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 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 Selective Loss and Selective Sparing of Neurons in the Thalamic Reticular Nucleus following Human Cardiac Arrest

1993 ◽  
Vol 13 (4) ◽  
pp. 558-567 ◽  
Author(s):  
Douglas T. Ross ◽  
David I. Graham
Keyword(s):  
Cardiac Arrest ◽  
Heart Surgery ◽  
Neuronal Damage ◽  
Open Heart Surgery ◽  
Thalamic Reticular Nucleus ◽  
Global Cerebral Ischemia ◽  
Reticular Nucleus ◽  
Thalamic Nuclei ◽  
Attentional Processing ◽  
Thalamic Relay Nuclei

Neurons in the portion of the human thalamic reticular nucleus (RT) associated with the prefrontal cortex and mediodorsal thalamic nuclei were found to be selectively vulnerable to ischemic neuronal damage following relatively short (≤5-min) duration cardiac arrest. In contrast, selective sparing of these RT neurons occurred in cases with longer (>10-min) duration of arrest that was sufficient to produce extensive ischemic neuronal damage throughout the cerebral cortex and thalamic relay nuclei. The selective degeneration of RT neurons appears to require the sustained activity of corticothalamic or thalamocortical projections to the RT following the ischemic insult. Loss of RT neurons associated with the frontal cortex and mediodorsal thalamus may be the biological basis of some types of persisting cognitive deficits in attentional processing experienced by patients following cardiac arrest, open heart surgery, or other forms of brief global cerebral ischemia.

The Effect of Perinatal Hypoxic/Ischemic Injury on Tyrosine Hydroxylase Expression in the Locus Coeruleus of the Human Neonate

2015 ◽  
Vol 38 (1) ◽  
pp. 41-53 ◽  
Author(s):  
Marianna A. Pagida ◽  
Anastasia E. Konstantinidou ◽  
Anna Korelidou ◽  
Dimitra Katsika ◽  
Effrosini Tsekoura ◽  
...  
Keyword(s):  
Tyrosine Hydroxylase ◽  
Locus Coeruleus ◽  
Dopaminergic Neurons ◽  
Ischemic Injury ◽  
Selective Vulnerability ◽  
Noradrenergic Neurons ◽  
Critical Periods ◽  
Human Neonate ◽  
Almost All ◽  
Hypoxic Ischemic Injury

We have previously shown that perinatal hypoxic/ischemic injury (HII) may cause selective vulnerability of the mesencephalic dopaminergic neurons of human neonate. In the present study, we investigated the effect of perinatal HII on the noradrenergic neurons of the locus coeruleus (LC) of the same sample. We studied immunohistochemically the expression of tyrosine hydroxylase (TH, first limiting enzyme for catecholamine synthesis) in LC neurons of 15 autopsied infants (brains collected from the Greek Brain Bank) in relation to the neuropathological changes of acute or chronic HII of the neonatal brain. Our results showed that perinatal HII appears to affect the expression of TH and the size of LC neurons of the human neonate. In subjects with neuropathological lesions consistent with abrupt/severe HII, intense TH immunoreactivity was found in almost all neurons of the LC. In most of the neonates with neuropathological changes of prolonged or older injury, however, reduction in cell size and a decrease or absence of TH staining were observed in the LC. Intense TH immunoreactivity was found in the LC of 3 infants of the latter group, who interestingly had a longer survival time and had been treated with anticonvulsant drugs. Based on our observations and in view of experimental evidence indicating that the reduction of TH-immunoreactive neurons occurring in the LC after perinatal hypoxic insults persists into adulthood, we suggest that a dysregulation of monoaminergic neurotransmission in critical periods of brain development in humans is likely to predispose the survivors of perinatal HII, in combination with genetic susceptibility, to psychiatric and/or neurological disorders later in life.

scholarly journals Prophylactic inhibition of NF-κB expression in microglia leads to attenuation of hypoxic ischemic injury of the immature brain

