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Deferoxamine Treatment Prevents Post-Stroke Vasoregression and Neurovascular
Unit Remodeling Leading to Improved Functional Outcomes in Type 2 Male Diabetic
Rats: Role of Endothelial Ferroptosis.
Authors Abdul Y, Li W, Ward R, Abdelsaid M, Hafez S, Dong G, Jamil S, Wolf V, Johnson
MH, Fagan SC, Ergul A
Submitted By Submitted Externally on 9/28/2020
Status Published
Journal Translational stroke research
Year 2020
Date Published 9/1/2020
Volume : Pages Not Specified : Not Specified
PubMed Reference 32875455
Abstract It is a clinically well-established fact that patients with diabetes have very
poor stroke outcomes. Yet, the underlying mechanisms remain largely unknown. Our
previous studies showed that male diabetic animals show greater hemorrhagic
transformation (HT), profound loss of cerebral vasculature in the recovery
period, and poor sensorimotor and cognitive outcomes after ischemic stroke. This
study aimed to determine the impact of iron chelation with deferoxamine (DFX) on
(1) cerebral vascularization patterns and (2) functional outcomes after stroke
in control and diabetic rats. After 8 weeks of type 2 diabetes induced by a
combination of high-fat diet and low-dose streptozotocin, male control and
diabetic animals were subjected to thromboembolic middle cerebral artery
occlusion (MCAO) and randomized to vehicle, DFX, or tPA/DFX and followed for
14 days with behavioral tests. Vascular indices (vascular volume and surface
area), neurovascular remodeling (AQP4 polarity), and microglia activation were
measured. Brain microvascular endothelial cells (BMVEC) from control and
diabetic animals were evaluated for the impact of DFX on ferroptotic cell death.
DFX treatment prevented vasoregression and microglia activation while improving
AQP4 polarity as well as blood-brain barrier permeability by day 14 in diabetic
rats. These pathological changes were associated with improvement of functional
outcomes. In control rats, DFX did not have an effect. Iron increased markers of
ferroptosis and lipid reactive oxygen species (ROS) to a greater extent in
BMVECs from diabetic animals, and this was prevented by DFX. These results
strongly suggest that (1) HT impacts post-stroke vascularization patterns and
recovery responses in diabetes, (2) treatment of bleeding with iron chelation
has differential effects on outcomes in comorbid disease conditions, and (3)
iron chelation and possibly inhibition of ferroptosis may provide a novel
disease-modifying therapeutic strategy in the prevention of post-stroke
cognitive impairment in diabetes.


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