Orally Administered Ginkgolide C Alleviates MPTP-Induced Neurodegeneration by Suppressing Neuroinflammation and Oxidative Stress through Microbiota–Gut–Brain Axis in Mice

Parkinson's disease (PD) is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra, the etiology of which remains unclear. Studies have shown that neuroinflammation and oxidative stress (OS) play an important role in neuronal damage in patients with PD. Disturbances in the gut microbiota influence neuroinflammation and OS through the microbiota-gut-brain axis. Ginkgolide C (GC), a traditional Chinese medicine extracted from the leaves of <i>Ginkgo biloba</i>, has been reported to exhibit anti-inflammatory effects and the ability to modulate intestinal microbial composition. However, the potential of GC to positively impact PD by modulating the gut microbiota remains unexplored. This study aimed to explore the effects of GC on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice and elucidate its underlying mechanisms. Our findings elucidated that GC treatment significantly ameliorates behavioral deficits as well as pathological damage via restoring gut microbial homeostasis to downgrade OS and neuroinflammation in MPTP-induced PD mice. Mechanistically, GC treatment exerts antioxidant effects via activating the AKT/Nrf2/HO-1 pathway in MPP⁺-exposed SN4741 neuronal cells and significantly downregulates the expression of inflammatory mediators via regulating NF-κB and MAPK signaling in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Overall, our study demonstrates that GC administration alleviates MPTP-induced neurodegeneration via rebuilding gut microbial homeostasis to inhibit OS and neuroinflammation in mice, indicating that GC might serve as a promising candidate medicine for PD.