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Nahla Zaghloul ◽  
Dalibor Kurepa ◽  
Mohammad Y. Bader ◽  
Nadia Nagy ◽  
Mohamed N. Ahmed
Keyword(s):  
Brain Injury ◽  
Grip Strength ◽  
Microglial Activation ◽  
Periventricular Leukomalacia ◽  
Specific Inhibitor ◽  
Ischemic Injury ◽  
Selective Inhibition ◽  
Immature Brain ◽  
Activation Markers ◽  
Hypoxic Ischemic Injury

Abstract Background Periventricular leukomalacia (PVL), a devastating brain injury affecting premature infants, is the most common cause of cerebral palsy. PVL is caused by hypoxia ischemia (HI) and is characterized by white matter necrotic lesions, microglial activation, upregulation of NF-κB, and neuronal death. The microglia is the main cell involved in PVL pathogenesis. The goal of this study was to investigate the role of microglial NF-κB activity and its prophylactic inhibition in a neonate mouse model of HI. Methods Transgenic mice with specific knockout NF-κB in microglia and colony stimulating factor 1 receptor Cre with floxed IKKβ (CSF-1R Cre + IKKβflox/wt ) were used. Postnatal day 5 (P5) mice underwent sham or bilateral temporary carotid artery ligation followed by hypoxia. After HI insult, inflammatory cytokines, volumetric MRI, histopathology, and immunohistochemistry for oligodendroglia and microglial activation markers were analyzed. Long-term neurobehavioral assessment, including grip strength, rotarod, and open field testing, was performed at P60. Results We demonstrate that selective inhibition of NF-κB in microglia decreases HI-induced brain injury by decreasing microglial activation, proinflammatory cytokines, and nitrative stress. Rescue of oligodendroglia is evidenced by immunohistochemistry, decreased ventriculomegaly on MRI, and histopathology. This selective inhibition leads to attenuation of paresis, incoordination, and improved grip strength, gait, and locomotion. Conclusion We conclude that NF-κb activation in microglia plays a major role in the pathogenesis of hypoxic ischemic injury of the immature brain, and its prophylactic inhibition offers significant neuroprotection. Using a specific inhibitor of microglial NF-κB may offer a new prophylactic or therapeutic alternative in preterm infants affected by HI and possibly other neurological diseases in which microglial activation plays a role.

scholarly journals Limited but Significant Protective Effect of Hypothermia on Ultra-Early-Type Ischemic Neuronal Injury in the Thalamus

1997 ◽  
Vol 17 (5) ◽  
pp. 543-552 ◽  
Author(s):  
Kensuke Kawai ◽  
Hitoshi Nakayama ◽  
Akira Tamura
Keyword(s):  
Cardiac Arrest ◽  
Protective Effect ◽  
Morphological Changes ◽  
Thalamic Reticular Nucleus ◽  
Reticular Nucleus ◽  
Early Type ◽  
Density Analysis ◽  
Normothermic Group ◽  
Ischemic Neuronal Injury ◽  
Hypothermic Group

We investigated the protective effect of hypothermia on ultra-early-type ischemic injury in the thalamic reticular nucleus of the rat. Cerebral ischemia was produced by 5 min of cardiac arrest followed by resuscitation. Rectal and cranial temperature during and after cardiac arrest was maintained at 37–38°C in the normothermic group and at 32–33°C in the hypothermic group. In the postischemic hypothermic group, temperature was maintained at 32–33°C starting 15 min after normothermic ischemia. Histological damage was evaluated quantitatively. While after 5 min of recirculation there was no difference in morphological changes in terms of neuronal halo formation, intraischemic hypothermia reduced the severity of the degenerative changes represented by vacuolated or dark neurons by 15 min. Postischemic hypothermia failed to show any evidence of protection by 30 min. The protective effect of intraischemic hypothermia remained significant when evaluated at 14 days after ischemia by volumetry of the lesion and neuronal density analysis, whereas postischemic hypothermia had no clear protective effect. These results suggest that the protective effect of intraischemic hypothermia applies to neurons susceptible to ultra-early-type injury, but the effect of postischemic hypothermia is limited because normothermic ischemia results in extensive degeneration in these neurons by 15 min.

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.

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