Trans-2-phenylcyclopropylamine induces nerve cells apoptosis in zebrafish mediated by depression of LSD1 activity.
Trans-2-phenylcyclopropylamine (referred to as PCPA hereafter, also known as tranylcypromine and Parnate) is used clinically as an antidepressant. Here, we use a new model-zebrafish (Danio rerio) to study the molecular mechanisms of its adverse reactions in vivo. Following a PCPA exposure (75 microM), embryos showed "sluggish" action (slow swim and slow escape action). Whole mount in situ hybridization showed that sox1a and huc expressions were downregulated in PCPA-treated embryos, which indicated a decrease in the number of nerve cells. TUNEL assay diplayed that the drop of nerve cells number due to excessive apoptosis. Moreover, lysine-specific demethylase 1 morpholino injection (LSD1 MO) also induced increased cellular apoptosis in embryos just as PCPA. RT-PCR at 24hpf evaluated that the absence of LSD1 resulted in increased expression of two p53 target genes (p21 and bax2). These findings demonstrate for the first time that PCPA-induced apoptosis through inhibition of LSD1 demethylase activity and p53-dependent signaling pathway might be required for the maintenance of nerve cell apoptosis.
Jie
Zhang
Z
Department of Biochemistry and Molecular Biology, Shanghai Medical School and Key Laboratory of Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China.
Li
Tan
T
Jia-Yun
Hou
H
Qiu
Jiang
J
Ping-Yao
Zen
Z
Houyan
Song
S
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014191:Tranylcypromine / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015027:Zebrafish / Q000033:anatomy & histology / Q000196:embryology / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D000928:Antidepressive Agents; D015415:Biomarkers; D016376:Oligonucleotides, Antisense; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; D014191:Tranylcypromine; D010089:Oxidoreductases, N-Demethylating