Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and α-synuclein aggregation
Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and α-synuclein aggregation
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DOI：
10.1006/exnr.2002.8072
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发表时间：
2003-01-01
影响因子：
5.3
通讯作者：
Greenamyre, JT
中科院分区：
文献类型：
--
作者：
Sherer, TB;Kim, JH;Greenamyre, JT
先前的研究表明，通过颈静脉导管长期暴露于农药和线粒体毒素鱼藤酮，可以重现大鼠帕金森病（PD）的许多特征，包括黑质纹状体多巴胺能变性和黑质神经元α -突触核蛋白阳性细胞质包涵体的形成（R. Betarbet et aL, 2000, journal of Neurosci. 3, 1301-1306）。尽管鱼藤酮模型新颖且在概念上很重要，但它的劳动强度非常大。目前的论文表明，PD的这些相同的特征可以通过皮下渗透泵植入后长期、全身暴露于鱼藤酮而重现。长期皮下暴露于低剂量鱼藤酮（2.0-3.0 mg/kg/天）引起高选择性黑质纹状体多巴胺能损伤。含有DARPP-32（多巴胺和camp调节的磷酸化蛋白）的纹状体神经元保持完整，形态正常，NeuN染色显示神经元核形态正常。苍白球和丘底核的神经元未受影响。皮下鱼藤酮暴露引起神经神经元α -突触核蛋白阳性的细胞质聚集。这种慢性鱼藤酮管理的新方案是在简单性和吞吐量方面的实质性改进。(C) 2002 Elsevier Science （USA）。
Previous studies demonstrated that chronic systemic exposure to the pesticide and mitochondrial toxin rotenone through jugular vein cannulation reproduced many features of Parkinson's disease (PD) in rats, including nigrostriatal dopaminergic degeneration and formation of alpha-synuclein-positive cytoplasmic inclusions in nigral neurons (R. Betarbet et aL, 2000, Nat Neurosci. 3, 1301-1306). Although novel and conceptually important, the rotenone model of PD suffered from being extremely labor-intensive. The current paper demonstrates that these same features of PD can be reproduced by chronic, systemic exposure to rotenone following implantation of subcutaneous osmotic pumps. Chronic subcutaneous exposure to low doses of rotenone (2.0-3.0 mg/kg/day) caused highly selective nigrostriatal dopaminergic lesions. Striatal neurons containing DARPP-32 (dopamine and cAMP-regulated phosphoprotein) remained intact with normal morphology, and NeuN staining revealed normal neuronal nuclear morphology. Neurons of the globus pallidus and subthalamic nucleus were spared. Subcutaneous rotenone exposure caused alpha-synuclein-positive cytoplasmic aggregates in nigral neurons. This new protocol for chronic rotenone administration is a substantial improvement in terms of simplicity and throughput. (C) 2002 Elsevier Science (USA).