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

Abstract

BackgroundCardiac 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.MethodsFemale 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 = 31 WT 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.ResultsTLR2 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).ConclusionDeficiency 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.

RNase alleviates neurological dysfunction in mice undergoing cardiac arrest and cardiopulmonary resuscitation

“…Protocol of CA/CPR procedure was based on previous studies [ 30 , 50 , 51 ] and modified according to the result of our pilot study. Mice were anesthetized by intraperitoneal (i.p.)…”

Pravastatin But Not Simvastatin Improves Survival and Neurofunctional Outcome After Cardiac Arrest and Cardiopulmonary Resuscitation

“…Poor neurological outcome correlated with signs of hypoxic brain damage detected by nuclear magnetic resonance imaging 5 days after CA/CPR. In addition, pulmonary edema in mice was frequently encountered after CA/CPR (15) . Here, pravastatin treatment was associated with faster recovery of pulmonary function and reduced pulmonary edema.…”

“…All animal procedures were approved by the governmental ethical board (LALLF 7221.3-1.1-022/11) in accordance with institutional, national, and European guidelines for the care and use of laboratory animals. The model of CA/(CPR) was conducted as described previously (15) . A total of 124 female C57BL/6J mice (12 to 16 weeks of age; 19 to 22 g) were anesthetized by intraperitoneal injection of 12 μg/g ketamine and 8 μg/g xylazine and subjected to oral intubation and mechanical ventilation (0.21 inspired oxygen fraction).…”

“…Analysis of neurological function was performed as previously described (15) . The NeuroScore scoring system including consciousness, corneal reflex, respirations, righting reflex, coordination, and movement/activity was used.…”

“…We hypothesized that the potential modulation of survival and neurofunctional outcome after CA/CPR may differ when a hydrophilic statin such as pravastatin or a lipophilic statin such as simvastatin is administered. For the purpose of the study, we used a previously established mouse model of CA/CPR, using a modified sewing machine (15) . We conducted potassium-induced CA for 10 min before initiating CPR and monitored survival and neurofunction for a period of 28 consecutive days.…”