Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.
PLoS One. 2009 Nov 18;4(11):e7878. doi: 10.1371/journal.pone.0007878.
A clinically-related animal model of Parkinson's disease (PD) may enable the elucidation of the etiology of the disease and assist the development of medications. However, none of the current neurotoxin-based models recapitulates the main clinical features of the disease or the pathological hallmarks, such as dopamine (DA) neuron specificity of degeneration and Lewy body formation, which limits the use of these models in PD research. To overcome these limitations, we developed a rat model by stereotaxically (ST) infusing small doses of the mitochondrial complex-I inhibitor, rotenone, into two brain sites: the right ventral tegmental area and the substantia nigra. Four weeks after ST rotenone administration, tyrosine hydroxylase (TH) immunoreactivity in the infusion side decreased by 43.7%, in contrast to a 75.8% decrease observed in rats treated systemically with rotenone (SYS). The rotenone infusion also reduced the DA content, the glutathione and superoxide dismutase activities, and induced alpha-synuclein expression, when compared to the contralateral side. This ST model displays neither peripheral toxicity or mortality and has a high success rate. This rotenone-based ST model thus recapitulates the slow and specific loss of DA neurons and better mimics the clinical features of idiopathic PD, representing a reliable and more clinically-related model for PD research.
一种与临床相关的帕金森病（PD）动物模型可能有助于阐明该疾病的病因，并有助于开发药物。然而，目前基于神经毒素的模型都无法重现该疾病的主要临床特征或病理特征，例如多巴胺（DA）神经元特异性退化和路易体形成，这限制了这些模型在 PD 研究中的应用。为了克服这些限制，我们通过立体定向（ST）将小剂量的线粒体复合物-I 抑制剂鱼藤酮注入两个脑区：右侧腹侧被盖区和黑质，从而建立了一种大鼠模型。ST 鱼藤酮给药 4 周后，与全身给予鱼藤酮（SYS）的大鼠相比，右侧黑质的酪氨酸羟化酶（TH）免疫反应性下降了 43.7%，而 SYS 大鼠则下降了 75.8%。与对侧相比，鱼藤酮输注还降低了 DA 含量、谷胱甘肽和超氧化物歧化酶活性，并诱导了α-突触核蛋白的表达。与 SYS 模型相比，这种 ST 模型既没有外周毒性或死亡率，而且成功率也很高。因此，这种基于鱼藤酮的 ST 模型再现了缓慢而特异的 DA 神经元丧失，并且更好地模拟了特发性 PD 的临床特征，代表了一种更可靠和更具临床相关性的 PD 研究模型。
