ABSTRACT
Proteasomes degrade most of the proteins inside eukaryotic cells, including transcription factors and regulators of cell cycle progression. Here we show that nanomolar concentrations of lactacystin, a specific irreversible inhibitor of the 20S proteasome, inhibit development of the exoerythrocytic and erythrocytic stages of the malaria parasite. Although lactacystin-treated Plasmodium berghei sporozoites are still invasive, their development into exoerythrocytic forms (EEF) is inhibited in vitro and in vivo. Erythrocytic schizogony of P. falciparum in vitro is also profoundly inhibited when drug treatment of the synchronized parasites is prior, but not subsequent, to the initiation of DNA synthesis, suggesting that the inhibitory effect of lactacystin is cell cycle specific. Lactacystin reduces P. berghei parasitemia in rats, but the therapeutic index is very low. Along with other studies showing that lactacystin inhibits stage-specific transformation in Trypanosoma and Entamoeba spp., these findings highlight the potential of proteasome inhibitors as drugs for the treatment of diseases caused by protozoan parasites.
Subject(s)
Antimalarials/pharmacology , Cysteine Endopeptidases/drug effects , Cysteine Proteinase Inhibitors/pharmacology , Multienzyme Complexes/drug effects , Plasmodium/drug effects , Acetylcysteine/analogs & derivatives , Acetylcysteine/pharmacology , Animals , Erythrocytes/parasitology , Humans , Hypoxanthine/metabolism , Plasmodium/growth & development , Proteasome Endopeptidase Complex , Rats , Rats, Sprague-DawleyABSTRACT
The report concerns as experimental study utilizing thirty-three mice inoculated subcutaneously with 1000 blood forms of Trypanosoma cruzi. Intestinal transit and morphology of colon were studies by means of X-rays. In subacute stage intestinal transit was normal. In chronic stages the mice displayed a delay in evacuation time. In one out of 12 animals the opaque enema documented the existence of megacolon.
