Protective effects of 2,3,5,4’-tetrahydroxystilbene-2-O-β-D-glucoside against cadmium toxicity involve BDNF/TrkB and PI3K/Akt signaling pathways

Polygonum multiflorum is a traditional Chinese medicinal herb used to nourish the blood, promote hair growth, and support neurological health. Its key bioactive component, 2,3,5,4’-tetrahydroxystilbene-2-O-β-D-glucoside (THSG), has shown potent antioxidant and anti-aging properties, making it a representative marker compound in modern pharmacological studies. We aimed to investigate the neuroprotective effects of THSG against cadmium (Cd)-induced neurotoxicity and to elucidate its underlying molecular mechanisms using both in vitro cellular models and an in vivo murine model. Male mice, 8 weeks of age, were randomly assigned to four groups: control, Cd-exposed, THSG-treated, and Cd+THSG co-treated. After 30 days of Cd exposure with or without THSG, behavioral tests, histological analysis, and assays for oxidative stress and inflammatory markers were conducted. In vitro, SH-SY5Y, BV2, and GL261 cells were used to investigate the cytoprotective and mechanistic effects of THSG against Cd-induced neurotoxicity via WST-1, RT-qPCR, Western blotting, LDH release, and immunofluorescence assays. THSG treatment significantly improved spatial learning and memory performance in Cd-exposed mice, while also effectively suppressing microglial and astrocyte activation and alleviating neuronal damage. In vitro, THSG alleviated Cd-induced cytotoxicity and morphological damage in neurons and glial cells. Western blot and immunofluorescence analyses revealed that THSG activated the BDNF/TrkB and PI3K/Akt signaling pathways, contributing to its neuroprotective effects. THSG confers robust neuroprotection against Cd-induced toxicity through multi-target mechanisms involving BDNF/TrkB and PI3K/Akt pathway activation, supporting its potential as a promising therapeutic agent for heavy metal-induced neurodegeneration. • THSG protects glial cells from Cd-induced toxicity via BDNF/TrkB activation. • THSG inhibits Cd-triggered microglial activation and neuroinflammation. • THSG restores neuronal viability and morphology in Cd-injured SY5Y cells. • THSG alleviates Cd-induced cognitive, behavioral, and organ impairments in mice. • THSG reduces oxidative stress and apoptosis likely via PI3K/Akt and TrkB pathways.