INHIBITION OF ENDOTOXIN-INDUCED HYPOTHERMIA AND SERUM TNF-ALPHA LEVELS IN CD-1 MICE BY VARIOUS PHARMACOLOGICAL AGENTS

Intraperitoneal injection of lipopolysaccharide (LPS) was used to elic it a sublethal, shock-like condition in mice. LPS, 2.5 mg/kg i.p., ind uced hypothermia, elevated serum TNF-alpha levels and lethality over a 48 h period in male CD-1 mice. The 5-lipoxygenase (LO) inhibitors, WY -50,295 tromethamine and zileuton (100 mg/kg p.o), significantly inhib ited hypothermia at 4, 24 and 48 h after LPS. Interestingly, whereas c yclooxygenase (CO) inhibitors (ibuprofen, etodolac, naproxen and tenid ap) at 40-80 mg/kg p.o. stimulated hypothermia at 4 h, they significan tly reduced the later stages of hypothermia at 24-48 h. Rolipram (PDE- IV inhibitor) and dexamethasone significantly reduced hypothermia at 4 -24 h and 1-24 h, respectively. All the anti-inflammatory agents signi ficantly reduced elevated TNF-alpha levels at approximately 70 min pos t-LPS, except for ibuprofen. In conclusion, these anti-inflammatory st andards indicate that LPS-induced shock involves multiple lipid mediat ors (PG's, LT's and possibly PAF) and secondary cytokine generation. T his sublethal model of LPS-induced shock represents a sensitive model for estimating the efficacy of potential drug candidates for the treat ment of endotoxic shock.