Department of Pharmacology and Therapeutics, National University of Ireland, Galway, Ireland.
Neuroscience. 2011 Feb 23;175:251-61. doi: 10.1016/j.neuroscience.2010.12.005. Epub 2010 Dec 9.
The pathogenesis of Parkinson's disease is thought to involve a self-sustaining cycle of neuroinflammation and neurodegeneration. In order to develop novel anti-inflammatory therapies to break this cycle, it is crucial that the temporal relationship between neurodegeneration and neuroinflammation is characterised in pre-clinical models to maximise their predictive validity. Thus, this study aimed to investigate the progression of neuroinflammation relative to nigrostriatal neurodegeneration in the two most commonly-used rat models of Parkinson's disease. Male Sprague-Dawley rats were lesioned by terminal or axonal administration of 6-hydroxydopamine, and were sacrificed for quantitative immunohistochemistry (to assess nigrostriatal integrity (anti-tyrosine hydroxylase), microgliosis (anti-OX42) and astrocytosis (anti-GFAP)) at 6 h 24 h 72 h or 2 weeks post-lesion. Following terminal lesion, dopaminergic deafferentation of the striatum was evident from 6 h post-lesion and was accompanied by microglial and astroglial activation. Dopamine neuron loss from the substantia nigra did not occur until 2 weeks after terminal lesion, and this was preceded by microglial, but not astroglial, activation. Following axonal lesion, retraction of nigrostriatal terminals from the striatum was not observed until the 72 h time-point, and this was associated with a slight astrocytosis, but not microgliosis. Degeneration of dopaminergic neurons from the substantia nigra was also evident from 72 h after axonal lesion, and was accompanied by nigral microgliosis and astrocytosis by 2 weeks. This study highlights the temporal relationship between neurodegeneration and neuroinflammation in models of Parkinson's disease, and should facilitate use of these models in the development of anti-inflammatory therapies for the human condition.
帕金森病的发病机制被认为涉及神经炎症和神经退行性变的自我维持循环。为了开发新型抗炎疗法来打破这种循环，在临床前模型中描述神经退行性变与神经炎症之间的时间关系至关重要，以最大限度地提高其预测有效性。因此，本研究旨在研究两种最常用的帕金森病大鼠模型中神经炎症相对于黑质纹状体神经退行性变的进展。雄性 Sprague-Dawley 大鼠通过 6-羟多巴胺的末端或轴突给药进行损伤，并在损伤后 6 h、24 h、72 h 或 2 周时进行定量免疫组织化学（评估黑质纹状体完整性（抗酪氨酸羟化酶）、小胶质细胞增生（抗 OX42）和星形胶质细胞增生（抗 GFAP））处死。在末端损伤后，纹状体的多巴胺能传入纤维脱髓鞘从损伤后 6 h 开始，并伴有小胶质细胞和星形胶质细胞的激活。黑质多巴胺神经元的丢失直到末端损伤后 2 周才发生，并且在此之前发生了小胶质细胞的激活，但没有星形胶质细胞的激活。在轴突损伤后，黑质纹状体末端从纹状体的回缩直到 72 h 时间点才观察到，并且与轻微的星形胶质细胞增生有关，但没有小胶质细胞增生。黑质多巴胺神经元的变性从轴突损伤后 72 h 开始明显，并伴有黑质小胶质细胞增生和星形胶质细胞增生到 2 周。本研究强调了帕金森病模型中神经退行性变与神经炎症之间的时间关系，这将有助于这些模型在开发人类疾病抗炎治疗中的应用。
