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.
Keywords: phosphatidylserine; thioridazine; calcium; cell volume; eryptosis
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Lang, E.; Modicano, P.; Arnold, M.; Bissinger, R.; Faggio, C.; Abed, M.; Lang, F. Effect of Thioridazine on Erythrocytes. Toxins 2013, 5, 1918-1931.
Lang E, Modicano P, Arnold M, Bissinger R, Faggio C, Abed M, Lang F. Effect of Thioridazine on Erythrocytes. Toxins. 2013; 5(10):1918-1931.
Lang, Elisabeth; Modicano, Paola; Arnold, Markus; Bissinger, Rosi; Faggio, Caterina; Abed, Majed; Lang, Florian. 2013. "Effect of Thioridazine on Erythrocytes." Toxins 5, no. 10: 1918-1931.