Gastrodin Mitigates Vascular Dementia via SIRT1-Mediated eIF2α Deacetylation and ER Stress Reduction

Background Gastrodin (GAS), the primary bioactive constituent of Gastrodia elata , exhibits significant neuroprotective activity and is clinically used for neurological cardio- and cerebrovascular disorders, but its mechanism against vascular dementia (VaD) related cognitive deficits is unclear. Purpose To elucidate the therapeutic effects of GAS and the underlying mechanism in VaD. Methods VaD was induced in rats by permanent bilateral common carotid artery occlusion (2-VO). Cognitive performance, hippocampal neuronal injury, oxidative stress, endoplasmic reticulum stress (ERS), and apoptosis were evaluated. In vitro , HT22 neurons were exposed to hypoxia to assess mitochondrial dysfunction and apoptotic signaling. The GAS-SIRT1 interaction was examined by molecular docking and surface plasmon resonance (SPR). To verify SIRT1-dependent ERS modulation, 4-PBA, RES, and SIRT1-RNAi were applied. Protein interactions and post-translational regulation were analyzed by co-immunoprecipitation (Co-IP) and immunoblotting. Results GAS significantly improved learning and memory, attenuated hippocampal neuronal loss, and reduced oxidative stress and apoptosis in 2-VO rats. GAS suppressed ERS activation, decreasing GRP78, p-PERK, p-eIF2α, and ATF4, and downregulated the pro-apoptotic effector CHOP. In hypoxic HT22 cells, GAS alleviated mitochondrial impairment and inhibited apoptosis. SIRT1 knockdown abolished GAS-mediated ERS inhibition and anti-apoptotic protection, indicating an essential role for SIRT1. Docking and SPR demonstrated direct binding of GAS to SIRT1, accompanied by increased SIRT1 expression. Co-IP further supported a mechanistic link whereby SIRT1 promoted eIF2α deacetylation, dampening ERS signaling and its downstream apoptotic program. Conclusion GAS mitigates VaD-associated cognitive impairment and hippocampal damage by binding and activating SIRT1, enhancing eIF2α deacetylation, and thereby suppressing ERS-induced apoptosis. The SIRT1/eIF2α axis represents a potential therapeutic target for vascular cognitive impairment.