Evaluation of Cyclosporine a as a Cardio- and Neuroprotective Agent After Cardiopulmonary Resuscitation in a Rat Model

Authors:
  • JRJoachim Roewer
    Joachim Roewer
  • TBThomas Bruckner
    Thomas Bruckner
  • BBBernd W. Böttiger
    Bernd W. Böttiger
  • EPErik Popp
    Erik Popp
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Abstract
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 ischemic preconditioning and postconditioning. We studied the neuroprotective and cardioprotective effect of CsA after cardiac arrest (CA) in a rat model of cardiopulmonary resuscitation. After institutional approval by the Governmental Animal Care Committee, 83 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, left ventricular ejection fraction, preload adjusted maximum power, and end diastolic volume 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 7 days of reperfusion, coronal brain sections were analyzed by counting Nissl-positive (i.e., viable) neurons and terminal deoxynucleotidyl transferase dUTP nick end labeling positive (i.e., apoptotic) cells. Animals treated with CsA had a higher stroke volume (96 [93; 107] μL vs. 78 [73; 94] μL; P = 0.02), higher ejection fraction (58% [51%; 63%] vs. 42% [35%; 51%]; P = 0.002), and higher preload adjusted maximum power (4.8 [3.9; 6.1] vs. 2.3 [2.0; 2.6] mW/μL; P < 0.001). End diastolic volume remained stable in the CsA group 3 h after ROSC in comparison to baseline (160 [143; 181] μL vs. 157 [148; 192] μL; P = 0.56), whereas it increased in the placebo group (169 [153; 221] μL 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]; P = 0.005). Compared to placebo-treated animals, the time in the tape removal test 7 days after ROSC was reduced by half in the CsA group without reaching statistical significance (26 [22; 51] vs. placebo 53 [38; 56] s; P = 0.13). Cyclosporine A treatment neither affected the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells nor the survival rate. Pharmacological postconditioning with CsA after successful cardiopulmonary resuscitation attenuates myocardial dysfunction and reduces neuronal damage.

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