Astrocyte-Derived Lipocalin-2 Is Involved in Mitochondrion-Related Neuronal Apoptosis Induced by Methamphetamine
Astrocyte-Derived Lipocalin-2 Is Involved in Mitochondrion-Related Neuronal Apoptosis Induced by Methamphetamine
复制标题
星形胶质细胞来源的脂质运载蛋白-2参与甲基苯丙胺诱导的线粒体相关神经元凋亡
DOI：
10.1021/acschemneuro.9b00559
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发表时间：
2020-04-15
影响因子：
5
通讯作者：
Wang, Huijun
中科院分区：
文献类型：
--
作者：
Chen, Xuebing;Qiu, Feng;Wang, Huijun
甲基苯丙胺 (METH) 是一种广泛滥用且高度成瘾的精神兴奋剂，可诱导神经元凋亡。 Lipocalin-2 (LCN2) 是脂质运载蛋白家族的成员，其上调与成人大脑中的细胞死亡有关。然而，LCN2 在 METH 诱导的神经毒性中的作用尚未见报道。在本研究中，我们发现 LCN2 在 METH 暴露后主要在海马星形胶质细胞中表达，并且重组 LCN2（Re LCN2）可以在体外和体内诱导神经元凋亡。在原代大鼠神经元和动物模型培养物中，抑制 LCN2 和 LCN2R（LCN2 的细胞表面受体）可减少 METH- 和 Re LCN2 诱导的线粒体相关神经元凋亡。我们的研究支持活性氧 (ROS) 生成和 PRKR 样 ER 激酶 (PERK) 介导的信号通路在 METH 暴露后星形胶质细胞衍生的 LCN2 上调中的作用。此外，接触 METH 后，血清和脑脊液 (CSF) 中 LCN2 的水平显着上调。这些结果表明，星形胶质细胞衍生的 LCN2 与 LCN2R 结合的上调参与了 METH 诱导的线粒体相关神经元凋亡。
Methamphetamine (METH) is a widely abused and highly addictive psychoactive stimulant that can induce neuronal apoptosis. Lipocalin-2 (LCN2) is a member of the lipocalin family, and its upregulation is involved in cell death in the adult brain. However, the role of LCN2 in METH-induced neurotoxicity has not been reported. In this study, we found that LCN2 was predominantly expressed in hippocampal astrocytes after METH exposure and that recombinant LCN2 (Re LCN2) can induce neuronal apoptosis in vitro and in vivo. The inhibition of LCN2 and LCN2R, a cell surface receptor for LCN2, reduced METH- and Re LCN2-induced mitochondrion-related neuronal apoptosis in cultures of primary rat neurons and animal models. Our study supports the role of reactive oxygen species (ROS) generation and the PRKR-like ER kinase (PERK)-mediated signaling pathway in the upregulation of astrocyte-derived LCN2 after METH exposure. Additionally, the serum and cerebrospinal fluid (CSF) levels of LCN2 were significantly upregulated after METH exposure. These results indicate that upregulation of astrocyte-derived LCN2 binding to LCN2R is involved in METH-induced mitochondrion-related neuronal apoptosis.