Abstract WP152: Iron Chelation Improves Stroke Outcomes in Diabetes: Impact on Neurovascular Remodeling, Microglial Activation and Ferroptotic Endothelial Cell Death

Abstract

Introduction: We have shown that 1) poor recovery in diabetes is associated with greater hemorrhagic transformation (HT) and significant loss the cerebrovasculature, and 2) iron chelation therapy with deferoxamine (DFX) improves functional outcomes while preventing vasoregression in diabetic animals after embolic stroke. However, underlying mechanisms remained unknown. Current study was designed to test the hypotheses that DFX attenuates 1) microglial activation and pathological neurovascular remodeling, and 2) ferroptosis, iron-dependent cell death, of brain microvascular endothelial cells (BMVECs). Methods: Control and type 2 diabetic animals were subjected to embolic middle cerebral artery occlusion (MCAO). DFX (100 mg/kg) or vehicle was given 1hour after MCAO and repeated every 12 h for 7 days after stroke. At Day 14, microglial activation and neurovascular integrity were evaluated by immunohistochemical analyses of Iba1 and Aquaporin-4 (AQP4) polarity, respectively. BMVECs isolated from control Wistar and diabetic Goto-Kakizaki rats were treated with iron(III)sulfate (0.1mM) in presence/absence of DFX (100μM) for 6 hours. Cell viability and ferroptotic cell death markers like IREB2, ACSL4, MDA formation and total glutathione content were measured. Results: Ischemia/reperfusion injury amplified microglial activation and neurovascular remodeling in diabetes while DFX treatment reduced these changes to control levels (Table 1). DFX treatment also prevented iron-mediated cell death and decreased the expression of ferroptotic cell death markers (Table 1). Conclusions: Mechanisms underlying DFX-mediated improvement of sensorimotor and cognitive functions after stroke in diabetes involve attenuation of neuroinflammation, pathological neurovascular remodeling and endothelial ferroptosis. Iron chelation is a potential therapeutic strategy to improve outcomes in diabetic stroke that is associated with greater HT.