Inhibition of ferroptosis using UAMC-3203 in the post stroke period does not impact cognitive outcomes in diabetic rats.

Faculty Mentor and Department: Adviye Ergul MD, PhD, Pathology and Laboratory Medicine, Medical University of South Carolina

Funding Source: Administrative supplement for Ashley Phoenix NIH RF1 NS083559-S1

Background:Post-stroke cognitive impairment (PCSI) contributes to significant long-term disability in stroke victims. 30% of ischemic stroke victims in the United States also have diabetes, a disease that disproportionately effects African Americans, Native Indians, and Hispanics. Diabetes increases the risk of hemorrhagic transformation as well as PCSI. Ferroptosis, an iron-induced cell death can instigate increased oxidative stress and contribute to impaired neurovascular repair leading to PSCI in diabetic patients. 

Hypothesis:Inhibiting ferroptosis in the post-stroke period will improve cognitive recovery in diabetic animals.

Methods: 8 weeks after diabetes onset, male rats underwent 60 min middle cerebral artery occlusion (MCAO). On Day 3, after stroke injury was confirmed by MRI, animals were randomized to UAMC-3 (2mg/kg) or vehicle treatment for 2 weeks. Sensorimotor and cognitive behavioral tests were performed after 8 weeks of MCAO

Results: (Table 1): 60 min occlusion caused significant acute neurological deficits. There were no differences in indices measured by novel object recognition (NOR), Y-maze and sucrose preference tests. Interestingly, step through latency in passive avoidance test (PAT) was lower in the UAMC-3203 group.

Conclusions: Treatment with a ferroptosis inhibitor for 2 weeks after stroke did not impact recognition and working memory but worsened aversive learning in diabetic male rats. Further evaluation of tissue markers of neurovascular degeneration, inflammation and ferroptosis are required to better understand whether ferroptosis contributes to poor stroke recovery in diabetes.