Decreased astrocytic thrombospondin-1 secretion after chronic ammonia treatment reduces the level of synaptic proteins: in vitro and in vivo studies.
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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DOI：
10.1111/jnc.12810
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发表时间：
2014-11
影响因子：
4.7
通讯作者：
Norenberg MD
中科院分区：
文献类型：
--
作者：
Jayakumar AR;Tong XY;Curtis KM;Ruiz-Cordero R;Shamaladevi N;Abuzamel M;Johnstone J;Gaidosh G;Rama Rao KV;Norenberg MD
慢性肝性脑病（CHE）是严重肝脏疾病患者的主要并发症。血液和脑氨水平升高与其发病机制有关，星形胶质细胞是参与这种疾病的主要神经细胞。由于缺陷的合成和释放的星形胶质细胞因子已被证明损害突触的完整性在其他神经系统疾病，我们研究是否血小板反应蛋白-1（TSP-1），星形胶质细胞因子参与维持突触的完整性，也改变了CHE。将培养的星形胶质细胞暴露于氨（NH 4Cl，0.5- 2.5mM）1-10天，并测量细胞提取物和培养基中的TSP-1含量。暴露于氨的星形胶质细胞表现出降低细胞内和细胞外TSP-1水平。暴露于氨处理的星形胶质细胞的条件培养基（CM）培养的神经元显示突触素，PSD 95和synaptotagmin水平下降。CM从TSP-1过表达的星形胶质细胞用氨处理，当加入到培养的神经元，逆转突触蛋白的下降。重组TSP-1同样逆转了突触蛋白的减少。已知在其他细胞类型中增加TSP-1合成的试剂甲氨蝶呤也逆转了氨诱导的TSP-1减少。同样，我们发现皮质星形胶质细胞中TSP-1水平显著下降，以及CHE大鼠模型体内突触素含量减少。这些发现表明，TSP-1可能是CHE的重要治疗靶点。
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, 0.5–2.5 mM) for 1–10 days, 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 (CM) from ammonia-treated astrocytes showed a decrease in synaptophysin, PSD95 and synaptotagmin levels. CM from TSP-1 overexpressing 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.
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影响因子：
3.7
作者：
Garcia O;Torres M;Helguera P;Coskun P;Busciglio J
通讯作者：
Busciglio J
影响因子：
3.6
作者：
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通讯作者：
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影响因子：
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作者：
Jayakumar, A. R.;Bethea, J. R.;Tong, X. Y.;Gomez, J.;Norenberg, M. D.
通讯作者：
Norenberg, M. D.
影响因子：
3.7
作者：
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通讯作者：
Romero-Gomez, Manuel
影响因子：
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作者：
Höcker, M;Rosenberg, I;Wang, TC
通讯作者：
Wang, TC