Sherer Todd B, Kim Jin Ho, Betarbet Ranjita, Greenamyre J Timothy
Center for Neurodegenerative Disease, Department of Neurology, Emory University, Atlanta, GA 30032, USA.
Exp Neurol. 2003 Jan;179(1):9-16. doi: 10.1006/exnr.2002.8072.
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.
先前的研究表明，通过颈静脉插管使大鼠长期全身性暴露于农药及线粒体毒素鱼藤酮，可重现帕金森病（PD）的许多特征，包括黑质纹状体多巴胺能神经元变性以及黑质神经元中α-突触核蛋白阳性胞质内含物的形成（R. Betarbet等人，2000年，《自然神经科学》3，1301 - 1306）。尽管鱼藤酮诱导的PD模型新颖且具有重要的概念意义，但该模型极为耗费人力。本文证明，通过皮下植入渗透泵使大鼠长期全身性暴露于鱼藤酮，同样可重现PD的这些特征。长期皮下暴露于低剂量鱼藤酮（2.0 - 3.0毫克/千克/天）会导致高度选择性的黑质纹状体多巴胺能损伤。含有多巴胺和cAMP调节磷蛋白（DARPP - 32）的纹状体神经元形态正常且保持完整，NeuN染色显示神经元细胞核形态正常。苍白球和丘脑底核的神经元未受影响。皮下给予鱼藤酮会导致黑质神经元中出现α-突触核蛋白阳性胞质聚集体。这种新的长期给予鱼藤酮的方案在简便性和通量方面有了显著改进。
