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

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.

• Authors: Michael Glas, Tamara Frick, Dirk Springe, Alessandro Putzu, Patrick Zuercher, Denis Grandgirard, Stephen L Leib, Stephan M Jakob, Jukka Takala, Matthias Haenggi
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 49 Issue 2 Pg. 229-234 (02 2018) ISSN: 1540-0514 [Electronic] United States
• PMID: 28562478 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzothiazoles
• Tumor Suppressor Protein p53
• Toluene
• pifithrin

Topics

• Animals
• Apoptosis (drug effects)
• Benzothiazoles (therapeutic use)
• Heart Arrest (drug therapy, metabolism)
• Male
• Neuroprotection (drug effects)
• Random Allocation
• Rats
• Rats, Wistar
• Toluene (analogs & derivatives, therapeutic use)
• Tumor Suppressor Protein p53 (antagonists & inhibitors, metabolism)