Molecular hydrogen alleviates asphyxia-induced neuronal cyclooxygenase-2 expression in newborn pigs

Acta Pharmacol Sin. 2018 Aug;39(8):1273-1283. doi: 10.1038/aps.2017.148. Epub 2018 Mar 22.


Cyclooxygenase-2 (COX-2) has an established role in the pathogenesis of hypoxic-ischemic encephalopathy (HIE). In this study we sought to determine whether COX-2 was induced by asphyxia in newborn pigs, and whether neuronal COX-2 levels were affected by H2 treatment. Piglets were subjected to either 8 min of asphyxia or a more severe 20 min of asphyxia followed by H2 treatment (inhaling room air containing 2.1% H2 for 4 h). COX-2 immunohistochemistry was performed on brain samples from surviving piglets 24 h after asphyxia. The percentages of COX-2-immunopositive neurons were determined in cortical and subcortical areas. Only in piglets with more severe HIE, we observed significant, region-specific increases in neuronal COX-2 expression within the parietal and occipital cortices and in the CA3 hippocampal subfield. H2 treatment essentially prevented the increases in COX-2-immunopositive neurons. In the parietal cortex, the attenuation of COX-2 induction was associated with reduced 8'-hydroxy-2'-deoxyguanozine immunoreactivity and retained microglial ramifcation index, which are markers of oxidative stress and neuroinfiammation, respectively. This study demonstrates for the first time that asphyxia elevates neuronal COX-2 expression in a piglet HIE model. Neuronal COX-2 induction may play region-specific roles in brain lesion progression during HIE development, and inhibition of this response may contribute to the antioxidant/anti-infiammatory neuroprotective effects of H2 treatment.

Keywords: 8′-hydroxy-2′-deoxyguanozine; COX-2; hypoxic-ischemic encephalopathy; microglia; molecular hydrogen; neuroprotection; newborn pigs.

MeSH terms

  • Animals
  • Animals, Newborn
  • Asphyxia / prevention & control*
  • Cyclooxygenase 2 / metabolism*
  • Hippocampus / physiopathology
  • Hydrogen / therapeutic use*
  • Hypoxia-Ischemia, Brain / prevention & control*
  • Male
  • Microglia / metabolism
  • Neurons / metabolism
  • Neuroprotective Agents / therapeutic use*
  • Parietal Lobe / physiopathology
  • Swine


  • Neuroprotective Agents
  • Hydrogen
  • Cyclooxygenase 2