Endotoxin-induced hypoxic-ischemic tolerance is mediated by up-regulation of corticosterone in neonatal rat.
Previous studies suggest that the endotoxin lipopolysaccharide (LPS) may have dual effects on brain damage induced by hypoxia-ischemia (HI) in 7-d-old rats, depending on the exposure paradigm. Although a 4-h interval between LPS administration and HI results in sensitization to HI brain injury, tolerance is observed when LPS is administered 24 h before HI. Our hypothesis is that endogenous corticosteroids are important in acquiring tolerance to HI. Neonatal rats received a single injection of LPS (1.0 mg/kg) either 4 h or 24 h before HI, or two LPS injections (4 h and 24 h) before HI. Increased brain injury was seen in animals subjected to a single LPS injection made 4 h before HI. In contrast, both the single 24-h exposure and the double injections of LPS resulted in tolerance to HI brain damage. To study the effects of corticosteroids on HI tolerance, RU486, a glucocorticoid receptor blocker, was subcutaneously injected at the same time as LPS (1.0 mg/kg), 24 h before HI stress. RU486-LPS treatment counteracted the LPS-induced tolerance effect, and aggravated the HI-induced brain injury compared with the vehicle-LPS-treated group. RU486 did not aggravate the HI-induced brain injury produced 24 h later in saline-injected animals. LPS (1.0 mg/kg) injected into 6-d-old rats transiently up-regulated serum corticosterone levels (119.6, 57.9, 56.8, and 28.3 ng/mL at 6, 12, 24, and 48 h after the LPS injection, respectively). We conclude that endotoxin-induced up-regulation of endogenous corticosterone appears to be critical for acquiring endotoxin-induced HI tolerance.
Ikeda
Tomoaki
T
Department of Obstetrics and Gynecology, Miyazaki Medical College, University of Miyazaki, Kihara, Japan. tikeda44@hotmail.com
Yang
Li
L
Ikenoue
Tsuyomu
T
Mallard
Carina
C
Hagberg
Henrik
H
D000818:Animals; D000831:Animals, Newborn; D003345:Corticosterone / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D006727:Hormone Antagonists / Q000494:pharmacology; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000627:therapeutic use*; D015735:Mifepristone / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
D006727:Hormone Antagonists; D008070:Lipopolysaccharides; D015735:Mifepristone; D003345:Corticosterone