Oral administration of geranylgeranylacetone improves survival rate in a rat endotoxin shock model: administration timing and heat shock protein 70 induction.
The present study was performed to determine whether oral pretreatment with geranylgeranylacetone (GGA) inhibits proinflammatory cytokine liberation and nitric oxide (NO) production in lipopolysaccharide (LPS)-treated rats and protects rats against death from LPS-induced endotoxin shock, and whether such protection by GGA is related to heat shock protein (HSP) 70 induction in multiple organs of rats. GGA (200 mg/kg) was given orally to rats. LPS (20 mg/kg) was administered intraperitoneally 4, 8, 16, or 24 h after GGA administration. The survival of rats was monitored over 24 h after LPS administration. GGA treatment at 8 or 16 h before LPS dramatically improved the survival rate of LPS-treated rats. Plasma levels of proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) and NO 6 h after LPS administration in these GGA-pretreated rats were less than one-half of those in rats treated with LPS alone. A GGA challenge 8 or 16 h before LPS administration enhanced HSP70 expression in rat organs after LPS. Treatment with GGA 8 h before LPS minimized hepatic and renal damage. Furthermore, the protective effect of GGA on mortality in LPS-treated rats was inhibited with quercetin, known as an HSP70 inhibitor. These results suggest that oral administration of GGA at an optimal time before LPS injection induces and enhances HSP70 expression in several organs, inhibits proinflammatory cytokine and NO production, and prevents organ damage, resulting in an improved survival rate.
Nakada
Junya
J
Division of Medical Biochemistry, Tottori University Faculty of Medicine, Yonago 683-8503, Japan.
Matsura
Tatsuya
T
Okazaki
Naoto
N
Nishida
Tadashi
T
Togawa
Aki
A
Minami
Yukari
Y
Inagaki
Yoshimi
Y
Ito
Hisao
H
Yamada
Kazuo
K
Ishibe
Yuichi
Y
D000284:Administration, Oral; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D015153:Blotting, Western; D004195:Disease Models, Animal; D004224:Diterpenes / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012769:Shock / Q000188:drug therapy* / Q000401:mortality*; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000897:Anti-Ulcer Agents; D004224:Diterpenes; D004731:Endotoxins; D018840:HSP70 Heat-Shock Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C031049:geranylgeranylacetone