Combination treatment of neonatal rats with hypoxia-ischemia and endotoxin induces long-lasting memory and learning impairment that is associated with extended cerebral damage

Am J Obstet Gynecol. 2004 Dec;191(6):2132-41. doi: 10.1016/j.ajog.2004.04.039.


Objective: We assessed the long-term effects of perinatal hypoxia-ischemia and endotoxin on attention and short- and long-term memory in neonatal rats with the use of behavioral tasks and brain histologic results.

Study design: Four hours after injections of lipopolysaccharide (1 mg/kg, intraperitoneally) or saline solution, 7-day-old Wistar rat pups were subjected to unilateral hypoxia-ischemia for 1 hour. We studied 4 groups: controls (n = 43 rats), lipopolysaccharide alone (n = 12 rats), hypoxia-ischemia alone (n = 29 rats), and combined lipopolysaccharide + hypoxia-ischemia treatment (n = 34 rats). Seven to 16 weeks after the treatment, we measured attention with a choice reaction time task, short-term memory with an 8-arm radial maze task, and long-term memory with a water maze task. At 19 weeks of age, the brain was removed, fixed, and sectioned coronally; and the volume of each part was measured.

Results: A loss of volume in the hippocampus was observed in the lipopolysaccharide, hypoxia-ischemia, and lipopolysaccharide + hypoxia-ischemia groups; a loss of striatum was observed in the hypoxia-ischemia and lipopolysaccharide + hypoxia-ischemia groups, but loss of cortex was observed only in the lipopolysaccharide + hypoxia-ischemia group. The lipopolysaccharide, hypoxia-ischemia, and lipopolysaccharide + hypoxia-ischemia groups showed significantly poorer performance (attention deficit) than controls in the choice reaction time task. Correct choices decreased, and error increased in the lipopolysaccharide + hypoxia-ischemia group compared with the other groups in the radial maze task, which shows short-term memory impairment. Swimming distance was significantly greater in the hypoxia-ischemia and lipopolysaccharide + hypoxia-ischemia groups than in the other 2 groups in the water maze test, which shows long-term memory impairment.

Conclusion: Combined lipopolysaccharide and hypoxia-ischemia treatment synergistically induced short-term memory impairment that is associated with loss of cortical volume.

Publication types

  • Comparative Study

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Avoidance Learning
  • Brain Injury, Chronic / physiopathology*
  • Combined Modality Therapy
  • Disease Models, Animal
  • Endotoxins
  • Female
  • Hypoxia-Ischemia, Brain / psychology
  • Hypoxia-Ischemia, Brain / therapy*
  • Learning Disabilities / diagnosis
  • Learning Disabilities / therapy*
  • Lipopolysaccharides / pharmacology*
  • Male
  • Maze Learning
  • Memory Disorders / diagnosis
  • Memory Disorders / therapy*
  • Models, Neurological
  • Probability
  • Random Allocation
  • Rats
  • Rats, Wistar
  • Reaction Time
  • Reference Values
  • Sensitivity and Specificity


  • Endotoxins
  • Lipopolysaccharides