Neuroinflammation and Blood Brain Barrier Injury in a Murine Model of Cardiac Arrest

Abstract

Background Neurological injury is often evident following resuscitation from cardiac arrest and yet, the pathophysiology of this injury is not well understood. Moreover, treatment options are limited to targeted temperature management (TTM) and conservative care. We hypothesize that neuroinflammation and blood brain barrier (BBB) injury are associated with neurological injury following cardiac arrest and represent potential targets for therapeutic intervention. Methods We randomized adult C57BL/6 male/female mice to either a 12‐minute KCl‐induced asystolic CA ‐ under anesthesia and ventilation ‐ followed by CPR (N=12) or sham intervention (N=9). Neurological assessments of mice were performed using standardized neurological scoring, video motion tracking, and sensory/motor testing. BBB permeability was assessed by injection of fluorescein isothiocyanate (FITC) dextran beads. Changes to immune cell number in the brain was assessed by immunohistochemistry using the microglia marker (Iba1+). Results Neurological injury following cardiac arrest was evident by neurological scores (difference of 3.419 ± 0.5576, 95% CI 2.25–4.586), sensory scores (difference of −61.39 ± 16.65 seconds, 95% CI −97.10 to −25.67), motor scores (difference of −107.3 ± 6.503 seconds, 95% CI −121.2 to −93.35) and video analysis of distance (difference of 8.914 meters ± 1.411, 95% CI 4.425 −13.40) and speed (difference of 0.07428 m/s ±0.01175, 95% CI 0.03687 to 0.1117). Post‐CA brains demonstrated increased bead fluorescence compared to controls indicative of increased blood brain barrier injury. Moreover, Iba1+ cell number was approximately 2.47 times greater and integrity density was approximately 4.66 times greater post‐CA suggesting neuroinflammation following CA. Conclusions Global neurological injury is evident following asystolic cardiac arrest in mice but is particularly prominent in regard to motor movements. This injury is associated with BBB injury and nueroinflammation. Ongoing studies are determining the mechanisms and possible therapeutic targets of this injury. Support or Funding Information The project described was supported by Grant Number T32HL007381 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.