Parkinsonian Rotenone Mouse Model: Reevaluation of Long-Term Administration of Rotenone in C57BL/6 Mice
Parkinsonian Rotenone Mouse Model: Reevaluation of Long-Term Administration of Rotenone in C57BL/6 Mice
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DOI：
10.1248/bpb.34.92
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发表时间：
2011-01-01
影响因子：
2
通讯作者：
Taniguchi, Takashi
中科院分区：
文献类型：
--
作者：
Inden, Masatoshi;Kitamura, Yoshihisa;Taniguchi, Takashi
刘易斯大鼠长期全身暴露于鱼藤酮可引起帕金森病（PD）的许多特征，包括黑质纹状体多巴胺（DA）神经元变性和黑质DA神经元胞质内含物的形成。我们还报道了C57 BL/6小鼠长期口服30 mg/kg鱼藤酮28 d可引起黑质纹状体DA神经元变性。为了建立一种更适合于评价黑质纹状体DA神经变性的PD模型，本研究设计了C57 BL/6小鼠连续56 d口服30或100 mg/kg鱼藤酮后的神经毒性。30 mg/kg鱼藤酮处理的小鼠的存活率从28天到56天没有变化，尽管30 mg/kg鱼藤酮处理的小鼠的存活率在一周内下降到约70%。100 mg/kg鱼藤酮处理组小鼠的存活率在28 d后突然下降，56 d时降至15%左右。鱼藤酮在30毫克/公斤，但不是100毫克/公斤，28天造成了显着的损失酪氨酸羟化酶（TH）阳性神经元在黑质。在100毫克/公斤的鱼藤酮引起高度可变的损失TH阳性神经元个体小鼠之间。鱼藤酮30 mg/kg染毒56 d后，TH阳性神经元数量明显减少，行为功能明显受损。此外，α-突触核蛋白的免疫反应性增加，在存活TH阳性神经元的时间依赖性的方式。因此，鱼藤酮30 mg/kg持续56 d的长期给药方案更有助于了解DA神经变性的机制。
Chronic systemic exposure of Lewis rats to rotenone produced many features of Parkinson's disease (PD), including nigrostriatal dopamine (DA) neurodegeneration and the formation of cytoplasmic inclusions in nigral DA neurons. We also reported that chronic oral administration of rotenone at 30 mg/kg for 28 d caused specific nigrostriatal DA neurodegeneration in C57BL/6 mice. To establish a PD model more suitable for evaluating nigrostriatal DA neurodegeneration, the present study has been designed to assess the neurotoxicity of rotenone after daily oral administration at 30 or 100 mg/kg for 56d in C57BL/6 mice. The survival rate of rotenone-treated mice at 30 mg/kg did not change from 28 to 56 d, although the survival rate of rotenone-treated mice at 30 mg/kg was decreased to about 70% within one week. The survival rate of the rotenone-treated mice at 100 mg/kg was suddenly decreased after 28 d, and finally to about 15% at 56d. Rotenone at 30 mg/kg, but not 100 mg/kg, for 28 d caused a significant loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra. Rotenone at 100 mg/kg caused a highly variable loss of TH-positive neurons among individual mice. Rotenone at 30 mg/kg for 56 d caused a significant loss of TH-positive neurons and behavioral impairment. In addition, a-synuclein immunoreactivity was increased in surviving TH-positive neurons in a time-dependent manner. Thus, this protocol for chronic administration of rotenone at 30 mg/kg for 56 d is more useful for understanding the mechanism of DA neurodegeneration.