title: Chlorpromazine inhibits mitochondrial apoptotic pathway via increasing expression of tissue factor.
abstract: Chlorpromazine (CPZ) is a widely used antipsychotic drug with antagonistic effect on dopamine receptors. Accumulating evidence has shown that CPZ plays a neuroprotective role in various models of toxicity and apoptosis. However, the underlying mechanism contributing to this protective effect remains unclear. Here, we evaluate the effect of CPZ on mitochondrial apoptotic pathway in the neuron system. Higher levels of B-cell lymphoma-2 (Bcl-2) and tissue factor (TF) but lower apoptotic rate were found in hippocampus of CPZ-treated schizophrenic patients compared with non-antipsychotic treated controls. Additionally, both short-term and long-term treatment of CPZ in rats could up-regulate the levels of Bcl-2 and TF with no cytotoxic effects. In the in vitro experiment, expression of Bcl-2 was up-regulated in the C6 glioma cells transfected with pEGFP-N1-TF recombinant plasmid. Furthermore, in another independent rat model of apoptosis, compared with the group administrated with alcohol only, the brains of the CPZ-pretreated rats showed lower expression of cleaved caspase-3, cytochrome c and Bax, but higher expression of Bcl-2 and TF. Our data demonstrate that CPZ exerts its neuronal protective effects through inhibiting the activation of mitochondrial apoptotic pathway by up-regulating TF expression, thus providing new insight into CPZ function and application.
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogen Biology, Harbin 150086, Heilongjiang, PR China. Electronic address: wujing.jing@ems.hrbmu.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogen Biology, Harbin 150086, Heilongjiang, PR China. Electronic address: liaimeiandamy@126.com.
authors.forename: Aimei
authors.initials: A
authors.lastname: Li
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogen Biology, Harbin 150086, Heilongjiang, PR China. Electronic address: Li_Yujun@126.com.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogen Biology, Harbin 150086, Heilongjiang, PR China. Electronic address: liqian0041@139.com.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Li
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogen Biology, Harbin 150086, Heilongjiang, PR China. Electronic address: qmzhang@126.com.
authors.forename: Qingmeng
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogen Biology, Harbin 150086, Heilongjiang, PR China. Electronic address: songwuqi@aliyun.com.
authors.forename: Wuqi
authors.initials: W
authors.lastname: Song
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogen Biology, Harbin 150086, Heilongjiang, PR China. Electronic address: 77684507@qq.com.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogen Biology, Harbin 150086, Heilongjiang, PR China; Department of Pathology, School of Medicine, Kenyatta University, P.O. Box 43844, 00100 Nairobi, Kenya. Electronic address: ogutujim@yahoo.co.uk.
authors.forename: James O
authors.initials: JO
authors.lastname: Ogutu
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogen Biology, Harbin 150086, Heilongjiang, PR China. Electronic address: wangjd1110@163.com.
authors.forename: Jindong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Forensic Medicine, Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, PR China. Electronic address: lijianbo136@163.com.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Forensic Medicine, Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, PR China. Electronic address: tangcqum@163.com.
authors.forename: Renkuan
authors.initials: R
authors.lastname: Tang
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogen Biology, Harbin 150086, Heilongjiang, PR China. Electronic address: fengminzhang@ems.hrbmu.edu.cn.
authors.forename: Fengmin
authors.initials: F
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001344:Autopsy; D016022:Case-Control Studies; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002746:Chlorpromazine / Q000494:pharmacology*; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013925:Thromboplastin / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; C494826:BAX protein, human; C000595707:BCL2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D013925:Thromboplastin; C505407:CASP3 protein, human; D053148:Caspase 3; D002746:Chlorpromazine
keywords: Bcl-2; Chlorpromazine; Mitochondrial apoptotic pathway; Neuronal apoptosis; Tissue factor