Ca 2+ signaling as a mechanism of haloperidol-induced cytotoxicity in human astrocytes and assessing the protective role
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ORIGINAL ARTICLE
Ca2+ signaling as a mechanism of haloperidol-induced cytotoxicity in human astrocytes and assessing the protective role of a Ca2+ chelator Shu-Shong Hsu 1,2,3 & Wei-Zhe Liang 4,5 Received: 4 May 2020 / Accepted: 18 June 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Haloperidol, a typical antipsychotic medication, has been shown to possess various biological effects in different brain models. However, the impact of haloperidol on Ca2+ signaling in astrocytes is elusive. This study explored the effect of haloperidol on cytosolic free Ca2+ levels ([Ca2+]i) and viability, and established these two connections in Gibco® Human Astrocytes (GHAs) and DI TNC1 rat astrocytes. Haloperidol (5–20 μM) caused [Ca2+]i rises in a concentration-dependent manner in GHAs but not in DI TNC1 cells. Furthermore, removal of extracellular Ca2+ reduced haloperidol’s effect by approximately 30% in GHAs. Haloperidol (20–40 μM) evoked concentration-dependent cytotoxicity in GHAs and DI TNC1 cells. However, chelating cytosolic Ca2+ with the Ca2+ chelator BAPTA/AM significantly reversed haloperidol’s cytotoxicity only in GHAs. In GHAs, haloperidol-induced Ca2+ entry was inhibited by store-operated Ca2+ modulators (2-APB and SKF96365) and the protein kinase C (PKC) inhibitor GF109203X. This Ca2+ entry induced by haloperidol was confirmed by Mn2+ entry-induced quench of fura-2 fluorescence. In Ca2+-free medium, treatment with the endoplasmic reticulum Ca2+ pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) abolished haloperidol-induced [Ca2+]i rises. Conversely, treatment with haloperidol inhibited 45% of BHQ-evoked [Ca2+]i rises. Moreover, haloperidol-induced Ca2+ release from the endoplasmic reticulum was abolished by inhibition of phospholipase C (PLC) by U73122. Together, in GHAs but not in DI TNC1 cells, haloperidol caused Ca2+-associated cell death, induced Ca2+ entry via PKC-sensitive store-operated Ca2+ channels, and evoked PLC-dependent Ca2+ release from the endoplasmic reticulum. The protective effect of Ca2+ chelating on haloperidol-induced cytotoxicity in human astrocytes was also demonstrated. Keywords Ca2+ signaling . Haloperidol . Astrocytes . Store-operated Ca2+ channels . Endoplasmic reticulum . Cytotoxicity
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00210-020-01929-8) contains supplementary material, which is available to authorized users. * Wei-Zhe Liang [email protected] 1
Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
2
Department of Surgery, National Defense Medical Center, Taipei 11490, Taiwan
3
College of Health and Nursing, Meiho University, Pingtung 91202, Taiwan
4
Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
5
Department of Pharmacy and Master Program, College of Pharmacy and Health Care, Tajen University, Pingtung County 90741, Taiwan
Haloperidol, a typical antipsychotic medication, was discovere
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