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.

Nyckelord

Animals

Animals

Newborn

Apoptosis

drug effects

Calpain

drug effects

Caspases

drug effects

Cystine

analogs & derivatives

pharmacology

Enzyme Activation

drug effects

Glutathione

drug effects

Hypoxia-Ischemia

Brain

chemically induced

prevention & control

Isoprostanes

metabolism

Lipopolysaccharides

toxicity

Membrane Proteins

drug effects

Neuroprotective Agents

pharmacology

Oxidation-Reduction

drug effects

Rats

Rats

Wistar

Thioredoxin

drug effects

Tyrosine

analogs & derivatives

drug effects

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)