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.
Department of Biochemistry and Molecular Biology, Shanghai Medical School and Key Laboratory of Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China.
Zhang
Z
Jie
Tan
T
Li
Hou
H
Jia-Yun
Jiang
J
Qiu
Zen
Z
Ping-Yao
Song
S
Houyan
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