Kendall Grace E, Underwood Conor F, Parr-Brownlie Louise C
Department of Anatomy, Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
Eur J Neurosci. 2025 Jan;61(2):e16667. doi: 10.1111/ejn.16667.
Gut inflammation is a salient prodromal feature of Parkinson's disease (PD) implicated in pathologic processes leading to nigrostriatal dopaminergic degeneration. However, existing rodent models of PD are suboptimal for investigating the interaction between gut inflammation and neuropathology. This study aimed to develop a rat model of PD in which gut inflammation exacerbated PD symptoms induced by a parkinsonian lesion. This was achieved by combining the 6-hydroxydopamine (6-OHDA) rat model for PD and the dextran sodium sulfate (DSS) rat model for colitis. The model was characterised using behavioural tests, including reaching, step, gait, open-field and cylinder tests, plus stereological quantification of substantia nigra (SN) DA neurodegeneration, and histological analysis of SN microglial activation and distal colon morphology. The combination of 6-OHDA and DSS resulted in greater stool softening and bleeding, shorter colons and greater distal colon histological damage, when compared with the 6-OHDA model. Additionally, 6-OHDA and DSS rats displayed similar DA neurodegeneration, yet less SN microglial activation, when compared to 6-OHDA rats that did not receive DSS. Finally, DSS + 6-OHDA rats exhibited impaired forelimb motor function compared with 6-OHDA rats, with decreased performance in reaching and step tests. In conclusion, DSS administration exacerbated forelimb motor dysfunction in 6-OHDA rats. Behavioural changes in DSS + 6-OHDA rats were associated with lower levels of microglial activation and similar levels of dopamine depletion compared with 6-OHDA-only rats. These results support that the DSS + 6-OHDA rat model is a promising PD animal model to investigate deleterious gut-brain interactions in PD.
肠道炎症是帕金森病（PD）的一个显著前驱特征，与导致黑质纹状体多巴胺能神经元变性的病理过程有关。然而，现有的PD啮齿动物模型在研究肠道炎症与神经病理学之间的相互作用方面并不理想。本研究旨在建立一种PD大鼠模型，其中肠道炎症会加剧帕金森病损诱导的PD症状。这是通过将用于PD的6-羟基多巴胺（6-OHDA）大鼠模型和用于结肠炎的葡聚糖硫酸钠（DSS）大鼠模型相结合来实现的。使用行为测试对该模型进行表征，包括抓握、步态、步幅、旷场和圆筒测试，以及黑质（SN）多巴胺能神经变性的体视学定量，以及SN小胶质细胞活化和远端结肠形态的组织学分析。与6-OHDA模型相比，6-OHDA和DSS联合使用导致更严重的粪便软化和出血、结肠缩短以及更严重的远端结肠组织学损伤。此外，与未接受DSS的6-OHDA大鼠相比，6-OHDA和DSS大鼠表现出相似的多巴胺能神经变性，但SN小胶质细胞活化较少。最后，与6-OHDA大鼠相比，DSS + 6-OHDA大鼠的前肢运动功能受损，在抓握和步态测试中的表现下降。总之，给予DSS会加剧6-OHDA大鼠的前肢运动功能障碍。与仅使用6-OHDA的大鼠相比，DSS + 6-OHDA大鼠的行为变化与较低水平的小胶质细胞活化和相似水平的多巴胺耗竭有关。这些结果支持DSS + 6-OHDA大鼠模型是一种有前途的PD动物模型，可用于研究PD中有害的肠-脑相互作用。
