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Ultrastructural changes associated with reversal of chloroquine resistance by verapamil in Plasmodium chabaudi

Published online by Cambridge University Press:  06 April 2009

K. Ohsawa ,
K. Tanabe ,
I. Kimata  and
A. Miki
K. Ohsawa
Affiliation:
Department of Medical Zoology, Osaka City University Medical School, Asahi-machi, Abeno-ku, Osaka 545, Japan
K. Tanabe
Affiliation:
Laboratory of Biology, Osaka Institute of Technology, Ohmiya, Asahi-ku, Osaka 535, Japan
I. Kimata
Affiliation:
Department of Medical Zoology, Osaka City University Medical School, Asahi-machi, Abeno-ku, Osaka 545, Japan
A. Miki
Affiliation:
Department of Medical Zoology, Osaka City University Medical School, Asahi-machi, Abeno-ku, Osaka 545, Japan
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Abstract

Reversal of chloroquine (CQ) resistance by verapamil, a Ca2+ antagonist, has been shown in CQ-resistant human and rodent malaria parasites. Here, we report ultrastructural changes associated with this phenomenon in CQ-resistant Plasmodium chabaudi (AS strain) after infected mice were administered CQ and verapamil. At parasitaemias of 5–7%, CQ at 6 mg/kg caused little morphological effect on CQ-resistant parasites. In contrast, co-administration of CQ and verapamil at 50 mg/kg induced swelling of food vacuoles with clumped pigment at 2.5 h. Morphological changes other than food vacuole enlargement occurred at 21 and 45 h: disappearance of endoplasmic reticulum, formation of myelin structures, focal cytoplasmic vacuolization and coarse clumping of electron-dense material in nuclei. These structural changes appeared to be very similar to those observed in CQ-sensitive P. chabaudi in mice injected with CQ alone or CQ plus verapamil. On the other hand, verapamil at 50 mg/kg alone did not induce any effect on both CQ-sensitive and CQ-resistant P. chabaudi. These results suggest that swelling of the food vacuoles is an initial event associated with reversal of CQ-resistance by verapamil.

Keywords

Plasmodium chabaudichloroquinedrug resistanceCa2+ antagonistverapamil
Type
Research Article
Information
Parasitology , Volume 103 , Issue 2 , October 1991 , pp. 185 - 189
Copyright
Copyright © Cambridge University Press 1991

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References

Aikawa, M. (1972). High-resolution autoradiography of malarial parasites treated with 3H-chloroquine. American Journal of Pathology 67, 277–84.Google Scholar
Basco, L. K. & Bras, J. L. (1990). Reversal of chloroquine resistance with desipramine in isolates of Plasmodium falciparum from Central and West Africa. Transactions of the Royal Society of Tropical Medicine and Hygiene 84, 479–81.CrossRefGoogle ScholarPubMed
Bitonti, A. J., Sjoerdsma, A., McCann, P. P., Kyle, D. E., Oduola, A. M. J., Rossan, R. N., Milhous, W. K. & Davidson, D. E. Jr (1988). Reversal of chloroquine resistance in malaria parasite Plasmodium falciparum by desipramine. Science 242, 1301–3.CrossRefGoogle ScholarPubMed
Foote, S. J., Kyle, D. E., Martin, R. K., Oduola, A. M. J., Forsyth, K., Kemp, D. J. & Cowman, A. F. (1990). Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in Plasmodium falciparum. Nature, London 345, 255–8.CrossRefGoogle ScholarPubMed
Jacobs, G. H., Oduola, A. M., Kyle, D. E., Milhous, W. K., Martin, S. K. & Aikawa, M. (1988). Ultrastructural study of the effect of chloroquine and verapamil on Plasmodium falciparum. American Journal of Tropical Medicine and Hygiene 39, 15–20.CrossRefGoogle ScholarPubMed
Krogstad, D. J., Gluzman, I. Y., Kyle, D. E., Oduola, A. M. J., Martin, S. K., Milhous, W. K. & Schlesinger, P. H. (1987). Efflux of chloroquine from Plasmodium falciparum: Mechanism of chloroquine resistance. Science 238, 1283–5.CrossRefGoogle ScholarPubMed
Kyle, D. E., Oduola, A. M. J., Martin, S. K. & Milhous, W. K. (1990). Plasmodium falciparum: modulation by calcium antagonists of resistance to chloroquine, desethyl chloroquine, quinine, and quinidine in vitro. Transactions of the Royal Society of Tropical Medicine and Hygiene 84, 474–8.CrossRefGoogle Scholar
Macomber, P. B. & Sprinz, H. (1967). Morophological effects of chloroquine on Plasmodium berghei in mice. Nature, London 214, 937–9.CrossRefGoogle Scholar
Martin, S. K., Oduola, A. M. J. & Milhous, W. K. (1987). Reversal of chloroquine resistance in Plasmodium falciparum by verapamil. Science 235, 899–901.CrossRefGoogle ScholarPubMed
Moreau, S., Prensier, G., Maalla, J. & Fortier, B. (1986). Identification of distinct accumulation sites of 4-aminoquinoline in chloroquine sensitive and resistant Plasmodium berghei strains. European Journal of Cell Biology 42, 207–10.Google ScholarPubMed
Peters, W., Ekong, R., Robinson, B. L., Warhurst, D. C. & Pan, X.-Q. (1989). Antihistaminic drugs that reverse chloroquine resistance in Plasmodium falciparum. Lancet 2, 334–5.CrossRefGoogle ScholarPubMed
Rosario, V. E. (1976). Genetics of chloroquine resistance in malaria parasites. Nature, London 261, 585–6.CrossRefGoogle ScholarPubMed
Tanabe, K., Kato, M., Izumo, A., Hagiwara, A. & Doi, S. (1990). Plasmodium chabaudi: in vivo effects of Ca2+ antagonists on chloroquine-resistant and chloroquine-sensitive parasites. Experimental Parasitology 70, 419–26.CrossRefGoogle ScholarPubMed
Ye, Z. & Van Dyke, K. (1988). Reversal of chloroquine resistance in falciparum malaria independent of calcium channels. Biochemical and Biophysical Research Communications 155, 476.Google ScholarPubMed
Warhurst, D. C. & Hockley, D. J. (1967). Mode of action of chloroquine on Plasmodium berghei and P. cynomolgi. Nature, London 214, 935–6.CrossRefGoogle ScholarPubMed
Wellems, T. E., Panton, L. J., Gluzman, I. Y., Do Rosario, V. E., Gwadz, R. W., Walker-Jonah, A. & Krogstad, D. J. (1990). Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum cross. Nature, London 345, 253–5.CrossRefGoogle ScholarPubMed
Wunderlich, F., Stubig, H. & Konigh, E. (1981). Chloroquine effects on parasite and host membranes of intraerythrocytic Plasmodium chabaudi. Tropenmedizin und Parasitologie 32, 77–81.Google Scholar