N-acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury

Ann Neurol. 2007 Mar;61(3):263-71. doi: 10.1002/ana.21066.


Objective: Maternal inflammation/infection alone or in combination with birth asphyxia increases the risk for perinatal brain injury. Free radicals are implicated as major mediators of inflammation and hypoxia-ischemia (HI)-induced perinatal brain injury. This study evaluated the neuroprotective efficacy of a scavenging agent, N-acetylcysteine (NAC), in a clinically relevant model.

Methods: Lipopolysaccharide (LPS)-sensitized HI brain injury was induced in 8-day-old neonatal rats. NAC was administered in multiple doses, and brain injury was evaluated at 7 days after HI.

Results: NAC (200mg/kg) provided marked neuroprotection with up to 78% reduction of brain injury in the pre+post-HI treatment group and 41% in the early (0 hour) post-HI treatment group, which was much more pronounced protection than another free radical scavenger, melatonin. Protection by NAC was associated with the following factors: (1) reduced isoprostane activation and nitrotyrosine formation; (2) increased levels of the antioxidants glutathione, thioredoxin-2, and (3) inhibition of caspase-3, calpain, and caspase-1 activation.

Interpretation: NAC provides substantial neuroprotection against brain injury in a model that combines infection/inflammation and HI. Protection by NAC was associated with improvement of the redox state and inhibition of apoptosis, suggesting that these events play critical roles in the development of lipopolysaccharide-sensitized HI brain injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Calpain / drug effects
  • Caspases / drug effects
  • Cystine / analogs & derivatives*
  • Cystine / pharmacology
  • Enzyme Activation / drug effects
  • Glutathione / drug effects
  • Hypoxia-Ischemia, Brain / chemically induced
  • Hypoxia-Ischemia, Brain / prevention & control*
  • Isoprostanes / metabolism
  • Lipopolysaccharides / toxicity
  • Membrane Proteins / drug effects
  • Neuroprotective Agents / pharmacology*
  • Oxidation-Reduction / drug effects*
  • Rats
  • Rats, Wistar
  • Thioredoxins / drug effects
  • Tyrosine / analogs & derivatives
  • Tyrosine / drug effects


  • Isoprostanes
  • Lipopolysaccharides
  • Membrane Proteins
  • Neuroprotective Agents
  • Txn2 protein, rat
  • 3-nitrotyrosine
  • Tyrosine
  • Cystine
  • Thioredoxins
  • Calpain
  • Caspases
  • Glutathione
  • N-monoacetylcystine