Substantial evidence points to the early onset of peripheral inflammation in the development of Parkinson's disease (PD), supporting the "body-first" hypothesis. However, there remains a notable absence of PD-specific animal models induced by inflammatory cytokines. This study introduces a novel mouse model of PD driven by the proinflammatory cytokine CXCL1, identified in our previous research. The involvement of CXCL1 in PD pathogenesis was validated using subacute and chronic MPTP-induced mouse models. Based on these findings, 2-month-old C57BL/6J mice were intravenously administered CXCL1 (20 ng/kg/day) for 2 weeks (5 days per week), successfully replicating motor deficits and pathological alterations in the substantia nigra observed in the chronic MPTP model. These results demonstrate the potential of CXCL1-induced inflammation as a mechanism for PD modeling. The model revealed activation of the PPAR signaling pathway in CXCL1-mediated neuronal damage by CXCL1. Linoleic acid, a PPAR-γ activator, significantly mitigated MPTP- and CXCL1-induced toxicity and reduced serum CXCL1 levels. In addition, the CXCL1-injected mouse model shortened the timeline for developing chronic PD mouse model to 2 weeks, offering an efficient platform for studying inflammation-driven processes in PD. The findings provide critical insights into the inflammatory mechanisms underlying PD and identify promising therapeutic targets for intervention.
大量研究表明，帕金森病（Parkinson’s disease，PD）发展过程中早期外周炎症发挥重要作用，为“外周起源”假说提供了证据。然而，目前尚缺乏由特定炎症细胞因子诱导的PD动物模型。该研究基于前期研究发现，提出了一种由促炎细胞因子CXCL1介导的新型小鼠模型。我们首先通过经典的亚急性和慢性MPTP小鼠模型验证了CXCL1升高在PD模型中的普遍性。在此基础上，我们对2月龄C57BL/6J小鼠进行了为期2周的CXCL1静脉注射（每周5天），剂量为20 ng/kg/天。CXCL1的静脉注射成功模拟了慢性MPTP模型小鼠的运动障碍和黑质的病理变化，表明这可能是一种新型的PD小鼠模型。对该模型病理损伤机制的初步研究发现，PPAR信号通路参与CXCL1诱发的炎症介导的神经元损伤；亚油酸作为一种PPAR-γ激活剂，能够抵消MPTP和CXCL1诱导的神经毒性，并降低血清中CXCL1的水平。此外，CXCL1注射小鼠模型将慢性PD小鼠模型的周期时间缩短至2周，为PD研究，尤其是PD中的炎症相关研究提供了一个新的工具，并为PD治疗提供了新的潜在靶点。.
Keywords: CXCL1; Inflammation; Mouse model; PPAR signaling pathway; Parkinson’s disease.