Rhapontin activates nuclear factor erythroid 2-related factor 2 to ameliorate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced gastrointestinal dysfunction in Parkinson's disease mice

Parkinson's disease (PD)-a progressive neurodegenerative disorder-is characterized by motor and gastrointestinal dysfunction. The exploration of novel therapeutic strategies for PD is vital. To investigate the potential mechanism of action of rhapontin-a natural compound with known antioxidant and anti-inflammatory properties-in the context of PD. Network pharmacology was used to predict the targets and mechanisms of action of rhapontin in PD. Behavioral tests and tyrosine hydroxylase immunofluorescence analysis were used to assess the effect of rhapontin on symptoms and pathology in MPTP-induced mice. Interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and IL-10 levels in tissues were measured using an enzyme-linked immunosorbent assay (ELISA). Additionally, nuclear factor erythroid 2-related factor 2 (NRF2) activation was confirmed using western blotting. NRF2 was predicted to be the key transcription factor underlying the therapeutic effects of rhapontin in PD, and its anti-PD action may be associated with its anti-inflammatory and antioxidant properties. Rhapontin ameliorated the loss of dopaminergic neurons and gastrointestinal dysfunction in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice by activating NRF2. Additionally, rhapontin treatment significantly decreased pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) in the substantia nigra, striatum, and colon, whereas it increased anti-inflammatory cytokine (IL-10) levels only in the colon, indicating the involvement of gut-brain axis in its neuroprotective potential. Finally, NRF2 was identified as a key transcription factor activated by rhapontin, particularly in the colon. We elucidated the effects of rhapontin in MPTP-induced PD mouse models using a combination of network pharmacology analysis, behavioral assessments, immunofluorescence, ELISA, and Western blotting. Our findings revealed the multifaceted role of rhapontin in ameliorating PD through its anti-inflammatory and antioxidant properties, particularly by activating NRF2, paving the way for future research into targeted therapies for PD.