4,4′-Dimethoxychalcone regulates redox homeostasis by targeting riboflavin metabolism in Parkinson's disease therapy

Oxidative stress damage plays a pivotal role in Parkinson's disease (PD) pathogenesis. Previously, we developed a blood brain barrier-penetrating peptide-based Trojan Horse strategy to deliver 4,4'-dimethoxychalcone (DMC) for PD therapy and revealed neuroprotective properties of DMC in a PD model; however, the underlying mechanisms remained unclear. Here, we report that DMC attenuated motor impairment, degeneration of DA neurons and alpha-synuclein aggregation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and exogenous human alpha-synuclein-induced PD mouse models. Mechanistically, DMC increased the expression of two critical intermediates in riboflavin metabolism: riboflavin kinase (RFK) and its metabolic product, flavin mononucleotide (FMN). We provide the first direct evidence that FMN ameliorated oxidative stress damage and dopaminergic neuron degeneration both in vitro and in vivo and that riboflavin metabolism was required for DMC-mediated neuroprotection. DMC-induced restoration of redox homeostasis was mediated via the activation of protein kinase C theta (PKC theta) signaling. Together, our findings reveal that DMC may serve as a novel antioxidant in PD intervention and also define a novel mechanism that underlies its therapeutic activity.

Automated summary

DMC attenuated motor impairment, degeneration of DA neurons, and alpha-synuclein aggregation in PD mouse models by increasing the expression of the riboflavin metabolic product, FMN. The restoration of redox homeostasis by DMC was mediated via the activation of PKCθ signaling.