Impact of Toll-Like Receptor 2 Deficiency on Survival and Neurological Function after Cardiac Arrest: A Murine Model of Cardiopulmonary Resuscitation

Abstract

Background:Cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) is associated with poor survival rate and neurofunctional outcome. Toll-like receptor 2 (TLR2) plays an important role in conditions of sterile inflammation such as reperfusion injury. Recent data demonstrated beneficial effects of the administration of TLR2-blocking antibodies in ischemia/reperfusion injury. In this study we investigated the role of TLR2 for survival and neurofunctional outcome after CA/CPR in mice.Methods:Female TLR2-deficient (TLR2-/-) and wild type (WT) mice were subjected to CA for eight min induced by intravenous injection of potassium chloride and CPR by external chest compression. Upon the beginning of CPR, n=15 WT mice received 5 μg/g T2.5 TLR2 inhibiting antibody intravenously while n=30 TLR2-/- and n=31WT controls were subjected to injection of normal saline. Survival and neurological outcome were evaluated during a 28-day follow up period. Basic neurological function, balance, coordination and overall motor function as well as spatial learning and memory were investigated, respectively. In a separate set of experiments, six mice per group were analysed for cytokine and corticosterone serum levels eight hours after CA/CPR.Results:TLR2 deficiency and treatment with a TLR2 blocking antibody were associated with increased survival (77% and 80% vs. 51% of WT control; both P<0.05). Neurofunctional performance was less compromised in TLR2-/- and antibody treated mice. Compared to WT and antibody treated mice, TLR2-/-mice exhibited reduced IL-6 (both P<0.05) but not IL-1β levels and increased corticosterone plasma concentrations (both P<0.05).Conclusion:Deficiency or functional blockade of TLR2 is associated with increased survival and improved neurofunctional outcome in a mouse model of CA/CPR. Thus, TLR2 inhibition could provide a novel therapeutic approach for reducing mortality and morbidity after cardiac arrest and cardiopulmonary resuscitation. © 2013 Bergt et al.