Deep Hypothermia Attenuates Microglial Proliferation Independent of Neuronal Death After Prolonged Cardiac Arrest in Rats

Drábek, Tomáš; Tisherman, Samuel A.; Beuke, Lauren; Stezoski, Jason; Janesko‐Feldman, Keri; Lahoud-Rahme, Manuella; Kochanek, Patrick M.

doi:10.1213/ane.0b013e3181b0511e

Cited by 23 publications

(24 citation statements)

References 41 publications

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“…10 We were not able to demonstrate this effect in the current study. It is possible that the intrahippocampal injections, with either clodronate or PBS containing liposomes, affected the microglial activation and proliferation in all groups, and the net effect of different levels of hypothermia were not as marked as they were in intact tissues.…”

Section: Discussioncontrasting

confidence: 67%

“…However, although successful, microglial depletion did not attenuate neuronal degeneration in CA1 region of hippocampus – a site of selective vulnerability that is accompanied by robust microglial activation and proliferation in our model. 10 While we achieved significant microglial depletion at the area of injection, the exact distribution of LEC-induced microglia depletion could not be determined in our model.…”

Section: Discussionmentioning

confidence: 69%

“…42,43 We have previously reported that our model of hypothermic CA is associated with persistent neurological and motor deficits. 10,44 Minocycline was only marginally beneficial. 10 These controversies underscore the need for a treatment paradigm that would enable us to study selective microglial depletion in a rat model.…”

Section: Discussionmentioning

confidence: 93%

“…10,44 Minocycline was only marginally beneficial. 10 These controversies underscore the need for a treatment paradigm that would enable us to study selective microglial depletion in a rat model.…”

Section: Discussionmentioning

confidence: 93%

“…1). 10 All rats received humane care in compliance with the “Guide for the Care and Use of Laboratory Animals” (www.nap.edu/catalog/5140.html). The study protocol has been approved by the Institutional Animal Care and Use Committee of the University of Pittsburgh.…”

Section: Methodsmentioning

confidence: 99%

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Microglial depletion using intrahippocampal injection of liposome-encapsulated clodronate in prolonged hypothermic cardiac arrest in rats

et al. 2012

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Trauma patients who suffer cardiac arrest (CA) from exsanguination rarely survive. Emergency preservation and resuscitation using hypothermia was developed to buy time for resuscitative surgery and delayed resuscitation with cardiopulmonary bypass (CPB), but intact survival is limited by neuronal death associated with microglial proliferation and activation. Pharmacological modulation of microglia may improve outcome following CA. Systemic injection of liposome-encapsulated clodronate (LEC) depletes macrophages. To test the hypothesis that intrahippocampal injection of LEC would attenuate local microglial proliferation after CA in rats, we administered LEC or PBS into the right or left hippocampus, respectively. After rapid exsanguination and 6 min no-flow, hypothermia was induced by ice-cold (IC) or room-temperature (RT) flush. Total duration of CA was 20 min. Pre-treatment (IC, RTpre) and post-treatment (RTpost) groups were studied, along with shams (cannulation only) and CPB controls. On day 7, shams and CPB groups showed neither neuronal death nor microglial activation. In contrast, the number of microglia in hippocampus in each individual group (IC, RTpre, RTpost) was decreased with LEC vs. PBS by ~34–46% (P < 0.05). Microglial proliferation was attenuated in the IC vs. RT groups (P < 0.05). Neuronal death did not differ between hemispheres or IC vs. RT groups. Thus, intrahippocampal injection of LEC attenuated microglial proliferation by ~40%, but did not alter neuronal death. This suggests that microglia may not play a pivotal role in mediating neuronal death in prolonged hypothermic CA. This novel strategy provides us with a tool to study the specific effects of microglia in hypothermic CA.

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Section: Discussioncontrasting

confidence: 67%

Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

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Microglial depletion using intrahippocampal injection of liposome-encapsulated clodronate in prolonged hypothermic cardiac arrest in rats

et al. 2012

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Cerebral Edema After Cardiopulmonary Resuscitation: A Therapeutic Target Following Cardiac Arrest?

et al. 2017

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We sought to review the role that cerebral edema plays in neurologic outcome following cardiac arrest, to understand whether cerebral edema might be an appropriate therapeutic target for neuroprotection in patients who survive cardiopulmonary resuscitation. Articles indexed in PubMed and written in English. Following cardiac arrest, cerebral edema is a cardinal feature of brain injury and is a powerful prognosticator of neurologic outcome. Like other conditions characterized by cerebral ischemia/reperfusion, neuroprotection after cardiac arrest has proven to be difficult to achieve. Neuroprotection after cardiac arrest generally has focused on protecting neurons, not the microvascular endothelium or blood-brain barrier. Limited preclinical data suggest that strategies to reduce cerebral edema may improve neurologic outcome. Ongoing research will be necessary to determine whether targeting cerebral edema will improve patient outcomes after cardiac arrest.

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Microglial Activation and Neurological Outcomes in a Murine Model of Cardiac Arrest

et al. 2021

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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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Deep Hypothermia Attenuates Microglial Proliferation Independent of Neuronal Death After Prolonged Cardiac Arrest in Rats

Cited by 23 publications

References 41 publications

Microglial depletion using intrahippocampal injection of liposome-encapsulated clodronate in prolonged hypothermic cardiac arrest in rats

Microglial depletion using intrahippocampal injection of liposome-encapsulated clodronate in prolonged hypothermic cardiac arrest in rats

Cerebral Edema After Cardiopulmonary Resuscitation: A Therapeutic Target Following Cardiac Arrest?

Microglial Activation and Neurological Outcomes in a Murine Model of Cardiac Arrest

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