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首页> 外文期刊>Journal of Neurochemistry: Offical Journal of the International Society for Neurochemistry >Decreased astrocytic thrombospondin-1 secretion after chronic ammonia treatment reduces the level of synaptic proteins: in vitro and in vivo studies
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Decreased astrocytic thrombospondin-1 secretion after chronic ammonia treatment reduces the level of synaptic proteins: in vitro and in vivo studies

机译：慢性氨处理后星形胶质血小板反应蛋白-1分泌减少会降低突触蛋白的水平：体内和体外研究

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Chronic hepatic encephalopathy (CHE) is a major complication in patients with severe liver disease. Elevated blood and brain ammonia levels have been implicated in its pathogenesis, and astrocytes are the principal neural cells involved in this disorder. Since defective synthesis and release of astrocytic factors have been shown to impair synaptic integrity in other neurological conditions, we examined whether thrombospondin-1 (TSP-1), an astrocytic factor involved in the maintenance of synaptic integrity, is also altered in CHE. Cultured astrocytes were exposed to ammonia (NH4Cl, 0.5-2.5mM) for 1-10days, and TSP-1 content was measured in cell extracts and culture media. Astrocytes exposed to ammonia exhibited a reduction in intra- and extracellular TSP-1 levels. Exposure of cultured neurons to conditioned media from ammonia-treated astrocytes showed a decrease in synaptophysin, PSD95, and synaptotagmin levels. Conditioned media from TSP-1 over-expressing astrocytes that were treated with ammonia, when added to cultured neurons, reversed the decline in synaptic proteins. Recombinant TSP-1 similarly reversed the decrease in synaptic proteins. Metformin, an agent known to increase TSP-1 synthesis in other cell types, also reversed the ammonia-induced TSP-1 reduction. Likewise, we found a significant decline in TSP-1 level in cortical astrocytes, as well as a reduction in synaptophysin content in vivo in a rat model of CHE. These findings suggest that TSP-1 may represent an important therapeutic target for CHE.
机译：慢性肝性脑病（CHE）是严重肝病患者的主要并发症。血液和脑中氨水平的升高已被认为与其发病有关，星形胶质细胞是参与该疾病的主要神经细胞。由于已经证明合成缺陷和星形细胞因子的释放会损害其他神经系统疾病的突触完整性，因此我们检查了CHE中是否也改变了维持突触完整性的星形细胞因子thrombospondin-1（TSP-1）。将培养的星形胶质细胞暴露于氨水（NH4Cl，0.5-2.5mM）中1-10天，并在细胞提取物和培养基中测量TSP-1含量。暴露于氨水的星形胶质细胞内和细胞外TSP-1水平降低。从氨处理过的星形胶质细胞向条件培养基中培养的神经元暴露显示突触素，PSD95和突触标记素水平降低。来自过表达TSP-1的星形胶质细胞的条件培养基，用氨水处理后，添加到培养的神经元后，可以逆转突触蛋白的下降。重组TSP-1类似地逆转了突触蛋白的减少。二甲双胍是一种已知能增加其他细胞类型中TSP-1合成的药物，它也逆转了氨水诱导的TSP-1的还原。同样，我们发现在CHE大鼠模型中，皮质星形胶质细胞中TSP-1的水平显着下降，并且体内的突触素含量降低。这些发现表明TSP-1可能代表CHE的重要治疗靶标。

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