Neuroprotective effects of levetiracetam target xCT in astrocytes in parkinsonian mice
Neuroprotective effects of levetiracetam target xCT in astrocytes in parkinsonian mice
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DOI：
10.1111/jnc.13405
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发表时间：
2016-01-01
影响因子：
4.7
通讯作者：
Asanuma, Masato
中科院分区：
文献类型：
--
作者：
Miyazaki, Ikuko;Murakami, Shinki;Asanuma, Masato
星形胶质细胞而非神经元表达胱氨酸/谷氨酸交换转运蛋白（xCT），其摄取胱氨酸，从而为神经元中GSH的合成提供底物。认识到神经元中的GSH合成依赖于星形胶质细胞中xCT的表达。先前的研究报道，抗癫痫药物左乙拉西坦（LEV）增加体内xCT表达。本研究的目的是检查LEV在帕金森病模型中的神经保护作用，并证明星形胶质细胞中的xCT作为针对多巴胺能神经变性的神经保护的靶点。我们鉴定了用LEV培养的纹状体星形胶质细胞显示xCT表达和GSH水平显著增加。预孵育的原代培养中脑多巴胺神经元与条件培养基从左列叶治疗星形胶质细胞保护6-羟基多巴胺（6-OHDA）诱导的神经毒性。这些保护作用被xCT抑制剂所抵消。此外，减少黑质纹状体多巴胺能神经元在6-OHDA损伤的帕金森病小鼠显着废除重复注射LEV。用LEV治疗显著增加了半帕金森病小鼠纹状体星形胶质细胞中xCT的表达。总之，LEV通过上调星形胶质细胞中的xCT和GSH发挥神经保护作用以对抗神经变性。因此，星形胶质细胞中的xCT可能是防止多巴胺能神经元变性的新型神经保护方法的潜在靶点。
Astrocytes but not neurons express cystine/glutamate exchange transporter (xCT), which takes up cystine, and consequently supplies the substrate for GSH synthesis in neurons. It is recognized that GSH synthesis in neurons is dependent on the expression of xCT in astrocytes. Previous studies reported that levetiracetam (LEV), an anti-epileptic drug, increased xCT expression invivo. The purpose of this study was to examine neuroprotective effects of LEV in parkinsonian models and demonstrate xCT in astrocytes as a target of neuroprotection against dopaminergic neurodegeneration. We identified striatal astrocytes cultured with LEV showed significant increase in xCT expression and GSH levels. Preincubation of primary cultured mesencephalic dopamine neurons with conditioned media from LEV-treated astrocytes protected against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. These protective effects were canceled by xCT inhibitor. Furthermore, reduction of nigrostriatal dopaminergic neurons in 6-OHDA-lesioned parkinsonian mice was significantly abrogated by repeated injections of LEV. Treatment with LEV significantly increased the expression of xCT in striatal astrocytes in the hemi-parkinsonian mice. In conclusion, LEV exerts neuroprotective effects against neurodegeneration via up-regulation of xCT and GSH in astrocytes. Thus, xCT in astrocytes could be a potential target in novel neuroprotective approaches to prevent degeneration of dopaminergic neurons.