Delayed neurovascular dysfunction is alleviated by hydrogen in asphyxiated newborn pigs

Neonatology. 2013;104(2):79-86. doi: 10.1159/000348445. Epub 2013 Jul 9.


Background: The neurovascular unit encompasses the functional interactions of cerebrovascular and brain parenchymal cells necessary for the metabolic homeostasis of neurons. Previous studies indicated marked but only transient (1-4 h) reactive oxygen species-dependent neurovascular dysfunction in newborn pigs after severe hypoxic/ischemic (H/I) stress contributing to the neuronal injury after birth asphyxia.

Objectives: Our major purpose was to determine if neurovascular dysfunction would also occur later, at 24 h after a milder H/I stress. We also tested if the putative hydroxyl radical scavenger hydrogen (H2) exerted neurovascular protection.

Methods: Anesthetized, ventilated piglets were assigned to three groups of 9 animals: time control, asphyxia/reventilation with air, and asphyxia/reventilation with air +2.1% H2 for 4 h. Asphyxia was induced by suspending ventilation for 8 min. Cerebrovascular reactivity (CR) of pial arterioles was determined using closed cranial window/intravital microscopy 24 h after asphyxia to the endothelium-dependent cerebrovascular stimulus hypercapnia, the neuronal function-dependent stimulus N-methyl-D-aspartate (NMDA), norepinephrine, and sodium nitroprusside. The brains were subjected to histopathology.

Results: Hemodynamic parameters, blood gases, and core temperature did not differ significantly among the experimental groups. In the early reventilation period, the recovery of electroencephalographic activity was significantly better in H2-treated animals. Asphyxia/reventilation severely attenuated CR to hypercapnia and NMDA; however, reactivity to norepinephrine and sodium nitroprusside were unaltered. H2 fully or partially preserved CR to hypercapnia or NMDA, respectively. Histopathology revealed modest neuroprotection afforded by H2.

Conclusions: Severe stimulus-selective delayed neurovascular dysfunction develops and persists even after mild H/I stress. H2 alleviates this delayed neurovascular dysfunction that can contribute to its neuroprotective effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Arterioles / drug effects
  • Arterioles / physiopathology
  • Asphyxia Neonatorum / drug therapy*
  • Asphyxia Neonatorum / metabolism
  • Asphyxia Neonatorum / pathology
  • Asphyxia Neonatorum / physiopathology
  • Blood Gas Analysis
  • Brain Waves / drug effects
  • Disease Models, Animal
  • Electroencephalography
  • Excitatory Amino Acid Agonists / pharmacology
  • Free Radical Scavengers / pharmacology*
  • Hemodynamics / drug effects
  • Hydrogen / pharmacology*
  • Hydroxyl Radical / metabolism
  • Hypercapnia / physiopathology
  • Hypoxia-Ischemia, Brain / metabolism
  • Hypoxia-Ischemia, Brain / pathology
  • Hypoxia-Ischemia, Brain / physiopathology
  • Hypoxia-Ischemia, Brain / prevention & control*
  • Neuroprotective Agents / pharmacology*
  • Pia Mater / blood supply*
  • Pia Mater / drug effects*
  • Pia Mater / metabolism
  • Pia Mater / pathology
  • Recovery of Function
  • Respiration, Artificial
  • Swine
  • Time Factors
  • Vasoconstrictor Agents / pharmacology
  • Vasodilator Agents / pharmacology


  • Excitatory Amino Acid Agonists
  • Free Radical Scavengers
  • Neuroprotective Agents
  • Vasoconstrictor Agents
  • Vasodilator Agents
  • Hydroxyl Radical
  • Hydrogen