Department of Anatomy and Neuroscience, College of Medicine, Eulji University, 143-5Jung-Gu, Yongdu-Dong, Daejeon, 301-746, Republic of Korea.
Department of Emergency Medical Technology, Daejeon University, Daejeon, 34520, Republic of Korea.
Mol Brain. 2020 Nov 13;13(1):153. doi: 10.1186/s13041-020-00686-2.
Excitatory amino acid carrier 1 (EAAC1) is an important subtype of excitatory amino acid transporters (EAATs) and is the route for neuronal cysteine uptake. CoCl is not only a hypoxia-mimetic reagent but also an oxidative stress inducer. Here, we found that CoCl induced significant EAAC1 overexpression in SH-SY5Y cells and the hippocampus of mice. Transient transfection of EAAC1 reduced CoCl-induced cytotoxicity in SH-SY5Y cells. Based on this result, upregulation of EAAC1 expression by CoCl 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 CoCl-induced upregulation of EAAC1 and tau expression. NRG1 plays a protective role in the CoCl-induced accumulation of reactive oxygen species (ROS) and reduction in antioxidative enzyme (SOD and GPx) activity. Moreover, NRG1 attenuated CoCl-induced apoptosis and cell death. NRG1 inhibited the CoCl-induced release of cleaved caspase-3 and reduction in Bcl-X 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.
兴奋性氨基酸载体 1（EAAC1）是兴奋性氨基酸转运体（EAATs）的重要亚型，是神经元半胱氨酸摄取的途径。CoCl 不仅是一种低氧模拟试剂，也是一种氧化应激诱导剂。在这里，我们发现 CoCl 诱导 SH-SY5Y 细胞和小鼠海马中 EAAC1 的显著过表达。EAAC1 的瞬时转染降低了 CoCl 诱导的 SH-SY5Y 细胞毒性。基于这一结果，认为 CoCl 诱导的 EAAC1 表达上调代表了急性低氧状态下对氧化应激的代偿反应。我们进一步证明，神经调节蛋白 1（NRG1）预处理可挽救 CoCl 诱导的 EAAC1 和 tau 表达上调。NRG1 在 CoCl 诱导的活性氧（ROS）积累和抗氧化酶（SOD 和 GPx）活性降低中发挥保护作用。此外，NRG1 减轻了 CoCl 诱导的细胞凋亡和细胞死亡。NRG1 抑制了 CoCl 诱导的半胱天冬酶-3 切割的释放和 Bcl-X 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。
