Neuroprotection with the P53-Inhibitor Pifithrin-µ after Cardiac Arrest in a Rodent Model.

BACKGROUND: The small molecule pifithrin-µ reversibility inhibits the mitochondrial pathway of apoptosis. The neuronal effects of pifithrin-µ applied after cardiac arrest are unknown. We hypothesized that pifithrin-µ reduces neuronal damage in the most vulnerable brain region, the hippocampus, after cardiac arrest. METHODS: In two randomized controlled series we administered pifithrin-µ or control in 109 rats resuscitated after 8 or 10 min of cardiac arrest. Neuronal damage was blindly assessed with histology (Fluoro Jade B: FJB, cresyl violet: CV) in the most vulnerable brain region (CA1 segment of hippocampus) and with a series of neurobehavioral tests (Open Field Task, Tape-Removal Test, Morris Water Maze test). Mixed ANOVA was used to combine both series, simple comparisons were done with t tests or Mann-Whitney U test. RESULTS: Pifithrin-µ reduced the number of degenerating, FJB-positive neurons by 25% (mixed ANOVA p group = 0.014). This was more prominent after 8 min cardiac arrest (8 min arrest pifithrin-µ 94 ±â€Š47 vs control 128 ±â€Š37; n = 11 each; 10 min arrest pifithrin-µ 78 ±â€Š44, n = 15 vs control 101 ±â€Š31, n = 18; p group* arrest length interaction = 0.622). The reduction of ischemic CV-positive neurons in pifithrin-µ animals was not significant (ANOVA p group = 0.063). No significant group differences were found in neurobehavioral testing. CONCLUSION: Temporarily inhibition of apoptosis with pifithrin-µ after cardiac arrest decreases the number of injured neurons in the CA1 segment of hippocampus in a cardiac arrest rat model, without clinical correlate. Further studies should elucidate the role of this neuroprotective agent in different settings and with longer cardiac arrest.