Rat Model Of Cardiac Arrest Research Articles

Ketone Body Improves Neurological Outcomes after Cardiac Arrest by Inhibiting Mitochondrial Fission in Rats.

Ketone bodies including β-hydroxybutyrate (β-HB) have been proved the therapeutic potential in diverse neurological disorders. However, the role of β-HB in the regulation of neurological injury after cardiac arrest (CA) remains unclear. We investigated the effect of β-HB on brain mitochondrial dysfunction and neurological function after CA. A rat model of CA was established by asphyxia. The rats were randomly divided into three groups: sham group, control group, and β-HB group. Animals received 200 mg/kg β-HB or same volume vehicle at 10 minutes after return of spontaneous circulation by intraperitoneal injection. Neurological function was evaluated by neurologic deficit score and Y-maze. Neuronal cell loss and apoptosis were detected through hematoxylin-eosin staining, Nissl staining, and TdT-mediated dUTP nick-end labeling assay. Oxidative stress levels were determined by immunohistochemical staining of 4-hydoxynonenal and 8-hydroxy-2′-deoxyguanosine. Furthermore, mitochondrial ultrastructure of brain cells was observed by transmission electron microscopy. In addition, the protein expression levels of Bak, caspase 3, gasdermin D, caspase 1, brain-derived neurotrophic factor, dynamin-related protein 1 (Drp1), and phospho-Drp1 (ser616) were measured. We found that neurological function and survival rate were significantly higher in the β-HB group compared with the control group. β-HB also reduced neurons death and neurological oxidative stress after CA. Moreover, β-HB reduced neurological injury from apoptosis and pyroptosis after CA. In addition, β-HB maintained the structural integrity of brain mitochondria, prevented mitochondrial fission, and increased brain energy metabolism after CA. In conclusion, β-HB beneficially affected the neurological function of rats after global cerebral ischemia, associated with decreased mitochondrial fission, and improved mitochondrial function. Our results suggest that β-HB might benefit patients suffering from neurological dysfunction after CA.

Inhibition of extracellular signal-regulated kinase downregulates endoplasmic reticulum stress-induced apoptosis and decreases brain injury in a cardiac arrest rat model.

Cerebral ischemia-reperfusion injury (CIRI) is the predominant cause of neurological disability after cardiac arrest/cardiopulmonary resuscitation (CA/CPR). The endoplasmic reticulum stress (ERs)-induced apoptosis plays an important role in neuronal survival/death in CIRI. Our previous studies reported that the extracellular signal-regulated kinase (ERK) inhibitor, PD98059, alleviates CIRI after CA/CPR. Whether ERs-induced apoptosis is involved in the neuroprotection of PD98059 remains unknown. This study aims to investigate the effects of ERK inhibition by PD98059 on ERs-induced apoptosis after CIRI in the CA/CPR rat model. The baseline characteristics of male adult Sprague-Dawley (SD) rats in all groups were evaluated before CA/CPR. The SD rats that survived from CA/CPR were randomly divided into 3 groups (n=12/group): normal saline group (1 ml/kg), dimethylsulfoxide (DMSO, the solvent of PD98059, 1 ml/kg) group, PD98059 group (0.3 mg/kg). Another 12 SD rats were randomly selected as the Sham group. Twenty-four hours after resuscitation, neural injury was assessed by survival rate, neurological deficit scores (NDS) and Nissl staining; apoptosis of brain cells was detected using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining; mRNA expression and protein levels of ERs-related protein BIP, PERK, ATF4 and CHOP were checked with RT-PCR and Western Blot. The results showed that there were no significant differences in baseline characteristics before CA/CPR among all groups. PD98059 significantly improved survival rate and NDS, increased the Nissl bodies in neurons, reduced apoptosis, downregulated the mRNA transcription and expression levels of BIP, PERK, ATF4 and CHOP at 24 h after CA/CPR. Our results demonstrate that inhibition of ERK by PD98059 alleviates ERs-induced apoptosis via BIP-PERK-ATF4-CHOP signaling pathway and mitigates CIRI in the CA/CPR rat model.

OR07 Conventional and Speckle-Tracking Echocardiography (STE) and Cardiac Circulating Biomarkers in a rat model of Cardiac Arrest

OR07 Conventional and Speckle-Tracking Echocardiography (STE) and Cardiac Circulating Biomarkers in a rat model of Cardiac Arrest

Cortical Anoxic Spreading Depolarization During Cardiac Arrest is Associated with Remote Effects on Peripheral Blood Pressure and Postresuscitation Neurological Outcome

BackgroundSpreading depolarizations (SDs) are self-propagating waves of neuronal and glial depolarizations often seen in neurological conditions in both humans and animal models. Because SD is thought to worsen neurological injury, the role of SD in a variety of cerebral insults has garnered significant investigation. Anoxic SD is a type of SD that occurs because of anoxia or asphyxia. Although asphyxia leading to a severe drop in blood pressure may affect cerebral hemodynamics and is widely known to cause anoxic SD, the effect of anoxic SD on peripheral blood pressure in the extremities has not been investigated. This relationship is especially important to understand for conditions such as circulatory shock and cardiac arrest that directly affect both peripheral and cerebral perfusion in addition to producing anoxic SD in the brain.MethodsIn this study, we used a rat model of asphyxial cardiac arrest to investigate the role of anoxic SD on cerebral hemodynamics and metabolism, peripheral blood pressure, and the relationship between these variables in 8- to 12-week-old male rats. We incorporated a multimodal monitoring platform measuring cortical direct current simultaneously with optical imaging.ResultsWe found that during anoxic SD, there is decoupling of peripheral blood pressure from cerebral blood flow and metabolism. We also observed that anoxic SD may modify cerebrovascular resistance. Furthermore, shorter time difference between anoxic SDs measured at different locations in the same rat was associated with better neurological outcome on the basis of the recovery of electrocorticography activity (bursting) immediately post resuscitation and the neurological deficit scale score 24 h post resuscitation.ConclusionsTo our knowledge, this is the first study to quantify the relationship between peripheral blood pressure, cerebral hemodynamics and metabolism, and neurological outcome in anoxic SD. These results indicate that the characteristics of SD may not be limited to cerebral hemodynamics and metabolism but rather may also encompass changes in peripheral blood flow, possibly through a brain–heart connection, providing new insights into the role of anoxic SD in global ischemia and recovery.

