Abstract
Chlorpromazine, an antipsychotic medication, is conventionally applied to cope with the psychotic disorder such as schizophrenia. In cellular studies, chlorpromazine exerts many different actions through calcium ion (Ca2+) signaling, but the underlying pathways are elusive. This study explored the effect of chlorpromazine on viability, Ca2+ signaling pathway and their relationship in glial cell models (GBM 8401 human glioblastoma cell line and Gibco® Human Astrocyte (GHA)). First, chlorpromazine between 10 and 40 μM induced cytotoxicity in GBM 8401 cells but not in GHA cells. Second, in terms of Ca2+ homeostasis, chlorpromazine (10–30 μM) increased intracellular Ca2+ concentrations ([Ca2+]i) rises in GBM 8401 cells but not in GHA cells. Ca2+ removal reduced the signal by approximately 55%. Furthermore, chelation of cytosolic Ca2+ with BAPTA-AM reduced chlorpromazine (10–40 μM)-induced cytotoxicity in GBM 8401 cells. Third, in Ca2+-containing medium of GBM 8401 cells, chlorpromazine-induced Ca2+ entry was inhibited by the modulators of store-operated Ca2+ channel (2-APB and SKF96365). Lastly, in Ca2+-free medium of GBM 8401 cells, treatment with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin completely inhibited chlorpromazine-increased [Ca2+]i rises. Conversely, treatment with chlorpromazine abolished thapsigargin-increased [Ca2+]i rises. Inhibition of phospholipase C (PLC) with U73122 abolished chlorpromazine-increased [Ca2+]i rises. Together, in GBM 8401 cells but not in GHA cells, chlorpromazine increased [Ca2+]i rises by Ca2+ influx via store-operated Ca2+ entry and PLC-dependent Ca2+ release from the endoplasmic reticulum. Moreover, the Ca2+ chelator BAPTA-AM inhibited cytotoxicity in chlorpromazine-treated GBM 8401 cells. Therefore, Ca2+ signaling was involved in chlorpromazine-induced cytotoxicity in GBM 8401 cells.
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Data availability Statement (Availability of Data and Materials)
The datasets used and/or analyzed during the current study are available from the corresponding author (E-mail address: lianggoole67@gmail.com) on reasonable request.
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This work was supported by grants from Department of Pharmacy and Master Program, College of Pharmacy and Health Care, Tajen University, Pingtung County 90741, Taiwan.
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Chu, CS., Lin, YS. & Liang, WZ. The Impact of the Antipsychotic Medication Chlorpromazine on Cytotoxicity through Ca2+ Signaling Pathway in Glial Cell Models. Neurotox Res 40, 791–802 (2022). https://doi.org/10.1007/s12640-022-00507-5
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DOI: https://doi.org/10.1007/s12640-022-00507-5