John van Geest Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK.
Eur J Neurosci. 2014 Mar;39(6):1042-1056. doi: 10.1111/ejn.12459. Epub 2013 Dec 26.
The 6-hydroxydopamine (6-OHDA) neurotoxic lesion of the midbrain dopamine (DA) system is one of the most widely used techniques for modelling Parkinson's disease in rodents. The majority of studies using this approach, however, largely limit their analysis to lesioning acutely, and looking at behavioural deficits and the number of surviving tyrosine hydroxylase (TH)-stained cells in the midbrain. Here we have analysed additional characteristics that occur following intrastriatal delivery of 6-OHDA, providing better understanding of the neurodegenerative process. Female C57/Black mice were given lesions at 10 weeks old, and killed at several different time points postoperatively (3 and 6 h, 1, 3, 6, 9 and 12 days). While the detrimental effect of the toxin on the TH+ fibres in the striatum was immediate, we found that the loss of TH+ dendritic fibres, reduction in cell size and intensity of TH expression, and eventual reduction in the number of TH+ neurons in the substantia nigra was delayed for several days post-surgery. We also investigated the expression of various transcription factors and proteins expressed by midbrain DA neurons following lesioning, and observed changes in the expression of Aldh1a1 (aldehyde dehydrogenase 1 family, member A1) as the neurodegenerative process evolved. Extracellularly, we looked at microglia and astrocytes in reaction to the 6-OHDA striatal lesion, and found a delay in their response and proliferation in the substantia nigra. In summary, this work highlights aspects of the neurodegenerative process in the 6-OHDA mouse model that can be applied to future studies looking at therapeutic interventions.
6-羟多巴胺（6-OHDA）中脑多巴胺（DA）系统毒性损伤是在啮齿动物中模拟帕金森病最广泛使用的技术之一。然而，使用这种方法的大多数研究主要局限于急性损伤，并观察行为缺陷和中脑酪氨酸羟化酶（TH）染色细胞的数量。在这里，我们分析了 6-OHDA 纹状体给药后发生的其他特征，从而更好地了解神经退行性过程。雌性 C57/Black 小鼠在 10 周龄时接受损伤，然后在手术后的不同时间点（3 和 6 h、1、3、6、9 和 12 天）杀死。虽然毒素对纹状体中 TH+纤维的有害影响是即时的，但我们发现 TH+树突纤维的丢失、细胞大小的减小和 TH 表达强度的降低，以及最终中脑黑质中 TH+神经元数量的减少，在手术后几天内会延迟。我们还研究了中脑 DA 神经元损伤后各种转录因子和蛋白的表达，并观察到醛脱氢酶 1 家族成员 A1（Aldh1a1）的表达随着神经退行性过程的演变而发生变化。细胞外，我们观察了纹状体 6-OHDA 损伤后小胶质细胞和星形胶质细胞的反应，发现它们在黑质中的反应和增殖延迟。总之，这项工作强调了 6-OHDA 小鼠模型中神经退行性过程的各个方面，可应用于未来研究治疗干预措施。
