Rhapontigenin reduced Parkinson-like neurodegeneration in mice by promoting microglial and dampening mtDNA-cGAS-STING-NF-kappaB inflammation.
Evidence
Preclinical mouse and BV2 microglia experiments found improved motor deficits, dopaminergic neuron loss, neuroinflammation, mitophagy, and mtDNA leakage after Rhap treatment, with PINK1 deficiency blocking key effects.
Caveat
The evidence is limited to MPTP-induced mice and cultured microglia, so it does not establish human efficacy for Parkinson's disease.
Simplified
Microglial activation-induced neuroinflammation and impaired neuronal are recognized as pivotal pathogeneses in Parkinson's disease (PD). However, the role of microglial mitophagy in microglial activation during PD development remains unclear, and therapeutic interventions targeting this interaction are lacking. Rhapontigenin (Rhap), a stilbenoid enriched in Vitis vinifera, exhibits dual anti-neuroinflammatory and mitophagy-enhancing properties, but its therapeutic potential and mechanisms in PD are unexplored. This study aimed to investigate the therapeutic efficacy of Rhap on neurodegeneration in a PD model and explore its underlying mechanism. Here, we showed that Rhap administration significantly ameliorated motor deficits, dopaminergic neuron loss, and neuroinflammation in MPTP-induced PD mice. Mechanistically, Rhap suppressed neuroinflammation by inhibiting the cGAS-STING-NF-κB signaling axis in both PD model mice and MPP⁺-induced BV2 microglia. Crucially, its anti-inflammatory effects depend on the PINK1-mediated enhancement of microglial mitophagy to control cytosolic mtDNA leakage. Specifically, Rhap bound to PINK1 strengthened the PINK1-DRP1 interaction, promoted mitochondrial fission in damaged organelles, and enhanced mitophagy clearance. This mitophagy activation prevents cytosolic leakage of mitochondrial DNA (mtDNA), thereby attenuating mtDNA-cGAS-STING-NF-κB-derived neuroinflammation and subsequent neurodegeneration in PD. PINK1 deficiency in BV2 microglia abolished Rhap's ability to suppress mtDNA-cGAS-STING-NF-κB activation and enhance mitophagy. Overall, our study reveals a previously unrecognized mechanism by which Rhap ameliorates PD-associated neurodegeneration through dual modulation of PINK1/DRP1-dependent microglial mitophagy and the mtDNA-cGAS-STING-NF-κB neuroinflammatory axis, suggesting a potential therapeutic strategy for PD and related neurodegenerative disorders.
Key numbers
3×
Increase in cytosolic mtDNA
Cytosolic mtDNA levels increased nearly 3 times with MPP exposure.
50 mg/kg or 100 mg/kg
dosage in mice
Mice received at doses of 50 mg/kg or 100 mg/kg.
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