scholarly journals Minocycline Reduces Neuronal Death and Attenuates Microglial Response after Pediatric Asphyxial Cardiac Arrest

2009 ◽  
Vol 30 (1) ◽  
pp. 119-129 ◽  
Author(s):  
Minke Tang ◽  
Henry Alexander ◽  
Robert SB Clark ◽  
Patrick M Kochanek ◽  
Valerian E Kagan ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Neuronal Death ◽  
Calcium Binding ◽  
Microglial Activation ◽  
Neuronal Degeneration ◽  
Spontaneous Circulation ◽  
Developing Brain ◽  
Fluoro Jade B ◽  
Microglial Response ◽  
Asphyxial Cardiac Arrest

The mechanisms leading to delayed neuronal death after asphyxial cardiac arrest (ACA) in the developing brain are unknown. This study aimed at investigating the possible role of microglial activation in neuronal death in developing brain after ACA. Postnatal day-17 rats were subjected to 9 mins of ACA followed by resuscitation. Rats were randomized to treatment with minocycline, (90 mg/kg, intraperitoneally (i.p.)) or vehicle (saline, i.p.) at 1 h after return of spontaneous circulation. Thereafter, minocycline (22.5 mg/kg, i.p.) was administrated every 12 h until sacrifice. Microglial activation (evaluated by immunohistochemistry using ionized calcium-binding adapter molecule-1 (Iba1) antibody) coincided with DNA fragmentation and neurodegeneration in CA1 hippocampus and cortex (assessed by deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL), Fluoro-Jade-B and Nissl stain). Minocycline significantly decreased both the microglial response and neuronal degeneration compared with the vehicle. Asphyxial CA significantly enhanced proinflammatory cytokine and chemokine levels in hippocampus versus control (assessed by multiplex bead array assay), specifically tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-1α (MIP-1α), regulated upon activation, normal T-cell expressed and secreted (RANTES), and growth-related oncogene (GRO-KC) ( P<0.05). Minocycline attenuated ACA-induced increases in MIP-1α and RANTES ( P<0.05). These data show that microglial activation and cytokine production are increased in immature brain after ACA. The beneficial effect of minocycline suggests an important role for microglia in selective neuronal death after pediatric ACA, and a possible therapeutic target.

scholarly journals Early Thalamic Injury After Resuscitation From Severe Asphyxial Cardiac Arrest in Developing Rats

2021 ◽  
Vol 9 ◽  
Author(s):  
Hoai T. Ton ◽  
Katherine Raffensperger ◽  
Michael Shoykhet
Keyword(s):  
Cardiac Arrest ◽  
Microglial Activation ◽  
Neuronal Degeneration ◽  
Ischemic Injury ◽  
Selective Vulnerability ◽  
Thalamic Reticular Nucleus ◽  
Reticular Nucleus ◽  
Severity Of Injury ◽  
Hypoxic Ischemic Injury ◽  
Asphyxial Cardiac Arrest

Children who survive cardiac arrest often develop debilitating sensorimotor and cognitive deficits. In animal models of cardiac arrest, delayed neuronal death in the hippocampal CA1 region has served as a fruitful paradigm for investigating mechanisms of injury and neuroprotection. Cardiac arrest in humans, however, is more prolonged than in most experimental models. Consequently, neurologic deficits in cardiac arrest survivors arise from injury not solely to CA1 but to multiple vulnerable brain structures. Here, we develop a rat model of prolonged pediatric asphyxial cardiac arrest and resuscitation, which better approximates arrest characteristics and injury severity in children. Using this model, we characterize features of microglial activation and neuronal degeneration in the thalamus 24 h after resuscitation from 11 and 12 min long cardiac arrest. In addition, we test the effect of mild hypothermia to 34°C for 8 h after 12.5 min of arrest. Microglial activation and neuronal degeneration are most prominent in the thalamic Reticular Nucleus (nRT). The severity of injury increases with increasing arrest duration, leading to frank loss of nRT neurons at longer arrest times. Hypothermia does not prevent nRT injury. Interestingly, injury occurs selectively in intermediate and posterior nRT segments while sparing the anterior segment. Since all nRT segments consist exclusively of GABA-ergic neurons, we asked if GABA-ergic neurons in general are more susceptible to hypoxic-ischemic injury. Surprisingly, cortical GABA-ergic neurons, like their counterparts in the anterior nRT segment, do not degenerate in this model. Hence, we propose that GABA-ergic identity alone is not sufficient to explain selective vulnerability of intermediate and posterior nRT neurons to hypoxic-ischemic injury after cardiac arrest and resuscitation. Our current findings align the animal model of pediatric cardiac arrest with human data and suggest novel mechanisms of selective vulnerability to hypoxic-ischemic injury among thalamic GABA-ergic neurons.

