Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons constituting the nigrostriatal pathway. Neuroinflammation, related to microglial activation, plays an important role in this process. Exploration of animal models of PD using neuroimaging modalities allows to better understand the pathophysiology of the disease. Here, we fully explored a moderate lesion model in the rat in which 6-hydroxydopamine was unilaterally delivered in three sites along the striatum. The degenerative process was assessed through in vivo Positron Emission Tomography (PET) imaging and in vitro autoradiographic quantitation of the striatal dopamine transporter (DAT) and immunostaining of tyrosine hydroxylase (TH). The microglial activation was studied through in vitro autoradiographic quantitation of the 18 kDa translocator protein (TSPO) in the striatum and CD11b staining in the SN. In addition, a targeted metabolomics exploration was performed in both these structures using mass spectrometry coupled to HPLC. Our results showed a reproducible decrease in the striatal DAT density associated with a reduction in the number of TH-positive cells in the SN and striatum, reflecting a robust moderate degeneration of nigrostriatal DA neurons. In addition, we observed strong microglia activation in both the striatum and SN ipsilateral to the lesion, highlighting that this moderate degeneration of DA neurons was associated with a marked neuroinflammation. Our metabolomics studies revealed alterations of specific metabolites and metabolic pathways such as carnitine, arginine/proline, and histidine metabolisms. These results bring new insights in the PD mechanism knowledge and new potential targets for future therapeutic strategies.

中文翻译：

---

使用多巴胺能神经元的部分6-羟基多巴胺损伤对帕金森氏病的新型大鼠模型进行广泛探索，提出了新的治疗方法。

帕金森氏病（PD）的特征在于构成黑质纹状体途径的多巴胺能（DA）神经元的变性。与小胶质细胞活化有关的神经炎症在该过程中起重要作用。使用神经影像学方法探索PD动物模型可以更好地了解该疾病的病理生理学。在这里，我们充分探索了大鼠的中度病变模型，其中6-羟基多巴胺在纹状体的三个部位单方面递送。通过体内正电子发射断层扫描（PET）成像以及纹状体多巴胺转运蛋白（DAT）的体外放射自显影定量和酪氨酸羟化酶（TH）的免疫染色来评估变性过程。通过体外放射自显影定量纹状体中18 kDa转运蛋白（TSPO）和SN中CD11b染色来研究小胶质细胞的激活。另外，使用质谱联用HPLC对这两种结构进行了靶向代谢组学研究。我们的结果显示，纹状体DAT密度可再现地降低，与SN和纹状体中TH阳性细胞数量的减少有关，反映了黑纹状体DA神经元的强烈中度变性。此外，我们在病变的纹状体和SN同侧均观察到了强烈的小胶质细胞活化，突出表明DA神经元的这种中等程度的变性与明显的神经炎症有关。我们的代谢组学研究表明特定代谢物和代谢途径（例如肉碱，精氨酸/脯氨酸和组氨酸代谢。这些结果为PD机制知识带来了新见解，并为未来的治疗策略提供了新的潜在目标。