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.

An improved simple rat model for global cerebral ischaemia by induced cardiac arrest.

OBJECTIVES: Cerebral hypoxic-ischaemic injury following cardiac arrest is a devastating disease affecting thousands of patients each year. There is a complex interaction between post-resuscitation injury after whole-body ischaemia-reperfusion and cerebral damage which cannot be explored in in vitro systems only; there is a need for animal models. In this study, we describe and evaluate the feasibility and efficiency of our simple rodent cardiac arrest model. > METHODS: Ten wistar rats were subjected to 9 and 10 minutes of cardiac arrest. Cardiac arrest was introduced with a mixture of the short-acting beta-blocking drug esmolol and potassium chloride. RESULTS: All animals could be resuscitated within 1 minute, and survived until day 5. General health score and neurobehavioural testing indicated substantial impairment after cardiac arrest, without differences between groups. Histological examination of the hippocampus CA1 segment, the most vulnerable segment of the cerebrum, demonstrated extensive damage in the cresyl violet staining, as well as in the Fluoro-Jade B staining and in the Iba-1 staining, indicating recruitment of microglia after the hypoxic-ischaemic event. Again, there were no differences between the 9- and 10-minute cardiac arrest groups. DISCUSSION: We were able to establish a simple and reproducible 9- and 10-minute rodent cardiac arrest model with a well-defined no-flow-time. Extensive damage can be found in the hippocampus CA1 segment. The lack of difference between 9- and 10-minute cardiac arrest time in the neuropsychological, the open field test and the histological evaluations is mainly due to the small sample size.