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


Glas, Michael; Frick, Tamara; Springe, Dirk; Putzu, Alessandro; Zuercher, Patrick; Grandgirard, Denis; Leib, Stephen L; Jakob, Stephan M; Takala, Jukka; Haenggi, Matthias (2018). Neuroprotection with the P53-Inhibitor Pifithrin-μ after Cardiac Arrest in a Rodent Model. Shock, 49(2):229-234.

Abstract

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 ± 47 vs control 128 ± 37; n = 11 each; 10 min arrest pifithrin-μ 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-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.

Abstract

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 ± 47 vs control 128 ± 37; n = 11 each; 10 min arrest pifithrin-μ 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-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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Cardiocentro Ticino
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Critical Care and Intensive Care Medicine, Emergency Medicine
Language:English
Date:February 2018
Deposited On:07 Feb 2018 16:30
Last Modified:19 Aug 2018 12:59
Publisher:Lippincott Williams & Wilkins
ISSN:1073-2322
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1097/SHK.0000000000000917
PubMed ID:28562478

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