The Impact of the Antipsychotic Medication Chlorpromazine on Cytotoxicity through Ca 2+ Signaling Pathway in Glial Cell Models

• Published in: Neurotoxicity research 2022-06, Vol.40 (3), p.791
• Main Authors: Chu, Che-Sheng, Lin, Yung-Shang, Liang, Wei-Zhe
• Format: Article
• Language: English
• ISSN: 1476-3524

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 (Ca ) signaling, but the underlying pathways are elusive. This study explored the effect of chlorpromazine on viability, Ca 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 Ca homeostasis, chlorpromazine (10-30 μM) increased intracellular Ca  concentrations ([Ca ] ) rises in GBM 8401 cells but not in GHA cells. Ca removal reduced the signal by approximately 55%. Furthermore, chelation of cytosolic Ca with BAPTA-AM reduced chlorpromazine (10-40 μM)-induced cytotoxicity in GBM 8401 cells. Third, in Ca -containing medium of GBM 8401 cells, chlorpromazine-induced Ca entry was inhibited by the modulators of store-operated Ca channel (2-APB and SKF96365). Lastly, in Ca -free medium of GBM 8401 cells, treatment with the endoplasmic reticulum Ca pump inhibitor thapsigargin completely inhibited chlorpromazine-increased [Ca ] rises. Conversely, treatment with chlorpromazine abolished thapsigargin-increased [Ca ] rises. Inhibition of phospholipase C (PLC) with U73122 abolished chlorpromazine-increased [Ca ] rises. Together, in GBM 8401 cells but not in GHA cells, chlorpromazine increased [Ca ] rises by Ca influx via store-operated Ca entry and PLC-dependent Ca release from the endoplasmic reticulum. Moreover, the Ca chelator BAPTA-AM inhibited cytotoxicity in chlorpromazine-treated GBM 8401 cells. Therefore, Ca signaling was involved in chlorpromazine-induced cytotoxicity in GBM 8401 cells.