Antioxidant and Cerebroprotective Roles of Carbon Monoxide (CO) Against Cerebrovascular Injury Caused by Prolonged Neonatal Asphyxia
Authors: Liu Jianxiong , Leffler Charles W. , Fedinec Alexander L. , Pourcyrous Massroor , Parfenova Helena 
Published: June 2021

Asphyxia occurring in the fetus and newborn infant frequently leads to hypoxic‐ischemic encephalopathy (HIE) in survivors. The neonatal brain circulatory system is compromised by asphyxia/reventilation via a mechanism that may involve oxidative stress. CO, a gaseous messenger with antioxidant properties, is produced from heme via the heme oxygenase (HO)‐catalyzed reaction. We tested the hypothesis that CO, either produced by the brain, or delivered systemically by the donor molecule CORM‐A1, has a cerebrovascular protective role during neonatal asphyxia. We developed a novel survival model of prolonged asphyxia (50 – 60 min) in newborn pigs that combines insults of severe hypoxia (PaO2, 20–30 mm Hg), hypercapnia (PaCO2, 70–80 mm Hg), and acidosis (pH, 6.9–7.0) while avoiding extreme systemic hypotension and cerebral ischemia. During the asphyxia conditions, we observed immediate and sustained activation of brain HO as detected by an elevated CO concentration in the cortical periarachnoid fluid. Cortical astrocytes are among the main sources of brain CO production in normal and asphyxiated brains. Asphyxia followed by a 60‐min reventilation with room air caused excessive formation of reactive oxygen species (ROS) in the neonatal brain. Brain oxidative stress was potentiated by the HO inhibitor tin protoporphyrin, suggesting that activation of astrocytic HO/CO during asphyxia has antioxidant effects. Administered 30 min before asphyxia, CORM‐A1 (2 mg/kg i.p.) prevented excessive ROS formation in the brain during reventilation. We tested the effects of prolonged neonatal asphyxia on cerebral vascular dilator functions after 24 and 48 h of recovery using the cranial window technique. Endothelium‐dependent vasodilatory responses to hypercapnia and bradykinin were not negatively affected by prolonged asphyxia. In contrast, astrocyte‐dependent cerebral vasodilatory responses to adenosine diphosphate (ADP) and glutamate were compromised, indicating that astrocytes are selectively injured by prolonged asphyxia. Endothelium‐ and astrocyte‐independent cerebral vascular smooth muscle functions tested by vasodilations to isoproterenol and sodium nitroprusside remained intact in post‐asphyxic newborn pigs. In CORM‐A1‐pretreated animals, prolonged asphyxia did not produce any cerebral vascular incapacities, suggesting that CO therapy protects astrocytes from asphyxia/reventilation injury. Overall, prolonged neonatal asphyxia without systemic hypotension or cerebral ischemia injures cortical astrocytes via an oxidative stress‐mediated mechanism that can be partially counteracted by activation of the endogenous HO/CO‐based antioxidant system in the brain or by CO/CORM‐A1 therapy. We propose that gaseous CO and CO donor molecules can be used as novel efficient therapeutic approaches to prevention of neonatal brain injury caused by prolonged asphyxia.Support or Funding InformationR01 NS 101717; R01 HL 034059; R01 HL 042851This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.