Astrocyte-Derived Metallothionein Protects Dopaminergic Neurons from Dopamine Quinone Toxicity
Astrocyte-Derived Metallothionein Protects Dopaminergic Neurons from Dopamine Quinone Toxicity
复制标题
DOI：
10.1002/glia.21112
复制
发表时间：
2011-03-01
期刊：
影响因子：
6.2
通讯作者：
Kita, Taizo
中科院分区：
文献类型：
--
作者：
Miyazaki, Ikuko;Asanuma, Masato;Kita, Taizo
我们以前的研究表明，醌形成参与多巴胺能神经元功能障碍的左旋多巴治疗的帕金森病模型和甲基苯丙胺（METH）的神经毒性。我们进一步报道了富含半胱氨酸的金属结合金属硫蛋白（MT）家族蛋白质通过其醌淬灭特性保护多巴胺能神经元免受多巴胺（DA）醌神经毒性。本研究的目的是研究MT诱导星形胶质细胞在响应过量的DA和潜在的神经保护作用的星形胶质细胞衍生的MT对DA醌毒性。DA暴露显著上调MT-1/-2在培养的纹状体星形胶质细胞，但不是在中脑神经元。DA-转运蛋白（DAT）抑制剂治疗可阻断DA-诱导的MT在星形胶质细胞中的上调，但DA-受体拮抗剂不能阻断。DA处理后星形胶质细胞核因子红细胞2相关因子（Nrf 2）表达及其与MT-1基因抗氧化反应元件的结合活性显著增加。DAT抑制剂可抑制Nrf 2的核转位。DA暴露后中脑DA神经元的醌形成和减少改善预孵育条件培养基DA处理的星形胶质细胞。这些保护作用被MT-1/-2特异性抗体所消除。加入外源性MT-1的胶质细胞条件培养基也表现出类似的神经保护作用。此外，MT-1/-2的表达显着升高，特别是在反应性星形胶质细胞在纹状体的左旋多巴治疗的偏侧帕金森病小鼠或甲基苯丙胺注射小鼠。这些结果表明，星形胶质细胞通过DAT摄取过量的DA，特异性地上调星形胶质细胞中MT-1/-2的表达，并且星形胶质细胞特异性地分泌的MT或相关分子通过醌淬灭和/或清除自由基来保护多巴胺能神经元免受损伤。（C）2010 Wiley-Liss，Inc.
Our previous studies demonstrated the involvement of quinone formation in dopaminergic neuron dysfunction in the L-DOPA-treated parkinsonian model and in methamphetamine (METH) neurotoxicity. We further reported that the cysteine-rich metal-binding metallothionein (MT) family of proteins protects dopaminergic neurons against dopamine (DA) quinone neurotoxicity by its quinone-quenching property. The aim of this study was to examine MT induction in astrocytes in response to excess DA and the potential neuroprotective effects of astrocyte-derived MTs against DA quinone toxicity. DA exposure significantly upregulated MT-1/-2 in cultured striatal astrocytes, but not in mesencephalic neurons. This DA-induced MT upregulation in astrocytes was blocked by treatment with a DA-transporter (DAT) inhibitor, but not by DA-receptor antagonists. Expression of nuclear factor erythroid 2-related factor (Nrf2) and its binding activity to antioxidant response element of MT-1 gene were significantly increased in the astrocytes after DA exposure. Nuclear translocation of Nrf2 was suppressed by the DAT inhibitor. Quinone formation and reduction of mesencephalic DA neurons after DA exposure were ameliorated by preincubation with conditioned media from DA-treated astrocytes. These protective effects were abrogated by MT-1/-2-specific antibody. Adding exogenous MT-1 to glial conditioned media also showed similar neuroprotective effects. Furthermore, MT-1/-2 expression was markedly elevated specifically in reactive astrocytes in the striatum of L-DOPA-treated hemi-parkinsonian mice or METH-injected mice. These results suggested that excess DA taken up by astrocytes via DAT upregulates MT-1/-2 expression specifically in astrocytes, and that MTs or related molecules secreted specifically by astrocytes protect dopaminergic neurons from damage through quinone quenching and/or scavenging of free radicals. (C)2010 Wiley-Liss, Inc.