CYCLOHEXIMIDE OR NORDIHYDROGUAIARETIC ACID PROTECTS MICE AGAINST THE LETHAL AND HEPATOCYTOLYTIC EFFECTS OF A COMBINED CHALLENGE WITH D-GALACTOSAMINE AND BACTERIAL-ENDOTOXIN

Both Cycloheximide and nordihydroguaiaretic acid protect mice against the fatalities and associated panlobular hepatocyte necrosis that follow a challenge with D-galactosamine and bacterial endotoxin. It is proposed that Cycloheximide acts as an inhibitor of the endotoxin-induced activation of phospholipase A2, thereby inhibiting the synthesis of leukotrienes which is now known to be a prerequisite for tumour necrosis factor-α (TNF) biosynthesis, the latter cytokine being regarded as the terminal mediator of the fatal D-galactosamine and endotoxin-induced syndrome. Nordihydroguaiaretic acid protection is explained by its inhibition of lipoxygenase enzymes, and thus ultimately of TNF production in response to endotoxin. © 1993, Academic Press Limited. All rights reserved.