Elevated CXCL1 triggers dopaminergic neuronal loss in the substantia nigra of C57BL/6J mice: Evaluation of a novel Parkinsonian mouse model.

Abstract

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.