Ginsenoside Rh2 Protects against Glutamate-Induced Neurotoxicity in PC12 Cells via Activation of the VEGF-Mediated PI3K/Akt/mTOR Signaling Pathway

Ginsenoside Rh2 (GRh2), a primary active constituent of red ginseng, demonstrates significant neuroprotection against glutamate-induced excitotoxic damage in differentiated PC12 cells, a model of depression. This study found that GRh2 concentration-dependently reversed the loss of cell viability caused by glutamate. It effectively mitigated key pathological events, including intracellular calcium overload, reactive oxygen species accumulation, and the collapse of mitochondrial membrane potential. Furthermore, GRh2 enhanced synaptic plasticity, as evidenced by improved neurite morphology and increased levels of the synaptic markers neurogranin and neuromodulin. Mechanistic investigations revealed that GRh2 upregulated vascular endothelial growth factor (VEGF) expression and subsequently activated the PI3K/Akt/mTOR signaling pathway. This activation led to increased expression of synaptic proteins (PSD-95 and synaptophysin), an elevated Bcl-2/Bax ratio. Critically, the specific VEGF inhibitor SU11248 and PI3K inhibitor LY294002 abolished all the protective effects of GRh2, confirming the indispensable role of the VEGF/PI3K/Akt/mTOR axis. These results indicate that GRh2 alleviates glutamate-induced neurotoxicity by activating the VEGF-mediated PI3K/Akt/mTOR pathway, thereby improving mitochondrial function, inhibiting oxidative stress and apoptosis, and promoting synaptic integrity. This work provides novel molecular insights into the antidepressant potential of GRh2.