Abstract
Background: Thioridazine, a neuroleptic phenothiazine with antimicrobial efficacy is known to trigger anemia. At least in theory, the anemia could result from stimulation of suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and by phospholipid scrambling of the cell membrane with phosphatidylserine exposure at the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca2+-concentration ([Ca2+]i) and activation of p38 kinase. The present study explored, whether thioridazine elicits eryptosis. Methods: [Ca2+]i has been estimated from Fluo3-fluorescence, cell volume from forward scatter, phosphatidylserine exposure from annexin-V-binding, and hemolysis from hemoglobin release. Results: A 48 hours exposure to thioridazine was followed by a significant increase of [Ca2+]i (30 µM), decrease of forward scatter (30 µM), and increase of annexin-V-binding (≥12 µM). Nominal absence of extracellular Ca2+ and p38 kinase inhibitor SB203580 (2 µM) significantly blunted but did not abolish annexin-V-binding following thioridazine exposure. Conclusions: Thioridazine stimulates eryptosis, an effect in part due to entry of extracellular Ca2+ and activation of p38 kinase.
Highlights
Thioridazine, a phenothiazine drug, has both antipsychotic efficacy [1,2] and anti-microbial activity [2].It is useful for the treatment of multidrug resistant tuberculosis [3,4,5,6].Side effects of thioridazine include anemia [7,8]
The present study explored whether thioridazine triggers eryptosis, the suicidal death of erythrocytes
The key hallmark of eryptosis is the triggering of cell membrane scrambling with increase of phosphatidylserine abundance at the cell surface
Summary
Thioridazine, a phenothiazine drug, has both antipsychotic efficacy [1,2] and anti-microbial activity [2]. It is useful for the treatment of multidrug resistant tuberculosis [3,4,5,6]. Eryptosis may be triggered by increased cytosolic Ca2+. Increased [Ca2+]i further leads to translocation of phosphatidylserine from the inner leaflet of the cell membrane to the erythrocyte surface [15]. The present study explored, whether thioridazine triggers eryptosis. To this end, the effect of thioridazine on [Ca2+]i, cell volume and phosphatidylserine abundance at the erythrocyte surface has been determined
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