Tumor Necrosis Factor-alpha (TNF-α) is an immunomodulatory and proinflammatory cytokine implicated in neuro-inflammation and neuronal damage in response to cerebral ischemia. The present study tested the hypothesis that anti-TNF-α agents may be protective against cerebral infarction. Transient focal ischemia was artificially induced in anesthetized adult male Wistar rats (300-350 g) by middle cerebral artery occlusion (MCAO) with an intraluminal suture. TNF-α function was interfered with either a chimeric monoclonal antibody against TNF-α (infliximab-7 mg/kg) aiming to TNF-α soluble and membrane-attached form; or a chimeric fusion protein of TNF-α receptor-2 with a fragment crystallizable (Fc) region of IgG1 (etanercept-5 mg/kg) aiming for the TNF-α soluble form. Both agents were administered intraperitoneally 0 or 6 h after inducing ischemia. Infarct volume was measured by 2,3,5-triphenyltetrazolium chloride staining. Cerebral infarct volume was significantly reduced in either etanercept or infliximab-treated group compared with non-treated MCAO rats 24 h after reperfusion. These results suggest that anti-TNF-α agents may reduce focal ischemic injury in rats.

Background Neurological 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. Methods Adult 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. Results Neurological 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. Conclusions Extensive 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.

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Adult neurogenesis allows for the continual generation of neurons throughout adulthood. It is implicated in the maintenance of normal hippocampal function and is tightly regulated by oxygen homeostasis. Sleep apnea causes periodic cessations in breathing and leads to intermittent hypoxia (IH), which can impair hippocampal based learning and memory. This ongoing study examines how IH influences neural precursors and remodels the neurogenic niche in the hippocampus. We hypothesize that IH destabilizes the pool of intermediate neural progenitors (INPs) and recruits microglia into the area. Our findings indicate that the number of INPs is reduced by IH. Moreover, while IH does not change the number of microglia in the molecular and granular layers of the dentate gyrus, microglia appear to be uniquely recruited into the neurogenic niche (i.e., the subgranular zone) following IH. These findings suggest that IH‐dependent changes in hippocampal adult neurogenesis may stimulate microglial activity which in turn further impact normal hippocampal function. Such effects may play a significant role in influencing hippocampal physiology during untreated sleep apnea. Support or Funding Information This work was supported by NIH PO 1 HL 144454, NIH R01 NS10742101 awarded to AJG, and a grant from The BSD Office of Diversity & Inclusion at The University of Chicago awarded to AJG.

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.