Piper Kadsura Extract and its Bioactive Components Attenuates Aβ25-35-Induced Neurotoxicity by Modulating Glycolysis and Activating the SIRT1/PPARγ/GLUT1 Axis.

Piper kadsura (Choisy) Ohwi, a traditional medicinal plant used in East Asia, is renowned for its anti-inflammatory and antioxidant properties. Its bioactive components, such as Hancinone and Futoquinol, show potential in treating neurodegenerative disorders like Alzheimer's disease (AD). Aim of the study: This study investigates the neuroprotective effects of Piper kadsura extract (PK) and its active components, Hancinone (C1) and Futoquinol (C2), in Aβ_25-35-induced AD models. PK, C1, and C2 were evaluated in Aβ_25-35-induced PC-12 and N9 cells, as well as a mouse model of AD. Cellular assays, Seahorse analysis, and molecular docking were used to explore glycolysis, oxidative stress, and apoptosis. Gut microbiota composition was analyzed via 16 S rDNA sequencing. PK, C1, and C2 significantly improved cell viability, restored glycolysis, and reduced oxidative stress by activating the SIRT1/PPARγ/GLUT1 pathway. PK also alleviated neuronal damage and enhanced cognitive performance in mice. Gut microbiota analysis revealed increased beneficial bacteria (e.g., Lactobacillus) and enriched glycolysis-related pathways. Piper kadsura and its components exhibit multifaceted neuroprotective effects by modulating energy metabolism, reducing oxidative stress, and regulating the gut-brain axis. These findings support the therapeutic potential of Piper kadsura in AD treatment.