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.