Excitatory amino acid carrier 1 (EAAC1) is an important subtype of excitatory amino acid transporters (EAATs) and is the route for neuronal cysteine uptake. CoCl2 is not only a hypoxia-mimetic reagent but also an oxidative stress inducer. Here, we found that CoCl2 induced significant EAAC1 overexpression in SH-SY5Y cells and the hippocampus of mice. Transient transfection of EAAC1 reduced CoCl2-induced cytotoxicity in SH-SY5Y cells. Based on this result, upregulation of EAAC1 expression by CoCl2 is thought to represent a compensatory response against oxidative stress in an acute hypoxic state. We further demonstrated that pretreatment with Neuregulin-1 (NRG1) rescued CoCl2-induced upregulation of EAAC1 and tau expression. NRG1 plays a protective role in the CoCl2-induced accumulation of reactive oxygen species (ROS) and reduction in antioxidative enzyme (SOD and GPx) activity. Moreover, NRG1 attenuated CoCl2-induced apoptosis and cell death. NRG1 inhibited the CoCl2-induced release of cleaved caspase-3 and reduction in Bcl-XL levels. Our novel finding suggests that NRG1 may play a protective role in hypoxia through the inhibition of oxidative stress and thereby maintain normal EAAC1 expression levels.

中文翻译：

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Neuregulin-1抑制CoCl2诱导的SH-SY5Y细胞和小鼠海马兴奋性氨基酸载体1表达和氧化应激的上调

兴奋性氨基酸载体 1 (EAAC1) 是兴奋性氨基酸转运蛋白 (EAAT) 的一个重要亚型，是神经元半胱氨酸摄取的途径。CoCl2 不仅是一种缺氧模拟试剂，而且还是一种氧化应激诱导剂。在这里，我们发现 CoCl2 在 SH-SY5Y 细胞和小鼠海马中诱导了显着的 EAAC1 过表达。EAAC1 的瞬时转染降低了 SH-SY5Y 细胞中 CoCl2 诱导的细胞毒性。基于这一结果，CoCl2 对 EAAC1 表达的上调被认为代表了在急性缺氧状态下对氧化应激的补偿反应。我们进一步证明，用 Neuregulin-1 (NRG1) 预处理可以挽救 CoCl2 诱导的 EAAC1 和 tau 表达的上调。NRG1 在 CoCl2 诱导的活性氧 (ROS) 积累和抗氧化酶 (SOD 和 GPx) 活性降低中起保护作用。此外，NRG1 减弱了 CoCl2 诱导的细胞凋亡和细胞死亡。NRG1 抑制 CoCl2 诱导的裂解 caspase-3 的释放和 Bcl-XL 水平的降低。我们的新发现表明 NRG1 可能通过抑制氧化应激在缺氧中发挥保护作用，从而维持正常的 EAAC1 表达水平。