The Impact of the Antipsychotic Medication Chlorpromazine on Cytotoxicity through Ca2+ Signaling Pathway in Glial Cell Models

• Published in: Neurotoxicity research Vol. 40; no. 3; pp. 791 - 802
• Main Authors: Chu, Che-Sheng, Lin, Yung-Shang, Liang, Wei-Zhe
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-06-2022
• Subjects: Biomedical and Life Sciences; Biomedicine; Cell Biology; Neurobiology; Neurochemistry; Neurology; Neurosciences; Original Article; Pharmacology/Toxicology; entry; Glial cell models; signaling; Store-operated Ca; Cytotoxicity; Chlorpromazine; Endoplasmic reticulum; Ca
• ISSN: 1029-8428; 1476-3524
• DOI: 10.1007/s12640-022-00507-5

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