Abstract / Summary
Abstract Background Vascular dementia (VaD) is a major subtype of dementia caused by cerebrovascular disease, with complex pathogenesis involving oxidative stress, calcium dyshomeostasis, and iron-dependent ferroptosis. Excessive reactive oxygen species (ROS) promote Ca 2+ influx via TRPM2 channels, leading to mitochondrial dysfunction and neuronal injury, while iron accumulation accelerates lipid peroxidation. The Nrf2/SLC7A11/GPX4 axis is a key antioxidant pathway that suppresses ferroptosis. Although spermine exhibits neuroprotective properties, its role in VaD and ferroptosis remains insufficiently defined. Methods and Results A modified two-vessel occlusion (2-VO) model was established in Sprague-Dawley rats, followed by spermine administration (150 mg/kg/day). Cognitive function was assessed using the Morris water maze. Histological and ultrastructural changes were evaluated by HE, Nissl staining, and transmission electron microscopy. Oxidative stress markers (ROS, MDA, GSH, SOD, Fe 2+ ) and protein expression (TRPM2, Nrf2, SLC7A11, GPX4) were analyzed by biochemical assays, Western blot, immunohistochemistry, and immunofluorescence. In vitro, SH-SY5Y cells subjected to OGD/R were treated with spermidine (1.4 µg/mL). VaD rats and OGD/R-treated cells exhibited cognitive deficits, neuronal damage, mitochondrial dysfunction, increased TRPM2 expression, decreased Nrf2/SLC7A11/GPX4 levels, and enhanced oxidative stress and ferroptosis. Spermine significantly improved cognitive performance, alleviated neuronal and mitochondrial injury, suppressed TRPM2 expression, restored Nrf2/SLC7A11/GPX4 signaling, and reduced oxidative stress and ferroptosis. Conclusion Spermine exerts neuroprotective effects in VaD by inhibiting TRPM2-mediated oxidative stress and activating the Nrf2/SLC7A11/GPX4 pathway, thereby suppressing ferroptosis. These findings highlight spermine as a promising therapeutic candidate targeting ferroptosis in vascular dementia.