TY  - JOUR
AU  - Hose, Matthias
AU  - Ninnemann, Anne
AU  - Abberger, Hanna
AU  - Schumacher, Fabian
AU  - Naser, Eyad
AU  - Purkart, Leopold
AU  - Korbmacher, Francois
AU  - Martins Nascentes Melo, Luiza
AU  - Beckmann, Nadine
AU  - Blietschau, Vivien
AU  - Falkenstein, Julia
AU  - Kleuser, Burkhard
AU  - Tasdogan, Alpaslan
AU  - Gulbins, Erich
AU  - Carpinteiro, Alexander
AU  - Klopfleisch, Robert
AU  - Buer, Jan
AU  - Westendorf, Astrid M
AU  - Matuschewski, Kai
AU  - Hansen, Wiebke
TI  - Amitriptyline inhibits Plasmodium development in infected red blood cells by modulating sphingolipid metabolism and glucose uptake.
JO  - Biomedicine & pharmacotherapy
VL  - 189
SN  - 0753-3322
CY  - Amsterdam [u.a.]
PB  - Elsevier Science
M1  - DKFZ-2025-01367
SP  - 118331
PY  - 2025
AB  - 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.
KW  - Acid sphingomyelinase (Other)
KW  - Amitriptyline (Other)
KW  - Ceramide (Other)
KW  - Glucose (Other)
KW  - Malaria (Other)
KW  - S1P (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40633203
DO  - DOI:10.1016/j.biopha.2025.118331
UR  - https://inrepo02.dkfz.de/record/302827
ER  -