Oral Administration of Geranylgeranylacetone Improves Survival Rate in a Rat Endotoxin Shock Model: Administration Timing and Heat Shock Protein 70 Induction

Abstract

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.

Recombinant human Hsp70 protects against lipoteichoic acid-induced inflammation manifestations at the cellular and organismal levels

“…Notably, the endogenous Hsp70 actively synthesized in all cells after heat shock also effectively inhibits bacterial pathogen-induced production of TNFα and other cytokines, and it appears to be responsible for normalization of the cardiovascular and coagulation systems that are strongly affected by bacterial endotoxins (Ding et al 2001;Suganuma et al 2002;Nakada et al 2005). Hsp70 preconditioning also normalized all hemostatic parameters, including fibrinogen concentration, disturbed by LTA challenge.…”

Geranylgeranylacetone Induces Cyclooxygenase-2 Expression in Cultured Rat Gastric Epithelial Cells Through NF-κB

“…GGA exerts protective actions against a variety of tissues and their injury, including neuronal injury [25], endotoxic shock [26], ischemiareperfusion [9], and myocardial ischemia [27]. GGA stimulates the synthesis and secretion of mucin in vivo [4] and in vitro [10] and prevents degradation of the gastric mucosa when it is exposed to several types of insults and/or stress Fig.…”

Protective effects of heat shock protein70 induced by geranylgeranylacetone in atrophic gastritis in rats

“…Quercetin is known to block the synthesis of HSP70 at the level of mRNA accumulation [19] and then eliminates the protective role of HSP70 to interrupt cell recovery from damage [20,21] . Our data showed that quercetin suppressed the accumulation of HSP70 in gastric cells, especially in the nucleus, and increased the infiltration of inflammatory cells in gastric mucosa.…”

“…Accompanied by the induction of atrophic gastritis, the rats (n=6) were treated with GGA (200 mg/kg, ig) for 8 weeks, from week 17 to the end of week 24. To further investigate whether GGA protected gastric mucosa via the induction of HSP70, we administered quercetin (100 mg/kg ig, n=6; Sigma, Saint Louis, MO, USA), an inhibitor of HSP70 synthesis [18][19][20] , in DMSO to rats daily for the final 8 weeks of the 24-week period of atrophic gastritis induction. The control rats were gavaged with DMSO (5 mL/kg, n=6).…”