title: Targeting glutathione by dimethylfumarate protects against experimental malaria by enhancing erythrocyte cell membrane scrambling.
abstract: 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.
authors.affiliation: Physiologisches Institut der Universität Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Ghashghaeinia
authors.forename: Diwakar
authors.initials: D
authors.lastname: Bobbala
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieder
authors.forename: Saisudha
authors.initials: S
authors.lastname: Koka
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brück
authors.forename: Birgit
authors.initials: B
authors.lastname: Fehrenbacher
authors.forename: Martin
authors.initials: M
authors.lastname: Röcken
authors.forename: Martin
authors.initials: M
authors.lastname: Schaller
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Kamran
authors.initials: K
authors.lastname: Ghoreschi
mesh_terms: 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
chemical_list: D000975:Antioxidants; D005650:Fumarates; D007166:Immunosuppressive Agents; D010718:Phosphatidylserines; D000069462:Dimethyl Fumarate; D005978:Glutathione