Inhibition, by trichothecene antibiotics, of brain protein synthesis and fever in rabbits.

Abstract

SUMMARY1. To test further the hypothesis that brain protein synthesis is necessary for fever, three structurally similar trichothecene antibiotics were injected into the cerebral ventricles of rabbits. They were 3,15-diacetoxy-12-hydroxytrichothec-9-ene (DAHT), 3,15-didesacetyl-calonectrin (DDAC) and T-2 toxin. Their actions on hypothalamic incorporation of [14C]leucine and fever were compared.2. DDAC (60 jag) and T-2 toxin (10 jug) strongly inhibited leucine incorporation and fever. DAHT (60 jug) did not diminish fever and had a smaller effect upon leucine incorporation.3. The findings strengthen considerably earlier suggestions that brain protein synthesis is an essential step in pyrogenesis.

Further observations on the suppression of fever in rabbits by intracerebral action of anisomycin.

“…If it can be shown that other inhibitors, with structures quite disparate from anisomycin and cycloheximide, also inhibit fever, then an alternative pharmacological explanation for our findings will be less likely. The following paper (Cannon, Cranston, Hellon & Townsend, 1982) supports this contention.…”

Intraventricular injections of drugs which inhibit phospholipase A2 suppress fever in rabbits.

“…We and others have previously demonstrated that the inhibition of cerebral protein synthesis by anisomycin and the trichothecenes suppresses the fever caused by endogenous pyrogen (Ruwe & Myers, 1979;Cranston, Hellon & Townsend, 1980;Cannon, Cranston, Hellon & Townsend, 1982) but not by arachidonic acid (Townsend, Gourine & Cranston, 1981). Furthermore, the action of the inhibitors is rapid because they are effective when given at the same time or even after endogenous pyrogen .…”

Progress in Molecular and Subcellular Biology

“…five times per day caused abnormal EEG's in several patients; neurological symptoms ranged from mild confusion to short periods of coma and hallucination. Cannon et al (1982) recently demonstrated that intraventricular injection of 3,15-didesacetylcalonection (60 Vg) or T-2 toxin (10 Vg) caused a significant decline in protein synthesis in the hypothalamus of the rabbit. In a separate study (phase II clinical trials) about 12% of the 93 patients treated with infusion doses of 3-4.5 mg/m 2 (80-120 Vg/kg body wt.)…”