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Effects of phenothiazine neuroleptic drugs on the microtubular–membrane complex in bloodstream forms of Trypanosoma brucei

Published online by Cambridge University Press:  06 April 2009

A. M. Page  and
J. R. Lagnado
A. M. Page
Affiliation:
Division of Biochemistry, School of Biological Science, Royal Holloway University of London, Egham, Surrey TW20 0EX
J. R. Lagnado
Affiliation:
Division of Biochemistry, School of Biological Science, Royal Holloway University of London, Egham, Surrey TW20 0EX
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Summary

African trypanosomes are parasitic protozoa causing sleeping sickness in humans and related diseases in domestic animals against which no entirely satisfactory forms of chemotherapy are yet available. It was previously shown that related species of trypanosomes, as well as procyclic (insect) forms of Trypanosoma brucei are extremely sensitive to the action of phenothiazine neuroleptic drugs in vitro. In this work, we have carried out a more detailed investigation of the effects of thioridazine, one of the most potent neuroleptic phenothiazine drugs known, on the morphology of the infective bloodstream forms of T. brucei, with particular reference to the parasite's prominent pellicular membrane complex. Our data show that this drug induces rapid changes in cell shape that appear to involve some reorganization of the microtubular membrane skeleton, but does not affect the structural integrity of the microtubular complex. Another early consequence of drug action involved damage to nuclear and cytoplasmic membranes and the appearance of tubular arrays of coated membrane within the flagellar pocket. It was also revealed that the drug induces a rapid release of the variant-specific glycoprotein (VSG) which makes up the surface coat protecting bloodstream forms of the parasite against the host immune system. Our evidence suggests that this release of VSG involves cleavage of the protein's glycosyl-phosphatidylinositol (GPI) membrane anchor by endogenous GPI-specific phospholipase C, probably as a consequence of minor damage to the parasite plasma membrane induced by the drug.

Keywords

Trypanosoma bruceineuroleptic drugsthioridazineVSGcytoskeletonglycosyl-phosphatidylinositol
Type
Research Article
Information
Parasitology , Volume 111 , Issue 4 , November 1995 , pp. 493 - 504
Copyright
Copyright © Cambridge University Press 1995

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