Neuroinflammation Protective Efficacy of Montelukast in a Mouse Model of Parkinson’s Disease Revealed by [18F]GSK1482160 PET Quantification Targeting P2X7R

Abstract

Abstract Purpose In vivo neuroinflammation was quantified via [18F]GSK1482160 positron emission tomography (PET) imaging targeting P2X7 receptor (P2X7R) to evaluate the therapeutic effect of Montelukast (MK) treatment in transgenic A53T mice model of Parkinson's disease (PD). Methods MK treatment (10 mg/kg, i.g.) was performed in a mice model of PD for 5 weeks. Movement disorder was measured by motor functional tests (grip tests, pole tests, and inverted screen tests), the expression of microglial P2X7R was quantified by [18F]GSK1482160 positron emission tomography-Magnetic Resonance Imaging (PET-MRI) as well as ex vivo autoradiography, and the damage of dopaminergic neurons (DA neurons) was quantified by [18F]L-DOPA PET-MRI in PD mice to monitor the therapeutic effect of MK. The movement abnormality was exploited by performing a correlation analysis between the PET quantification and motor functions. Immunofluorescence staining was performed to validate the results of PET-MRI. Results PD mice suffered from severe motor deficits accompanied by increased neuroinflammation throughout the brain regions, as well as partially damaged DA neurons in striatum. The MK treatment significantly improved the motor deficits (grip test: PD + NS: 0.630 ± 0.020 N vs. PD + MK: 0.736 ± 0.011 N, p < 0.0001). PET measurement indicated that MK treatment significantly reduced the brain uptakes of [18F]GSK1482160 (SUVRLV in striatum: PD + NS: 1.701 ± 0.047 vs. PD + MK: 1.313 ± 0.075, p < 0.0001). Correlation analyses showed that motor function was positively correlated with [18F]L-DOPA PET in stratum (p = 0.0482, r = 0.5565), and was negatively correlated with [18F]GSK1482160 PET in brain globally (p = 0.0008, r = -0.7342). Conclusions [18F]GSK1482160 is a promising PET tracer for assessing neuroinflammation in PD. In vivo monitoring of inflammation in PD is beneficial to explore the association between movement disorders and the neurological damage in the brain regions, and to detect potential damage to non-DA neurons, which facilitates the assessment of the disease and contributes to the early diagnosis and treatment of PD.