Narirutin reduces microglia-mediated neuroinflammation by inhibiting the JAK2/STAT3 pathway in MPP plus /MPTP-induced Parkinson's disease models

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, characterized by the loss of dopaminergic neurons in the substantia nigra compacta (SNc). Although the detailed molecular mechanisms of PD remain unknown, microglia-mediated neuroinflammation undoubtedly plays a key role in disease progression. Narirutin (Nar), a major flavonoid naturally occurring in citrus fruits, has garnered considerable research attention due to its various therapeutic applications and low toxicity. However, its effects on PD remain unclear. In this study, we explored the protective effects of Nar in 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)induced PD mouse model as well as in 1-methyl-4-phenyl-pyridinium (MPP+)-induced BV2 cells. Treatment with Nar (2.0, 10.0, and 50.0 mg/kg) reduced dopaminergic neuronal loss in a dose-dependent manner and ameliorated motor impairment in PD mice. Moreover, Nar administration inhibited microglia-mediated inflammation, evidenced by decreased microglial activation in SNc and BV2 cells, and lowered levels of proinflammatory cytokines (TNF-alpha, IL-1 beta, and IL-6) in the serum and cells. In addition, we found that Nar exerted anti-inflammatory effects by inhibiting the JAK2/STAT3 pathway. Importantly, using molecular docking and cellular thermal shift assay, we confirmed that JAK2 was a potential binding target of Nar. Overall, Nar attenuated MPTP/MPP+-induced neuroinflammation by inhibiting the JAK2/STAT3 pathway in activated microglia, thereby preventing dopaminergic neuron loss and improving motor disorders in PD mice. Our results provide new evidence supporting that Nar is promising for PD treatment and should be considered for further clinical development.