Abstract WP259: CaMKII Inhibitor tatCN21 Decreases Neuronal Damage Following Cardiac Arrest and Cardiopulmonary Resuscitation in Mice
INTRODUCTION: Glutamate excitotoxicity is considered an important mechanism of ischemic neuronal damage. However, directly inhibiting glutamate receptors can cause severe side effects due to their key physiological functions in the central nervous system (CNS). Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) is a major downstream target of glutamate-induced Ca2+ signaling. The aim of this study is to examine the neuroprotective potential of the CaMKII inhibitor tatCN21 on experimental cardiac arrest and cardiopulmonary resuscitation (CA/CPR).
Methods: Global cerebral ischemia was induced with 8 min of cardiac arrest followed by CPR in C57BL/6 male mice. The mice were randomly administered either tatCN21 (1 mg/kg, n=14) or vehicle (saline, n=13) 2 minutes after resuscitation (intravenous). Hippocampal neuronal damage was analyzed three days after resuscitation by H&E staining. Primary hippocampal neurons were insulted with 400 μm glutamate for 5 min and treated with tatCN21 (5 μm), the scrambled CN peptide (tatRev, 5 μm) or KN93 (10 μm) 1 hr after removal of glutamate, cell viability was measure by LDH release 24 hrs later. Statistical analyses were performed using ANOVA and t tests, with P<0.05 considered statistically significant.
Results: Analysis of histological damage 72 hrs after resuscitation revealed that tatCN21 significantly reduces hippocampal CA1 neuronal injury compared to vehicle-treated mice, reducing damage from 72.9±4.5% (n=13) for vehicle to 54.1±7.6% (n=14, P<0.05) for tatCN21 treated mice. tatCN21 significantly reduced glutamate-induced neuronal cell death, but not the classical CaMKII inhibitor KN93 (P<0.05). No difference in body weight, cardiac arrest parameters and survival rates were observed between each groups.
Conclusions: Our data showed that the novel CaMKII inhibitor tatCN21 decreases neuronal damage both in vivo and in vitro. Therefore, this study indicated that CaMKII may have an important role in glutamate excititoxicity and that tatCN21 may serve as a potential therapeutic strategy for minimizing brain injury following cardiac arrest.
- © 2012 by American Heart Association, Inc.