Ginsenoside Rh2 Alleviates Alzheimer Disease Models via Effects on Ferroptosis‐Related Neuroinflammation

Ginsenosides are the primary active constituents derived from the dried roots of ginseng, a staple in traditional Chinese medicine. This study aimed to evaluate the therapeutic efficacy of the Ginsenoside Rh2 (Rh2) monomer in both in vitro and in vivo models of Alzheimer disease (AD). An in vivo AD cell model was established by stimulating N2a mouse neuroblastoma cells with β-amyloid (Aβ) 1-42, while APP/PS1 transgenic mice served as the in vivo model. In vitro, Aβ1-42-stimulated N2a cells were co-incubated with 40 or 80 μM Rh2 for 24 h. In vivo, APP/PS1 mice received daily intraperitoneal injections of Rh2 (20 mg/kg) for 5 weeks. Our results demonstrated that Rh2 treatment significantly enhanced the viability of N2a cells and ameliorated mitochondrial membrane potential dysregulation. Furthermore, Rh2 attenuated oxidative stress by reducing reactive oxygen species production and decreasing malondialdehyde levels. It also suppressed the hypersecretion of pro-inflammatory mediators, including nitric oxide, interleukin-1β (IL-1β), and IL-6, in Aβ-treated cells. Mechanistically, Rh2 exerted potent anti-ferroptotic and anti-inflammatory effects via the activation of the Nrf2/GPX4 signaling pathway, which ultimately translated to improved spatial learning and memory in APP/PS1 mice. These findings elucidate a novel mechanistic paradigm for Rh2, highlighting its potential as a therapeutic candidate for AD drug development.