Abstract 9484: Ferroptosis Inhibitors Reduce Brain Inflammation Due to Cardiac Ischemia/Reperfusion Injury in Rats

Introduction: Brain inflammation and microglial hyperactivation are involved in the process of neuronal death including apoptosis, necroptosis, and ferroptosis, following cardiac and cerebral ischemia/reperfusion (I/R) injury. However, the roles of these cell death inhibitors on brain inflammation and microglia following cardiac I/R injury have not been investigated. Hypothesis: Inhibitors of apoptosis, necroptosis and ferroptosis effectively attenuate brain inflammation and microglial hyperactivation in rats with cardiac I/R injury. Methods: Rats were subjected to either sham or cardiac I/R operation (30 min-ischemia followed by 120-min reperfusion). Rats in cardiac I/R group were divided into 4 treatment groups: 1) vehicle, 2) apoptosis inhibitor (Z-VAD; 3.3 mg/kg), 3) necroptosis inhibitor (necrostatin-1; Nec-1; 3.3 mg/kg), and 4) ferroptosis inhibitor (ferrostatin-1; Fer-1; 2 mg/kg). These drugs were given intravenously at 15 min before ischemia. Finally, the heart and brain tissues were removed and used to determine cardiac infarct size, hippocampal-microglial morphology, and levels of cortical inflammatory cytokines. Results: Cardiac I/R injury caused myocardial infarction and brain inflammation as indicated by increased cortical IL-1β mRNA level and hippocampal microglial hyperactivation. Treatment with Z-VAD and Fer-1, but not Nec-1, reduced myocardial infarction and cortical IL-1β mRNA level. Z-VAD and Fer-1 also increased microglial process length and decreased microglial volume. Nec-1 increased microglial process length, but it did not decrease microglial volume. All treatments similarly decreased microglial number and increased microglial complexity after I/R injury (Fig 1) . Conclusions: Inhibition of apoptosis and ferroptosis, but not necroptosis, effectively reduced myocardial infarction and brain inflammation. Targeting these cell death pathways could be a novel strategy against brain injury due to cardiac I/R.