Neuroprotection with the P53-Inhibitor Pifithrin-&mgr; after Cardiac Arrest in a Rodent Model

Background: The small molecule pifithrin-&mgr; reversibility inhibits the mitochondrial pathway of apoptosis. The neuronal effects of pifithrin-&mgr; applied after cardiac arrest are unknown. We hypothesized that pifithrin-&mgr; reduces neuronal damage in the most vulnerable brain region, the hippocampus, after cardiac arrest. Methods: In two randomized controlled series we administered pifithrin-&mgr; 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-&mgr; 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-&mgr; 94 ± 47 vs control 128 ± 37; n = 11 each; 10 min arrest pifithrin-&mgr; 78 ± 44, n = 15 vs control 101 ± 31, n = 18; p group* arrest length interaction = 0.622). The reduction of ischemic CV-positive neurons in pifithrin-&mgr; 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-&mgr; 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.

[1]  X. Jia,et al.  Cardiac arrest triggers hippocampal neuronal death through autophagic and apoptotic pathways , 2016, Scientific Reports.

[2]  J. Takala,et al.  A randomized trial of the effects of the noble gases helium and argon on neuroprotection in a rodent cardiac arrest model , 2016, BMC Neurology.

[3]  M. Haenggi,et al.  An improved simple rat model for global cerebral ischaemia by induced cardiac arrest , 2016, Neurological research.

[4]  Shuang Li,et al.  Cyclosporine A Suppressed Glucose Oxidase Induced P53 Mitochondrial Translocation and Hepatic Cell Apoptosis through Blocking Mitochondrial Permeability Transition , 2016, International journal of biological sciences.

[5]  Dana M. Zive,et al.  Out-of-hospital cardiac arrest survival improving over time: Results from the Resuscitation Outcomes Consortium (ROC). , 2015, Resuscitation.

[6]  A. Zaslavsky,et al.  Outcomes after out-of-hospital cardiac arrest treated by basic vs advanced life support. , 2015, JAMA internal medicine.

[7]  C. Werner,et al.  Comparison of different quantification methods to determine hippocampal damage after cerebral ischemia , 2015, Journal of Neuroscience Methods.

[8]  J. Takala,et al.  Do different anesthesia regimes affect hippocampal apoptosis and neurologic deficits in a rodent cardiac arrest model? , 2015, BMC Anesthesiology.

[9]  L. McCullough,et al.  Inhibition of Mitochondrial P53 Abolishes the Detrimental Effects of Social Isolation on Ischemic Brain Injury , 2014, Stroke.

[10]  J. Chipuk,et al.  How do I kill thee? Let me count the ways: p53 regulates PARP‐1 dependent necrosis , 2014, BioEssays : news and reviews in molecular, cellular and developmental biology.

[11]  R. Rossaint,et al.  Argon reduces neurohistopathological damage and preserves functional recovery after cardiac arrest in rats. , 2013, British journal of anaesthesia.

[12]  H. Naito,et al.  Quantitative Evaluation of the Neuroprotective Effects of a Short-acting &bgr;-Adrenoceptor Antagonist at a Clinical Dose on Forebrain Ischemia in Gerbils: Effects of Esmolol on Ischemic Depolarization and Histologic Outcome of Hippocampal CA1 , 2013, Journal of neurosurgical anesthesiology.

[13]  E. Camporesi,et al.  Hippocampal cellular loss after brief hypotension , 2013, SpringerPlus.

[14]  U. Moll,et al.  p53 Opens the Mitochondrial Permeability Transition Pore to Trigger Necrosis , 2012, Cell.

[15]  B. Zhivotovsky,et al.  Bak Compensated for Bax in p53-null Cells to Release Cytochrome c for the Initiation of Mitochondrial Signaling during Withanolide D-Induced Apoptosis , 2012, PloS one.

[16]  C. Culmsee,et al.  Targeting the p53 pathway to protect the neonatal ischemic brain , 2011, Annals of neurology.

[17]  Ying Zhang,et al.  Inhibition of p53 after acute myocardial infarction: reduction of apoptosis is counteracted by disturbed scar formation and cardiac rupture. , 2011, Journal of molecular and cellular cardiology.

[18]  U. Moll,et al.  The mitochondrial p53 pathway. , 2009, Biochimica et biophysica acta.

[19]  K. Hossmann.  Cerebral ischemia: Models, methods and outcomes , 2008, Neuropharmacology.

[20]  W. Foulkes.  p53--master and commander. , 2007, The New England journal of medicine.

[21]  N. Plesnila,et al.  Delayed neuronal death after brain trauma involves p53-dependent inhibition of NF-κB transcriptional activity , 2007, Cell Death and Differentiation.

[22]  Roger M Macklis,et al.  Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation , 2006, Nature chemical biology.

[23]  Achrol As,et al.  TNFα−238G > A Promoter Polymorphism is Associated With Increased Risk of New Hemorrhage in the Natural Course of Patients With Brain Arteriovenous Malformations , 2005, Neurological research.

[24]  S. Leib,et al.  Dexamethasone Aggravates Hippocampal Apoptosis and Learning Deficiency in Pneumococcal Meningitis in Infant Rats , 2003, Pediatric Research.

[25]  Xin Lu,et al.  Live or let die: the cell's response to p53 , 2002, Nature Reviews Cancer.

[26]  C. Culmsee,et al.  A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid β‐peptide , 2001 .

[27]  M V Chernov,et al.  A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. , 1999, Science.

[28]  R. Neumar,et al.  Outcome Model of Asphyxial Cardiac Arrest in Rats , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[29]  J. M. Lee,et al.  p53 mutations increase resistance to ionizing radiation. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[30]  R. Schmidt-Kastner,et al.  Selective vulnerability of the hippocampus in brain ischemia , 1991, Neuroscience.

[31]  M. Weil,et al.  Cardiopulmonary resuscitation in the rat. , 1988, Journal of applied physiology.

[32]  R N Walsh,et al.  The Open-Field Test: a critical review. , 1976, Psychological bulletin.

[33]  Mark D. Huffman,et al.  Executive summary: heart disease and stroke statistics--2013 update: a report from the American Heart Association. , 2013, Circulation.