Publikationsdatenbank

Amitriptyline inhibits Plasmodium development in infected red blood cells by modulating sphingolipid metabolism and glucose uptake (2025)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Hose, Matthias

Ninnemann, Anne

Abberger, Hanna

Schumacher, Fabian

Naser, Eyad

Purkart, Leopold

Korbmacher, Francois

Martins Nascentes Melo, Luiza

Beckmann, Nadine

Blietschau, Vivien

Falkenstein, Julia

Kleuser, Burkhard

Tasdogan, Alpaslan

Gulbins, Erich

Carpinteiro, Alexander

Klopfleisch, Robert (WE 12)

Buer, Jan

Westendorf, Astrid M.

Matuschewski, Kai

Hansen, Wiebke

Quelle

Biomedicine & pharmacotherapy

Bandzählung: 189

Seiten: 118331

ISSN: 0753-3322

Sprache

Englisch

Verweise

URL (Volltext): https://www.sciencedirect.com/science/article/pii/S0753332225005256?via%3Dihub

DOI: 10.1016/j.biopha.2025.118331

Pubmed: 40633203

Kontakt

Institut für Tierpathologie

Robert-von-Ostertag-Str. 15
14163 Berlin
+49 30 838 62450
pathologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Malaria remains a global health challenge, necessitating novel therapeutic approaches. Here, we explore the role of the sphingolipid metabolism in Plasmodium infection. We focus on the enzyme acid sphingomyelinase (Asm), which hydrolyzes sphingomyelin to ceramide, a structural but also bioactive membrane molecule. We demonstrate induction of Asm activity in infected mice, leading to elevated ceramide levels in infected red blood cells. Pharmacological inhibition of Asm with the functional inhibitor amitriptyline in Plasmodium yoelii (Py)- and Plasmodium berghei ANKA (PbA)-infected mice significantly reduces parasitemia and mitigates disease-associated pathology. Amitriptyline treatment also reduces T cell activation, preserving blood-brain barrier integrity upon PbA infection. Remarkably, we observe inhibition of Plasmodium falciparum growth in vitro upon exposure to amitriptyline. Mechanistically, we elucidate that amitriptyline impedes intra-erythrocytic parasite development, due to a reduced glucose uptake and thereby interfering with the spreading of blood-stage Plasmodium parasites. Our findings highlight the therapeutic promise of targeting sphingolipid metabolism to combat Plasmodium infections.