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

2021 ◽  
Author(s):  
Alaa Ousta ◽  
Lin Piao ◽  
Yong Hu Fang ◽  
Adrianna Vera ◽  
Thara Nallamothu ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Cardiopulmonary Resuscitation ◽  
Calcium Binding ◽  
Microglial Activation ◽  
Neuronal Degeneration ◽  
Treatment Options ◽  
Sudden Cardiac Arrest ◽  
Neurological Injury ◽  
Cell Integrity ◽  
Successful Resuscitation

Abstract 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.

scholarly journals D-Cycloserine 24 and 48 Hours after Asphyxial Cardiac Arrest has No Effect on Hippocampal CA1 Neuropathology

2014 ◽  
Vol 34 (10) ◽  
pp. e1-e8 ◽  
Author(s):  
Vélvá M Combs ◽  
Heather D Crispell ◽  
Kelly L Drew
Keyword(s):  
Cardiac Arrest ◽  
Closed Head Injury ◽  
Spontaneous Circulation ◽  
Neurological Deficits ◽  
Sprague Dawley ◽  
Cell Counts ◽  
Sprague Dawley Rats ◽  
Hippocampal Ca1 ◽  
Asphyxial Cardiac Arrest ◽  
Stimulation Of

Stimulation of N-methyl-D-aspartate receptors (NMDAR) contributes to regenerative neuroplasticity following the initial excitotoxic insult during cerebral ischemia. Stimulation of NMDAR with the partial NMDAR agonist D-cycloserine (DCS) improves outcome and restores hippocampal synaptic plasticity in models of closed head injury. We thus hypothesized that DCS would improve outcome following restoration of spontaneous circulation (ROSC) from cardiac arrest (CA). DCS (10 mg/kg, IP) was administered to Sprague-Dawley rats (male, 250–330 g; 63–84 days old) 24 and 48 hours after 6 or 8 minutes of asphyxial CA. Heart rate and blood pressure declined similarly in all groups. Animals showed neurological deficits after 6 and 8 minutes CA ( P < 0.05, Tukey) and these deficits recovered more quickly after 6 minutes than after 8 minutes of CA. CA decreased the number of healthy neurons within CA1 with no difference between 6 and 8 minutes duration of CA (180.8 ± 27.6 (naïve, n = 5) versus 46.3 ± 33.8 (all CA groups, n = 27) neurons per mm CA1). DCS had no effect on neurological deficits or CA1 hippocampal cell counts ( P > 0.05, Tukey).

scholarly journals Neuronal Death in the CNS Autonomic Control Center Comes Very Early after Cardiac Arrest and Is Not Significantly Attenuated by Prompt Hypothermic Treatment in Rats

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 60
Author(s):  
Ji Hyeon Ahn ◽  
Tae-Kyeong Lee ◽  
Hyun-Jin Tae ◽  
Bora Kim ◽  
Hyejin Sim ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Cardiac Arrest ◽  
Survival Rate ◽  
Mortality Rate ◽  
Motor Neurons ◽  
Neuronal Death ◽  
Neuronal Damage ◽  
Autonomic Control ◽  
Reticular Nucleus ◽  
Fluoro Jade B

