Plasmodium berghei: dehydroepiandrosterone sulfate reverses chloroquino-resistance in experimental malaria infection; correlation with glucose 6-phosphate dehydrogenase and glutathione synthesis pathway.
In Plasmodium falciparum-infected cells or in P. berghei infected mice, increase of reduced glutathione (GSH) levels confers resistance to chloroquine (CQ). GSH is synthesized within the cells through a complex biochemical pathway composed of several well known enzymes, in which glucose-6-phosphate dehydrogenase (G6PD) plays an important role. The physiological hormone dehydroepiandrosterone sulfate (DHEAS) is a potent inhibitor of G6PD activity, and G6PD deficiency is known to exert antimalaria protection. This study aimed to investigate the ability of DHEAS to enhance the antimalarial activity of CQ, via an inhibition of G6PD activity and GSH synthesis. Two P. berghei CQ resistant strains (CQR6 and CQR30) were selected in vivo from the sensitive strain NK65. Drug effects were checked both by monitoring the evolution of parasitaemia and by the survival of infected mice. In addition, intra-parasite levels of GSH and G6PD activity were measured before and after the treatment. Results demonstrate that acquisition of CQ resistance in P. berghei is associated with a significant increase in parasite G6PD activity and GSH level. Combination of CQ with DHEAS or buthionin sulfoximin (BSO, a specific inhibitor of GSH synthesis) significantly increased sensitivity of resistant parasites to CQ and increased the survival period of the infected mice. This reduction of parasitaemia and improvement of the survival of infected mice were associated with intra-parasite depletion of GSH and inhibition of G6PD activity due to DHEAS action. This experimental study suggests that DHEAS could be used to potentiate antimalarial action of CQ, particularly on CQ resistant strains.
Unité 3677, Bases thérapeutiques des inflammations et infections, Université Victor Segalen Bordeaux II, 146 rue Leo Saignat, 33076 Bordeaux Cedex, France. isafeukui_no@etud.u-bordeaux2.fr
Innocent
I
Safeukui
François
F
Mangou
Denis
D
Malvy
Philippe
P
Vincendeau
Djavad
D
Mossalayi
Gilbert
G
Haumont
Remi
R
Vatan
Piero
P
Olliaro
Pascal
P
Millet
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D002738:Chloroquine / Q000494:pharmacology* / Q000627:therapeutic use; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology*; D004347:Drug Interactions; D004351:Drug Resistance / Q000187:drug effects*; D005260:Female; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism*; D005978:Glutathione / Q000096:biosynthesis*; D019803:Glutathione Disulfide; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects*
D000962:Antimalarials; D019314:Dehydroepiandrosterone Sulfate; D002738:Chloroquine; D005954:Glucosephosphate Dehydrogenase; D005978:Glutathione; D019803:Glutathione Disulfide