Abstract
BackgroundNeurological injury following successful resuscitation from sudden cardiac arrest (CA) is common. The pathophysiological basis of this injury remains poorly understood, and treatment options are limited. Microglial activation and neuroinflammation are established contributors to many neuropathologies, such as Alzheimer disease and traumatic brain injury, but their potential role in post-CA injury has only recently been recognized. Here, we hypothesize that microglial activation that occurs following brief asystolic CA is associated with neurological injury and represents a potential therapeutic target.MethodsAdult C57BL/6 male and female mice were randomly assigned to 12-min, KCl-induced asystolic CA, under anesthesia and ventilation, followed by successful cardiopulmonary resuscitation (n = 19) or sham intervention (n = 11). Neurological assessments of mice were performed using standardized neurological scoring, video motion tracking, and sensory/motor testing. Mice were killed at 72 h for histological studies; neuronal degeneration was assessed using Fluoro-Jade C staining. Microglial characteristics were assessed by immunohistochemistry using the marker of ionized calcium binding adaptor molecule 1, followed by ImageJ analyses for cell integrity density and skeletal analyses.ResultsNeurological injury in post-cardiopulmonary-resuscitation mice vs. sham mice was evident by poorer neurological scores (difference of 3.626 ± 0.4921, 95% confidence interval 2.618–4.634), sensory and motor functions (worsened by sixfold and sevenfold, respectively, compared with baseline), and locomotion (75% slower with a 76% decrease in total distance traveled). Post-CA brains demonstrated evidence of neurodegeneration and neuroinflammatory microglial activation.ConclusionsExtensive microglial activation and neurodegeneration in the CA1 region and the dentate gyrus of the hippocampus are evident following brief asystolic CA and are associated with severe neurological injury.
Highlights
Out-of-hospital cardiac arrest (CA) affects as many as 424,000 people annually in the United States and millions worldwide and is associated with high morbidity and mortality [1, 2]
We investigated neurological deficits of mice resuscitated from a brief CA and, using confirmatory methods, determined the extent of microglial activation in this model
Neuronal Microglial Activation Following CA Consistent with previous studies of neurological injury in CA, we found evidence of increased microglial activation, as assessed through Iba1 staining [12,13,14,15,16,17,18,19,20]
Summary
Out-of-hospital cardiac arrest (CA) affects as many as 424,000 people annually in the United States and millions worldwide and is associated with high morbidity and mortality [1, 2]. There is a growing body of evidence that progressive neuronal injury continues long after the initial ischemia/reperfusion event and that this injury may be mediated by systemic and localized inflammatory responses in the brain [8, 9]. These inflammatory responses are believed to be mediated by macrophagelike cells in the central nervous system known as microglia. Microglial activation and neuroinflammation are established contributors to many neuropathologies, such as Alzheimer disease and traumatic brain injury, but their potential role in post-CA injury has only recently been recognized. We hypothesize that microglial activation that occurs following brief asystolic CA is associated with neurological injury and represents a potential therapeutic target
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