Autonomic dysfunction in the central nervous system (CNS) can cause death after recovery from a cardiac arrest (CA). However, few studies on histopathological changes in animal models of CA have been reported. In this study, we investigated the prevalence of neuronal death and damage in various brain regions and the spinal cord at early times after asphyxial CA and we studied the relationship between the mortality rate and neuronal damage following hypothermic treatment after CA. Rats were subjected to 7–8 min of asphyxial CA, followed by resuscitation and prompt hypothermic treatment. Eight regions related to autonomic control (the cingulate cortex, hippocampus, thalamus, hypothalamus, myelencephalon, and spinal cord) were examined using cresyl violet (a marker for Nissl substance) and Fluoro-Jade B (a marker for neuronal death). The survival rate was 44.5% 1 day post-CA, 18.2% 2 days post-CA and 0% 5 days post-CA. Neuronal death started 12 h post-CA in the gigantocellular reticular nucleus and caudoventrolateral reticular nucleus in the myelencephalon and lamina VII in the cervical, thoracic, lumbar, and sacral spinal cord, of which neurons are related to autonomic lower motor neurons. In these regions, Iba-1 immunoreactivity indicating microglial activation (microgliosis) was gradually increased with time after CA. Prompt hypothermic treatment increased the survival rate at 5 days after CA with an attenuation of neuronal damages and death in the damaged regions. However, the survival rate was 0% at 12 days after CA. Taken together, our study suggests that the early damage and death of neurons related to autonomic lower motor neurons was significantly related to the high mortality rate after CA and that prompt hypothermic therapy could increase the survival rate temporarily after CA, but could not ultimately save the animal.

scholarly journals Outcome Model of Asphyxial Cardiac Arrest in Rats

1995 ◽  
Vol 15 (6) ◽  
pp. 1032-1039 ◽  
Author(s):  
Laurence Katz ◽  
Uwe Ebmeyer ◽  
Peter Safar ◽  
Ann Radovsky ◽  
Robert Neumar
Keyword(s):  
Cardiac Arrest ◽  
Sham Group ◽  
Brain Regions ◽  
Spontaneous Circulation ◽  
Control Group ◽  
Ischemic Brain ◽  
Group Iii ◽  
Group I ◽  
Total Brain ◽  
Asphyxial Cardiac Arrest

An outcome model with asphyxial cardiac arrest in rats has been developed for quantifying brain damage. Twenty-two rats were randomized into three groups. Control group I was normal, was conscious, and had no asphyxia ( n = 6). Sham group II had anesthesia and surgery but no asphyxia ( n = 6). All 12 rats in groups I and II survived to 72 h and were functionally and histologically normal. Arrest group III (the model; n = 10) had light anesthesia and apneic asphyxia of 8 min, which led to cessation of circulation at 3–4 min of apnea, resulting in cardiac arrest (no flow) of 4–5 min. All 10 rats had spontaneous circulation restored by standard external cardiopulmonary resuscitation. Nine rats survived controlled ventilation for 1 h and observation to 72 h, while one rat died before extubation. All nine survivors were conscious at 72 h, with neurologic deficit scores (0% = best; 100% = worst) of 7 ± 69? (2–16%). All brain regions at five coronal levels were examined for ischemic neurons. The prevalence of ischemic neurons in five regions was categorically scored. The average total brain histopathologic damage score in group III ( n = 9) was 2.1 ( p < 0.05 vs. group I or II). A reproducible outcome model of cardiac arrest in rats was documented. It provides a tool for investigating pathophysiological mechanisms of neuronal death caused by a transient global hypoxic–ischemic brain insult.

scholarly journals Effects of the duration of postresuscitation hyperoxic ventilation on neurological outcome and survival in an asphyxial cardiac arrest rat model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Tongyi Hu ◽  
Jianjie Wang ◽  
Shuangwei Wang ◽  
Jingru Li ◽  
Bihua Chen ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Survival Rates ◽  
Spontaneous Circulation ◽  
Temperature Management ◽  
Sprague Dawley ◽  
High Concentration ◽  
Neurologic Recovery ◽  
Physiological Variables ◽  
Hyperoxic Ventilation ◽  
Asphyxial Cardiac Arrest

