Pyrimethamine induces oxidative stress in Plasmodium yoelii 17XL-infected mice: a novel immunomodulatory mechanism of action for an old antimalarial drug?
Pyrimethamine is an antimalarial drug that has also been used successfully to treat autoimmune diseases such as lymphoproliferative syndrome. In this work, the effect of pyrimethamine (PYR) on the production of free radicals in malaria-infected mice was studied to better understand the drug's immunomodulatory properties. BALB/c and CBA/Ca mice were infected with Plasmodium yoelii 17XL. Seven days after infection, mice were treated with PYR or vehicle and sacrificed 24h later. Treatment with PYR increased superoxide dismutase and glutathione peroxidase activities in erythrocytes and the liver, augmented the levels of nitric oxide in the serum, and upregulated mRNA levels of superoxide dismutase, glutathione peroxidase, catalase, and iNOS in the spleen. In addition, PYR increased lipoperoxidation and protein carbonylation in infected mice. Our results indicate that P. yoelii 17XL reduces oxidative stress in infected cells, while PYR induces it, which is associated with increased parasite elimination. Thus, it is possible that oxidative stress generated by pyrimethamine is also involved in its immunomodulatory mechanism of action.
Legorreta-Herrera
Martha
M
Laboratorio de Inmunología Molecular, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, México, D.F., Mexico. marthal@servidor.unam.mx
Retana-Ugalde
Raquel
R
Ventura-Gallegos
José Luis
JL
Narváez
Verónica
V
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D002374:Catalase / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008288:Malaria / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D009569:Nitric Oxide / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects* / Q000276:immunology; D010967:Plasmodium yoelii / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D050050:Protein Carbonylation / Q000187:drug effects; D011739:Pyrimethamine / Q000494:pharmacology* / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D013997:Time Factors
D000962:Antimalarials; D009569:Nitric Oxide; D008315:Malondialdehyde; D002374:Catalase; D005979:Glutathione Peroxidase; D052247:Nitric Oxide Synthase Type II; D013482:Superoxide Dismutase; D011739:Pyrimethamine