Abstract
Cardiac arrest is a leading cause of death in the United States and results in a large population with cognitive deficits. These deficits are due to transient global ischemia and the resulting cell death within the CA1 region of the hippocampus and associated brain regions. The administration of the specific protein kinase C epsilon activator drug, psi epsilon-Receptor for Activated C Kinase (WERACK), protects neurons within the CA1 region; however, the mechanism of action has not been fully elucidated. In this study, it was determined that ?eRACK treatment increased brain derived neurotrophic factor (BDNF) protein expression, tropomyosin related kinase B (TrkB) phosphorylation, and the expression of the protein activity-regulated cytoskeleton-associated protein (arc). The neuroprotective effect of WERACK is dependent upon TrkB phosphorylation and arc expression. WERACK treatment led to electrophysiological changes that were dependent upon arc expression, including decreased mEPSC amplitude and increased latency until anoxic depolarization. Additionally, it was determined that a middle-aged model of cardiac arrest resulted in cell death and behavioral deficits. Furthermore, it was determined that administration of WERACK at a higher dosage can overcome age-dependent reduction of arc protein expression and is a therapeutic candidate in the population most affected by ischemic injury, the elderly.