Abstract Cardiac arrest leads to sudden cessation of oxygen supply and cerebral hypoxia occurs when there is not sufficient oxygen supplied to the brain. Current Guidelines for adult cardiopulmonary resuscitation (CPR) and emergency cardiovascular care recommend the use of 100% oxygen during resuscitative efforts to maximize the probability of achieving the return of spontaneous circulation (ROSC). However, the optimal strategy for oxygen management after ROSC is still debatable. The aim of the present study was to evaluate the effects of the duration of post-resuscitation hyperoxic ventilation on neurological outcomes in asphyxial cardiac arrest rats treated with targeted temperature management (TTM). Asphyxia was induced by blocking the endotracheal tube in 80 adult male Sprague-Dawley rats. CPR begun after 7 min of untreated cardiac arrest. Animals were randomized to either the normoxic control under normothermia (NNC) group or to one of the 4 experimental groups (n = 16 each) immediately after ROSC: ventilated with 100% oxygen for 0 (O2_0h), 1 (O2_1h), 3 (O2_3h), or 5 (O2_5h) h and ventilated with room air thereafter under TTM. Physiological variables were recorded at baseline and during the 6 h postresuscitation monitoring period. Animals were closely observed for 96 h to assess neurologic recovery and survival. There were no significant differences in baseline measurements between groups, and all animals were successfully resuscitated. There were significant interactions between the duration of 100% oxygen administration and hemodynamics as well as, myocardial and cerebral injuries. Among all the durations of hyperoxic ventilation investigated, significantly lower neurological deficit scores and higher survival rates were observed in the O2_3h group than in the NNC group. In conclusion, postresuscitation hyperoxic ventilation leads to improved PaO2, PaCO2, hemodynamic, myocardial and cerebral recovery in asphyxial cardiac arrest rats treated with TTM. However, the beneficial effects of high concentration-oxygen are duration dependent and ventilation with 100% oxygen during induced hypothermia contributes to improved neurological recovery and survival after 96 h.

Abstract 3602: Inhibition of Soluble Epoxide Hydrolase Improves Neuronal Survival after Cardiac Arrest and Alters Microglial Activation towards a Neuroprotective Phenotype

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Jianming Wang ◽  
Tetsuhiro Fujiyoshi ◽  
Yasuharu Kosaka ◽  
Paco S Herson ◽  
Ines P Koerner
Keyword(s):  
Cardiac Arrest ◽  
Brain Injury ◽  
Inflammatory Cytokines ◽  
Neuronal Death ◽  
Epoxide Hydrolase ◽  
Microglial Activation ◽  
Soluble Epoxide Hydrolase ◽  
Functional Deficit ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Introduction: Ischemia/reperfusion during cardiac arrest and cardiopulmonary resuscitation (CA/CPR) causes significant neuronal death and leads to long-term functional deficits. While neuronal death in the hippocampus is one likely cause of memory loss after CA/CPR, the local inflammatory milieu present after CA/CPR also contributes to functional deficit. However, the signaling pathways involved in the inflammatory response are poorly understood. Microglia, the brain resident immune cells, are activated in response to different types of brain injury. We hypothesized that CA/CPR activates microglia, which then contribute to subsequent neuronal loss and functional deficit. We tested whether pharmacologic inhibition of the pro-inflammatory enzyme soluble epoxide hydrolase (sEH) alters microglial activation and neuronal death in a mouse model of CA/CPR. Methods: Male adult C57Bl/6 mice underwent 8 minutes of CA followed by CPR. The sEH inhibitor 4-phenylchalcone oxide (4-PCO; 5 mg/kg ip) was administered at 5 minutes and 24 hours after CA/CPR. Microglial activation was assessed histologically by immunostaining for the activation marker Mac-2 at 24 and 72 hours after CA/CPR. Surviving CA1 hippocampal neurons were counted at 72 hours after CA/CPR. Hippocampal expression of inflammatory cytokines was measured by quantitative RT-PCR. Results: Phenotypically activated microglia expressing Mac-2 appeared in the hippocampus as early as 24 hours after CA/CPR, before significant neuronal death was present. Concurrently, expression of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β increased. In animals treated with 4-PCO, hippocampal expression of the anti-inflammatory cytokine IL-10 was significantly increased (2-fold vs. vehicle), while expression of pro-inflammatory TNF- α and IL-1 β was unchanged. Subsequent death of CA1 neurons at 72 hours after CA/CPR was significantly reduced in animals treated with 4-PCO (34+/-3.7% 4-PCO vs. 52+/-7.1% vehicle), whereas the number of Mac-2 positive microglia was unchanged. Conclusions: Microglia are activated and produce pro-inflammatory cytokines early after CA/CPR. Inhibition of sEH induces hippocampal expression of anti-inflammatory and neuroprotective IL-10 and reduces subsequent neuronal death after CA/CPR, without altering the number of phenotypically activated Mac-2 positive microglia or expression of pro-inflammatory cytokines in the hippocampus. This suggests that sEH inhibition may alter gene expression in activated microglia after brain ischemia, thus protecting neurons and maintaining function. IL-10 induction by sEH inhibition is a promising therapeutic approach after ischemic brain injury from CA/CPR.

