Objective: This study aimed to investigate whether long noncoding RNA sprouty receptor tyrosine kinase signaling antagonist 4-intronic transcript 1 (SPRY4-IT1) is involved in the regulation of ketamine-induced neurotoxicity. Methods: Human embryonic stem cells (hESCs) were induced into neurons in vitro and treated with ketamine. Apoptosis and neurite degeneration assays were used to determine ketamine-induced neurotoxicity and qRT-PCR to determine SPRY4-IT1 expression. SPRY4-IT1 was downregulated in hESC-induced neurons to examine its regulation on ketamine-induced neurotoxicity. The correlation between enhancer of zeste homolog 2 (EZH2) and SPRY4-IT1 was also examined. EZH2 was upregulated in SPRY4-IT1-downregualted hESC-induced neurons to further examine its participation in SPRY4-IT1-mediated ketamine neurotoxicity. Results: Ketamine-induced dose-dependent apoptosis, neurite degeneration, and SPRY4-IT1 upregulation in hESC-induced neurons. Lentivirus-mediated SPRY4-IT1 downregulation protected ketamine neurotoxicity. EZH2 expression was positively correlated with SPRY4-IT1 in hESC-induced neurons. EZH2 overexpression markedly reversed the protective effects of SPRY4-IT1 knockdown on ketamine neurotoxicity. Conclusions: SPRY4-IT1 is involved in anesthesia-induced neurotoxicity, possibly through the regulation on EZH2 gene.
Dev Neurosci

中文翻译：

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长链非编码 RNA SPRY4-IT1 通过 EZH2 调节氯胺酮诱导的人类胚胎干细胞衍生神经元的神经毒性

目的：本研究旨在探讨长链非编码 RNA 芽孢受体酪氨酸激酶信号传导拮抗剂 4-内含子转录物 1 (SPRY4-IT1) 是否参与调节氯胺酮诱导的神经毒性。方法：人类胚胎干细胞 (hESCs) 在体外被诱导成神经元并用氯胺酮处理。细胞凋亡和神经突变性测定用于确定氯胺酮诱导的神经毒性和 qRT-PCR 以确定 SPRY4-IT1 表达。SPRY4-IT1 在 hESC 诱导的神经元中被下调，以检查其对氯胺酮诱导的神经毒性的调节。还检查了 zeste 同源物 2 (EZH2) 增强子与 SPRY4-IT1 之间的相关性。EZH2 在 SPRY4-IT1 下调的 hESC 诱导的神经元中上调，以进一步检查其参与 SPRY4-IT1 介导的氯胺酮神经毒性。结果：在 hESC 诱导的神经元中，氯胺酮诱导的剂量依赖性细胞凋亡、神经突变性和 SPRY4-IT1 上调。慢病毒介导的 SPRY4-IT1 下调保护了氯胺酮的神经毒性。在 hESC 诱导的神经元中，EZH2 表达与 SPRY4-IT1 呈正相关。EZH2 过表达显着逆转了 SPRY4-IT1 敲低对氯胺酮神经毒性的保护作用。结论： SPRY4-IT1参与麻醉诱导的神经毒性，可能通过对EZH2基因的调控。
开发神经科学