CXCR4 knockout induces neuropathological changes in the MPTP-lesioned model of Parkinson's disease

Abstract

C-X-C chemokine receptor type 4 (CXCR4) is highly expressed in Parkinson's disease (PD) mice's brains and is related to astrocyte signaling and microglial activation. This makes CXCR4 related to neuroinflammation and also makes CXCR4 considered to be the PD development mechanism and possible therapeutic targets. Therefore, it is worth studying the effect of CXCR4 on neuropathological changes and its potential therapeutic value for PD. This study aimed to investigate the effect of CXCR4 knockout on neuropathological changes in the mouse model of PD and its mechanism. In this study, CXCR4-WT and CXCR4+/− C57BL mice were used to make Parkinson's model. Behavioral experiments, dopaminergic neuron markers, neuroinflammation, and blood-brain barrier damage were detected to verify the effect of CXCR4 knockout on neuropathological changes. CXCR4 knockout improved the behavioral results and tyrosine hydroxylase (TH) expression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice. In the substantia nigra (SN) area of the brain of PD mouse model, the number of Iba1-positive (p = 0.0004) and GFAP-positive cells (p = 0.0349) was significantly lower in CXCR4 knockout group than CXCR4-WT group. CXCR4 knockout reduced MPTP-induced infiltration of peripheral immune cells and the expression of pro-inflammatory cytokines. CXCR4 knockout also protected blood-brain barrier (BBB) from MPTP-induced damage. In conclusion, CXCR4 knockout inhibits the degeneration of dopamine neurons, microglial and astrocyte activation, neuroinflammation, and BBB damages in the MPTP-lesioned PD mice.