scholarly journals Fate of Astrocytes in The Gerbil Hippocampus After Transient Global Cerebral Ischemia

2019 ◽  
Vol 20 (4) ◽  
pp. 845 ◽  
Author(s):  
Hyeyoung Kim ◽  
Joon Park ◽  
Myoung Shin ◽  
Jun Cho ◽  
Tae-Kyeong Lee ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Neuronal Death ◽  
Pyramidal Neurons ◽  
Neuronal Degeneration ◽  
Global Cerebral Ischemia ◽  
Transient Global Cerebral Ischemia ◽  
Progressive Degeneration ◽  
Fluoro Jade B ◽  
Ca1 Area ◽  
Brain Tissue Damage

Neuronal death and reactive gliosis are major features of brain tissue damage following transient global cerebral ischemia (tgCI). This study investigated long-term changes in neuronal death and astrogliosis in the gerbil hippocampus for 180 days after 5 min of tgCI. A massive loss of pyramidal neurons was found in the hippocampal CA1 area (CA1) area between 5 and 30 days after tgCI by Fluoro-Jade B (FJB, a marker for neuronal degeneration) histofluorescence staining, but pyramidal neurons in the CA2/3 area did not die. The reaction of astrocytes (astrogliosis) was examined by glial fibrillary acidic protein (GFAP) immunohistochemistry. Morphological change or degeneration (death) of the astrocytes was found in the CA1 area after tgCI, but, in the CA2/3 area, astrogliosis was hardly shown. GFAP immunoreactive astrocytes in the CA1 area was significantly increased in number with time and peaked at 30 days after tgCI, and they began to be degenerated or dead from 40 days after tgCI. The effect was examined by double immunofluorescence staining for FJB and GFAP. The number of FJB/GFAP+ cells (degenerating astrocytes) was gradually increased with time after tgCI. At 180 days after tgCI, FJB/GFAP+ cells were significantly decreased, but FJB+ cells (dead astrocytes) were significantly increased. In brief, 5 min of tgCI induced a progressive degeneration of CA1 pyramidal neurons from 5 until 30 days with an increase of reactive astrocytes, and, thereafter, astrocytes were degenerated with time and dead at later times. This phenomenon might be shown due to the death of neurons.

scholarly journals Real-Time Brain Monitoring by Near-Infrared Spectroscopy Predicts Neurological Outcome after Cardiac Arrest and Resuscitation in Rats: A Proof of Concept Study of a Novel Prognostic Measure after Cardiac Arrest

2021 ◽  
Vol 11 (1) ◽  
pp. 131
Author(s):  
Ryosuke Takegawa ◽  
Kei Hayashida ◽  
Tai Yin ◽  
Rishabh C. Choudhary ◽  
Santiago J. Miyara ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Brain Injury ◽  
Near Infrared ◽  
Mitochondrial Fission ◽  
Spontaneous Circulation ◽  
Gene Expressions ◽  
Dynamic Changes ◽  
Neurological Outcomes ◽  
Fluoro Jade B ◽  
The Brain

Clinical studies have demonstrated that dynamic changes in regional cerebral oxygen saturation (rSO2) after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) have a role in predicting neurological outcomes after the return of spontaneous circulation (ROSC). Our study evaluated whether the timing of rSO2 decline shortly after CPR reflects the severity of brain injury in a rat model of CA. Rats were subjected to different durations of asphyxia to produce variable severities of brain injury, due to CA. Time from ROSC to achieving the initial minimum rSO2 was defined as Tnadir. A Tnadir cut-off of 24 min had optimal sensitivity and specificity for predicting good neurological outcomes at 72 h after ROSC (AUC, 0.88; sensitivity, 89%; specificity, 86%; p < 0.01). Immunohistochemistry at 72 h post-CA revealed that the number of Fluoro-Jade B positive degenerating neurons in the hippocampus CA1 sector were markedly higher in animals with Tnadir > 24 min than that in animals with Tnadir ≤ 24 min. There was no difference in the gene expressions of cytokines and mitochondrial fission proteins in the brain at 2 h after ROSC between rats with Tnadir > 24 min and with Tnadir ≤ 24 min. In conclusion, Tnadir can be a novel predictor of good neurological outcomes after CA/CPR.

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