Deferoxamine Prevents Post-Stroke Memory Impairment in Female Diabetic Rats: Potential Links to Hemorrhagic Transformation and Ferroptosis

Diabetes increases the risk of post-stroke cognitive impairment (PSCI). Greater hemorrhagic transformation (HT) after stroke is associated with vasoregression and cognitive decline in male diabetic rats. Iron chelator deferoxamine (DFX) prevents vasoregression and improves outcomes. While diabetic female rats develop greater HT, its impact on post-stroke cerebrovascularization and cognitive outcomes remained unknown. We hypothesized that diabetes mediates pathological neovascularization, and DFX attenuates post-stroke cerebrovascular remodeling and improves neurological outcomes in female diabetic rats. Female control and diabetic animals were treated with DFX or vehicle for 7 days after stroke. Vascular indices, microglial activation, and blood-brain barrier (BBB) integrity were evaluated on Day 14. Results from diabetic female rats were partially compared to our previously published findings in male counterparts. Hemin-induced programmed cell death was studied in male and female brain microvascular endothelial cell lines (BMVEC). There was no vasoregression after stroke in either control or diabetic female animals. DFX prevented diabetes-mediated gliovascular remodeling and compromised BBB integrity while improving memory function in diabetes. Comparisons of female and male rats indicated sex differences in cognitive and vascular outcomes. Hemin mediated ferroptosis in both male and female BMVECs. DFX improved survival but had differential effects on ferroptosis signaling in female and male cells. These results suggest that stroke and associated HT do not affect cerebrovascularization in diabetic female rats, but iron chelation may provide a novel therapeutic strategy in the prevention of post-stroke memory impairment in females with diabetes via the preservation of gliovascular integrity and improvement of endothelial cell survival.