PMID- 32311669 OWN - NLM STAT- MEDLINE DCOM- 20210225 LR - 20210225 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 84 DP - 2020 Jul TI - The antipsychotic drug pimozide inhibits IgE-mediated mast cell degranulation and migration. PG - 106500 LID - S1567-5769(20)30231-9 [pii] LID - 10.1016/j.intimp.2020.106500 [doi] AB - BACKGROUND: Mast cells (MCs) mediate a key role in allergic diseases. Detailed studies of how the neuroleptic drug pimozide affects MC activity are lacking. The aim of this study was to investigate pimozide inhibition of immunoglobulin E (IgE)-mediated MC activation and MC-mediated allergic responses. METHOD: MCs were stimulated with anti-dinitrophenyl (DNP) IgE antibodies and DNP-horse serum albumin (HSA) antigen (Ag), and anti-allergic pimozide effects were detected by measuring beta-hexosaminidase levels. Morphological changes were observed histologically. In vivo pimozide effects were assessed in passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-sensitized active systemic anaphylaxis mouse (ASA) model experiments. Levels of phosphorylated (p-) SYK (spleen tyrosine kinase) and MAPKs (mitogen-activated protein kinases) were detected in western blots. RESULTS: We found that pimozide inhibited MC degranulation, reduced MC release of beta-hexosaminidase dose-dependently in activated RBL-2H3 (IC(50): 13.52 muM) and bone marrow derived MC (BMMC) (IC(50): 42.42 muM), and reduced MC morphological changes. The IgE/Ag-induced migration effect was suppressed by pimozide treatment dose-dependently. Pimozide down-regulated IgE/Ag-induced phosphorylation of SYK and MAPKs in activated MCs. Moreover, pimozide attenuated allergic reactions in PCA and ASA model mice, and decreased MC populations among splenic cells. CONCLUSIONS: The antipsychotic drug pimozide can suppress IgE-mediated MC activation in vitro and in vivo and should be considered for repurposing to suppress MC-mediated diseases. CI - Copyright (c) 2020 Elsevier B.V. All rights reserved. FAU - Hou, Yi-Bo AU - Hou YB AD - Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China. FAU - Zhang, Li-Na AU - Zhang LN AD - Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China. FAU - Wang, Hui-Na AU - Wang HN AD - Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China. FAU - Zhao, Zhen-Fu AU - Zhao ZF AD - Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China. Electronic address: zhb@szu.edu.cn. FAU - Sun, Yue-Tong AU - Sun YT AD - Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China. FAU - Ji, Kunmei AU - Ji K AD - Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China. Electronic address: jkm@szu.edu.cn. FAU - Chen, Jia-Jie AU - Chen JJ AD - Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China. Electronic address: chenjj@szu.edu.cn. LA - eng PT - Journal Article DEP - 20200417 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Anti-Allergic Agents) RN - 1HIZ4DL86F (Pimozide) RN - 37341-29-0 (Immunoglobulin E) RN - EC 2.7.10.2 (Syk Kinase) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) SB - IM MH - Anaphylaxis/drug therapy/immunology MH - Animals MH - Anti-Allergic Agents/*pharmacology/therapeutic use MH - Cell Degranulation/drug effects MH - Cell Line MH - Cell Movement/drug effects MH - Disease Models, Animal MH - Female MH - Immunoglobulin E/*drug effects/*metabolism MH - Mast Cells/cytology/*drug effects/*metabolism MH - Mice MH - Mice, Inbred BALB C MH - Mitogen-Activated Protein Kinases/metabolism MH - Passive Cutaneous Anaphylaxis/drug effects/immunology MH - Pimozide/*pharmacology/therapeutic use MH - Rats MH - Syk Kinase/metabolism OTO - NOTNLM OT - Cell degranulation OT - Drug repurposing OT - Mast cells OT - Pimozide EDAT- 2020/04/21 06:00 MHDA- 2021/02/26 06:00 CRDT- 2020/04/21 06:00 PHST- 2020/01/23 00:00 [received] PHST- 2020/03/27 00:00 [revised] PHST- 2020/04/09 00:00 [accepted] PHST- 2020/04/21 06:00 [pubmed] PHST- 2021/02/26 06:00 [medline] PHST- 2020/04/21 06:00 [entrez] AID - S1567-5769(20)30231-9 [pii] AID - 10.1016/j.intimp.2020.106500 [doi] PST - ppublish SO - Int Immunopharmacol. 2020 Jul;84:106500. doi: 10.1016/j.intimp.2020.106500. Epub 2020 Apr 17.