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


METHODS
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.


CONCLUSIONS
Combined lipopolysaccharide and hypoxia-ischemia treatment synergistically induced short-term memory impairment that is associated with loss of cortical volume.
Ikeda
Tomoaki
T
Department of Obstetrics and Gynecology, Miyazaki Medical College, 5200 Kihara, Kiyotake-Cho, Miyazaki 889-16, Japan. tikeda@post1.miyazaki-med.ac.jp
Mishima
Kenichi
K
Aoo
Naoya
N
Egashira
Nobuaki
N
Iwasaki
Katsunori
K
Fujiwara
Michihiro
M
Ikenoue
Tsuyomu
T
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001362:Avoidance Learning; D020208:Brain Injury, Chronic / Q000503:physiopathology*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004731:Endotoxins; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000523:psychology / Q000628:therapy*; D007859:Learning Disabilities / Q000175:diagnosis / Q000628:therapy*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning; D008569:Memory Disorders / Q000175:diagnosis / Q000628:therapy*; D008959:Models, Neurological; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time; D012016:Reference Values; D012680:Sensitivity and Specificity
D004731:Endotoxins; D008070:Lipopolysaccharides