Abstract 147: Cyclosporine a as a Neuro- and Cardioprotective Agent After Cardiopulmonary Resuscitation in a Rat Model

Abstract

Background: The immunosuppressant drug cyclosporine A (CsA) is a direct inhibitor of the mitochondrial permeability transition pore which is the common end point of many pathways of ischaemic pre- and postconditioning. We studied the neuro- and cardioprotective effect of CsA after cardiac arrest (CA) in a rat model of cardiopulmonary resuscitation. Methods and Results: Following institutional approval by the Governmental Animal Care Committee rats were subjected to 6 min of CA and were randomly and investigator-blinded allocated either to placebo (n=15) or interventional group (n=15, 10 mg/kg body weight CsA intravenously) after restoration of spontaneous circulation (ROSC). Before CA (baseline) as well as 1 h and 3 h after ROSC, continuous measurement of stroke volume (SV), ejection fraction (EF), preload adjusted maximum power (PAMP) and end diastolic volume (EDV) was performed using a conductance catheter. One day, 3 days, and 7 days after ROSC neurological outcome was evaluated by a tape removal test. After seven days of reperfusion coronal brain sections were analyzed by counting Nissl-positive (i.e. viable) neurons and TUNEL-positive (i.e. apoptotic) cells. Animals treated with CsA had a higher SV (96 [93; 107] vs. 78 [73; 94] μl, p=0.02), higher EF (58 [51; 63] vs. 42 [35; 51] %, p=0.002), and higher PAMP (4.8 [3.9; 6.1] vs. 2.3 [2.0; 2.6] mW/μl 2 , p<0.001). EDV remained stable in the CsA group 3 h after ROSC in comparison to baseline (160 [143; 181] vs. 157 [148; 192] μl, p=0.56), whereas it increased in the placebo group (169 [153; 221] vs. 156 [138; 166] μl, p=0.05). More neurons survived after administration of CsA (2.5 [1.6; 4.9] vs. 0.7 [0.4; 1.4] Nissl-positive cells/100 pixel; p=0.005). Animals in the CsA group needed less than half of the time in the tape removal test 7 days after ROSC than placebo treated animals without reaching statistical significance (26 [22; 51] vs. placebo 53 [38; 56] s; p=0.13). CsA treatment did not affect number of TUNEL-positive cells and survival rate. Conclusion: Pharmacological treatment with CsA after successful CPR attenuates myocardial dysfunction and reduces neuronal damage.