Inhibition of Ferroptosis Using UAMC‐3203 in the Post‐stroke Period Does Not Impact Cognitive Outcomes in Diabetic Rats

Abstract

IntroductionPost‐stroke cognitive impairment (PSCI) contributes to significant long‐term disability in stroke victims. 30% of ischemic stroke victims in the United States also have diabetes, which increases the risk of hemorrhagic transformation as well as PSCI. Ferroptosis, an iron‐induced cell death can instigate increased oxidative stress and contribute to impaired neurovascular repair leading to PSCI in diabetes. In our previous studies, we were able to identify that treating diabetic animals with an iron chelator, deferoxamine (DFX), prevents post‐stroke vasoregression and improves functional outcomes. Furthermore, DFX prevented the activation of ferroptosis in brain microvascular endothelial cells in vitro. Untreated diabetic animals experienced progressive cognitive decline while being monitored for 8 weeks. These findings led us to speculate that endothelial ferroptosis also plays a role in vasoregression and impacts cognitive outcomes post‐stroke. Therefore, this study was designed to test the hypothesis that inhibiting ferroptosis in the post‐stroke period will improve cognitive recovery in diabetic animals.MethodsAnimals were housed in reverse light cycle. 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 during the animals’ active hours up to 8 weeks post MCAO.Results(Table 1): 60 min occlusion caused significant acute neurological deficits. There were no differences between the groups 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.ConclusionTreatment with a ferroptosis inhibitor for 2 weeks after stroke did not impact recognition and working memory but worsened aversive learning in diabetic male rats. Unlike our previous study in which behavior tests were performed during rats’ passive hours, there was no progressive cognitive decline in untreated animals. Further evaluation of behavior testing times as well as tissue markers of neurovascular degeneration, inflammation and ferroptosis are required to determine whether molecular and cellular markers are affected by the treatment before overt changes in behavioral outcomes.