Targeting glutathione by dimethylfumarate protects against experimental malaria by enhancing erythrocyte cell membrane scrambling.
The balance between GSH-levels and oxidative stress is critical for cell survival. The GSH-levels of erythrocytes are dramatically decreased during infection with Plasmodium spp. We therefore investigated the consequences of targeting GSH for erythrocyte and Plasmodium survival in vitro and in vivo using dimethylfumarate (DMF) at therapeutically established dosage. We first show that noninfected red blood cells (RBC) exposed to DMF undergo changes typical of apoptosis or eryptosis, such as cell shrinkage and cell membrane scrambling with subsequent phosphatidylserine (PS) exposure. DMF did not induce appreciable hemolysis. DMF-triggered PS exposure was mediated by intracellular GSH depletion and reversed by the antioxidative N-acetyl-l-cysteine. DMF treatment controlled intraerythrocyte DNA amplification and in vitro parasitemia of Plasmodium falciparum-infected RBC. In vivo, DMF treatment had no effect on RBC count or GSH levels in noninfected mice. Consistent with its effects on infected RBC, DMF treatment abrogated parasitemia and enhanced the survival of mice infected with Plasmodium berghei from 0% to 60%. In conclusion, DMF sensitizes the erythrocytes to the effect of Plasmodium infection on PS exposure, thus accelerating the clearance of infected erythrocytes. Accordingly, DMF treatment favorably influences the clinical course of malaria. As DMF targets mechanisms within the host cell, it is not likely to generate resistance of the pathogen.
Ghashghaeinia
Mehrdad
M
Physiologisches Institut der Universität Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany.
Bobbala
Diwakar
D
Wieder
Thomas
T
Koka
Saisudha
S
Brück
Jürgen
J
Fehrenbacher
Birgit
B
Röcken
Martin
M
Schaller
Martin
M
Lang
Florian
F
Ghoreschi
Kamran
K
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D000069462:Dimethyl Fumarate; D004910:Erythrocyte Membrane / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D005650:Fumarates / Q000494:pharmacology / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D008288:Malaria / Q000097:blood / Q000188:drug therapy; D051379:Mice; D010718:Phosphatidylserines / Q000378:metabolism; D010961:Plasmodium / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology
D000975:Antioxidants; D005650:Fumarates; D007166:Immunosuppressive Agents; D010718:Phosphatidylserines; D000069462:Dimethyl Fumarate; D005978:Glutathione