, a commonly used medication, has significant effects on the neonatal brain.

  • Dosing, duration, and timing of administration of iNO can affect the developing brain.

  • This review article summarizes the roles of NO in association with various disease processes that impact neonates, such as brain hypoxia–ischemia, asphyxia, retinopathy of prematurity, and neuroinflammation.

  • The impact of this review is that it clearly describes gaps in knowledge, and makes the case for further, targeted studies in each of the identified areas.

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Fig. 1: Biochemical Effects of iNO.
Fig. 2: VEGF receptor activation induces an increase in the intracellular calcium by triggering an Src kinase-mediated activation of phospholipase C-gamma (PLC-γ), and a parallel activation of the PI3 kinase/Akt pathway system.


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R.S. holds the “William Buchanan Chair in Pediatrics,” and L.C. is supported by NIH Grant 1R01NS102617-01.

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D.A. contributed to the concept of the paper, wrote the initial and revised drafts of this manuscript, and approved the final manuscript as submitted; R.S. contributed to the conceptualization of the paper, reviewed and revised the manuscript, and approved the final manuscript as submitted; L.C. contributed to the conceptualization of the paper, reviewed and revised the manuscript, and approved the final manuscript as submitted.

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Correspondence to Dimitrios Angelis.

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R.S. is on the Scientific Advisory Council of Mallinckrodt Pharmaceuticals and had no role in the development of this review. D.A. and L.C. have no conflicts of interest to disclose.

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Angelis, D., Savani, R. & Chalak, L. Nitric oxide and the brain. Part 2: Effects following neonatal brain injury—friend or foe?. Pediatr Res 89, 746–752 (2021).

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