Neuroinflammation is one of the driving forces of progressive neurodegeneration in Parkinson's disease (PD). The metabolomics approach has been proved highly useful in identifying potential therapeutic targets. Here, to identify inflammation-relevant treatment targets for PD, mass spectrometry-based untargeted metabolomics was applied to characterize metabolic changes in the striatum of mice with double-hit PD induced by lipopolysaccharide plus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Seven days after the final MPTP administration, metabolites from the purine metabolism pathway, including adenosine, 1-methyladenosine, adenine, inosine, hypoxanthine, xanthine, xanthosine, and guanosine, were found to be significantly dysregulated. The metabolite-protein interaction network and changes in the concentration ratio of these metabolites indicated that adenosine and adenosine deaminase (ADA; EC 126.96.36.199) were the most promising therapeutic targets and adenosine augmentation might be a rational approach to slow PD progression. These findings were then verified in a subacute MPTP-induced PD mouse model treated with ADA inhibition alone or in conjunction with antagonism of adenosine A2A receptors (A2A R). Behavioral, biochemical, and immunohistochemical analysis demonstrated that ADA inhibition significantly ameliorated the MPTP-mediated motor disabilities, dopamine depletion, and dopaminergic cell death. Significantly enhanced neuroprotective effects were further observed when the ADA inhibitor was utilized in conjunction with an A2A R antagonist. Together, our study indicated for the first time that ADA inhibitors protected against neurodegeneration induced by the neurotoxin MPTP, and ADA inhibitors in combination with A2A R antagonists showed additive antiparkinsonian effects.
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