Amitriptyline inhibits Plasmodium development in infected red blood cells by modulating sphingolipid metabolism and glucose uptake
- Author(s)
- Hose, M; Ninnemann, A; Abberger, H; Schumacher, F; Naser, E; Purkart, L; Korbmacher, F; Martins Nascentes Melo, L; Beckmann, N; Blietschau, V; Falkenstein, J; Kleuser, B; Tasdogan, A; Gulbins, E; Carpinteiro, A; Klopfleisch, R; Buer, J; Westendorf, AM; Matuschewski, K; Hansen, W;
- Journal Title
- Biomedicine & Pharmacotherapy
- Abstract
- 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.
- Publisher
- Elsevier
- Keywords
- Animals; *Sphingolipids/metabolism; *Erythrocytes/parasitology/drug effects/metabolism; *Malaria/drug therapy/parasitology/blood/metabolism; *Glucose/metabolism; *Amitriptyline/pharmacology/therapeutic use; Mice; Plasmodium berghei/drug effects/growth & development; Sphingomyelin Phosphodiesterase/metabolism/antagonists & inhibitors; Mice, Inbred C57BL; *Antimalarials/pharmacology; Plasmodium falciparum/drug effects/growth & development; Parasitemia/drug therapy/parasitology; Blood-Brain Barrier/drug effects/metabolism; Plasmodium yoelii/drug effects/growth & development; Acid sphingomyelinase; Amitriptyline; Ceramide; Glucose; Malaria; S1p
- Research Division(s)
- Immunology
- PubMed ID
- 40633203
- Publisher's Version
- https://doi.org/10.1016/j.biopha.2025.118331
- Open Access at Publisher's Site
https://doi.org/10.1016/j.biopha.2025.118331- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-01-22 09:59:57
Last Modified: 2026-01-22 10:03:26