N-Acetylcysteine Amide Exerts Possible Neuroprotective Effects in Newborn Pigs after Perinatal Asphyxia

Neonatology. 2017;111(1):12-21. doi: 10.1159/000447255. Epub 2016 Aug 6.

Abstract

Background: Perinatal asphyxia and ensuing reoxygenation change the antioxidant capacity of cells and organs.

Objectives: To analyze the neuroprotective effect of the antioxidant N-acetylcysteine amide (NACA) after perinatal hypoxia-reoxygenation with an emphasis on proinflammatory cytokines and the transcription factor NF-κB in the prefrontal cortex of neonatal pigs.

Methods: Twenty-nine newborn pigs, aged 12-36 h, were subjected to global hypoxia and hypercapnia. One sham-operated group (n = 5) and 2 experimental groups (n = 12) were exposed to 8% oxygen, until the base excess was -20 mmol/l or the mean arterial blood pressure fell to <20 mm Hg (asphyxia with NACA or saline). The pigs were observed for 9.5 h after hypoxia. Samples of prefrontal cortex and plasma were analyzed.

Results: Cortex: there was no significant difference in mRNA expression between the intervention groups regarding IL-1β, IL6, TNFα, MMP2, MMP9 or IL18. Pigs exposed to hypoxia-reoxygenation and treatment with NACA (NACA-pigs) had a significantly lower protein concentration of IL-1β than pigs treated with saline (placebo controls), i.e. 8.8 ± 3.9 versus 16.8 ± 10.5 pg/mg protein (p = 0.02). The activation of the transcription factor NF-κB (measured as the fold-change of phosphorylated p65Ser 536), was reduced in the NACA-pigs when compared to the placebo controls (5.2 ± 4.3 vs. 16.0 ± 13.5; p = 0.02). No difference between the intervention groups regarding brain histopathology or in the levels of 8-oxoguanine measured in the prefrontal cortex were observed. Plasma: the NACA-pigs had a stronger reduction of TNFα in the first 30 min following asphyxia compared with the placebo controls, i.e. 36 (30-44) versus 24 (14-32)% (p = 0.01).

Conclusion: The reduced levels of the pivotal inflammatory markers IL-1β and TNFα and the transcription factor NF-κB may indicate that NACA has possible neuroprotective effects after perinatal asphyxia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / analogs & derivatives*
  • Acetylcysteine / pharmacology
  • Animals
  • Animals, Newborn
  • Asphyxia Neonatorum / therapy*
  • Biomarkers / blood
  • Brain / drug effects
  • Female
  • Hypoxia / therapy*
  • Interleukin-1beta / blood
  • Male
  • NF-kappa B / blood
  • Neuroprotective Agents / pharmacology*
  • Oxygen / administration & dosage*
  • Swine
  • Time Factors
  • Tumor Necrosis Factor-alpha / blood

Substances

  • Biomarkers
  • Interleukin-1beta
  • NF-kappa B
  • Neuroprotective Agents
  • Tumor Necrosis Factor-alpha
  • N-Acetylcysteinamide
  • Oxygen
  • Acetylcysteine