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

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. Ann Neurol 2007