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.


CONCLUSIONS
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.
Wang
Xiaoyang
X
Perinatal Center, Department of Physiology, Göteborg University, Göteborg, Sweden. xiaoyang.wang@fysiologi.gu.se
Svedin
Pernilla
P
Nie
Chunxia
C
Lapatto
Risto
R
Zhu
Changlian
C
Gustavsson
Malin
M
Sandberg
Mats
M
Karlsson
Jan-Olof
JO
Romero
Roberto
R
Hagberg
Henrik
H
Mallard
Carina
C
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002154:Calpain / Q000187:drug effects; D020169:Caspases / Q000187:drug effects; D003553:Cystine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000187:drug effects; D020925:Hypoxia-Ischemia, Brain / Q000139:chemically induced / Q000517:prevention & control*; D028421:Isoprostanes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008565:Membrane Proteins / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013879:Thioredoxins / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives / Q000187:drug effects
D028421:Isoprostanes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D018696:Neuroprotective Agents; C516113:Txn2 protein, rat; C002744:3-nitrotyrosine; D014443:Tyrosine; D003553:Cystine; D013879:Thioredoxins; D002154:Calpain; D020169:Caspases; D005978:Glutathione; C030905:N-monoacetylcystine