Brain injury continues when ischemia ends

“The damage is never done, said Donald DeGracia, PhD, assistant professor of emergency medicine. When a patient’s acute episode of cardiac arrest or stroke stops, brain injury continues in the reperfusion period. The primary cause of death following cardiac arrest is brain injury.

Understanding the pathological sequence of events resulting from ischemia and reperfusion is critical to saving the brain function and health of patients. Dr. DeGracia is looking specifically at neuronal injury following cardiac arrest. “Neurons cease protein synthesis, and our evidence suggests this is related to the death of these neurons,” he said.

Studies by Dr. DeGracia and his colleagues have shown that suppressed protein synthesis is caused by a nearly 25-fold increase in phosphorylation of eukaryotic initiation factor 2a, or eIF2a. The neurons of the cerebral cortex and hippocampus display sustained eIF2a phosphorylation, which co-occurs with signs of morbidity of these neurons.

Dr. DeGracia is currently investigating the role of nitric oxide (NO) on neuronal eIF2a phosphorylation by studying the NO-producing enzyme nitric oxide synthetase (NOS). "Our preliminary data suggests the isoform eNOS may play a role in brain eIF2a phosphorylation in whole animals.  This is particularly interesting because it suggests that a vascular response is regulating neuronal protein synthesis," Dr. DeGracia said.

Grants from the American Heart Association and NIH are allowing Dr. DeGracia to examine the causal pathways of eIF2a phosphorylation, which could yield new therapeutic approaches to ischemic brain injury.

“Effective therapy must not only limit damaging mechanisms, but also facilitate repair of the damage that has already occurred, a process certain to require new protein synthesis,” he said.

Dr. DeGracia earned his PhD in physiology from Wayne State University in 1996 and has worked with Drs. Gary Krause and Blaine White since 1988. Although many scientists study brain ischemia, Wayne State has the only lab in the country looking specifically at protein synthesis in relation to this process.