Vagus Nerve Stimulation Improves Mitochondrial Dysfunction in Post–cardiac Arrest Syndrome in the Asphyxial Cardiac Arrest Model in Rats

Cerebral mitochondrial dysfunction during post–cardiac arrest syndrome (PCAS) remains unclear, resulting in a lack of therapeutic options that protect against cerebral ischemia–reperfusion injury. We aimed to assess mitochondrial dysfunction in the hippocampus after cardiac arrest and whether vagus nerve stimulation (VNS) can improve mitochondrial dysfunction and neurological outcomes. In an asphyxial cardiac arrest model, male Sprague–Dawley rats were assigned to the vagus nerve isolation (CA) or VNS (CA + VNS) group. Cardiopulmonary resuscitation was performed 450 s after pulseless electrical activity. After the return of spontaneous circulation (ROSC), left cervical VNS was performed for 3 h in the CA + VNS group. Mitochondrial respiratory function was evaluated using high-resolution respirometry of the hippocampal tissue. The neurologic deficit score (NDS) and overall performance category (OPC) were assessed at 24, 48, and 72 h after resuscitation. The leak respiration and oxidative phosphorylation capacity of complex I (OXPHOS CI) at 6 h after ROSC were significantly higher in the CA + VNS group than in the CA group (p = 0.0308 and 0.0401, respectively). Compared with the trends of NDS and OPC in the CA group, the trends of those in the CA + VNS group were significantly different, thus suggesting a favorable neurological outcome in the CA + VNS group (p = 0.0087 and 0.0064 between times × groups interaction, respectively). VNS ameliorated mitochondrial dysfunction after ROSC and improved neurological outcomes in an asphyxial cardiac arrest rat model.

Inhibition of Nitrosative Stress Attenuates Myocardial Injury and Improves Outcomes after Cardiac Arrest and Resuscitation.

Nitrosative stress is widely involved in cell injury via inducing the nitration modification of a variety of proteins. This study aimed to investigate whether inhibition of nitrosative stress attenuated myocardial injury and improved outcomes in a rat model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Adult male Wistar rats were subjected to asphyxia-induced cardiac arrest and subsequently resuscitation. One minute after return of spontaneous circulation (ROSC), rats were randomized and administered the nitrosative stress inhibitor, FeTMPyP (1 or 3 mg/kg), or normal saline as a placebo. 3-Nitrotyrosine (3-NT), mean arterial pressure (MAP), heart rate (HR), mortality, electrocardiogram (ECG), left ventricular ejection fraction (EF) and fractional shortening (FS), and levels of myocardial apoptosis were evaluated. The concentrations of lactate, creatine kinase MB isoenzyme (CK-MB), and angiotensin II (Ang II), were measured in blood samples. 3-NT level was significantly increased in the heart after ROSC. Administration of FeTMPyP (1 or 3 mg/kg) attenuated the increase of 3-NT in the myocardium. Inhibition of nitrosative stress improved survival and attenuated CA/CPR-induced reperfusion injury by maintaining the stability of MAP and HR, and reducing the accumulation of lactic acid. Post-cardiac arrest rats had higher serum CK-MB and Ang II than healthy rats, while EF and FS were lower in healthy rats. Inhibition of nitrosative stress not only alleviated ischemic heart injury but also reduced the occurrence of CA/CPR-induced of arrhythmias. Moreover, nitrosative stress mediated the upregulation of Cleaved caspase-3 and downregulation Bcl-2, which was abolished by FeTMPyP. Inhibition of nitrosative stress is a novel molecular target to alleviate myocardial injury and improve outcomes in a rat model of CA/CPR.

Curcumin Improves Cardiopulmonary Resuscitation Outcomes by Modulating Mitochondrial Metabolism and Apoptosis in a Rat Model of Cardiac Arrest.

BackgroundCurcumin, a diarylheptanoid chemical compound extracted from curcuma longa, exerts a variety of biological and pharmacological effects in numerous pathological conditions, including ischemia/reperfusion (I/R) injury. In this study, we investigated its role in post-resuscitation myocardial dysfunction in a rat model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) by targeting on mitochondrial metabolism and apoptosis.MethodsAnimals were randomized into three groups: sham, control and curcumin, with fifteen rats in each group. Ventricular fibrillation (VF) was induced in the rats of the control and curcumin groups. The rats in the two groups were untreated for 8 min, followed by CPR for 8 min. Placebo (saline) or curcumin was administered by intraperitoneal injection, respectively, 5 min after successful resuscitation. Myocardial function was measured at baseline and post-resuscitation for 6 h consecutively. Ten rats in each group were closely observed for an additional 66 h to analyze the survival status, and the remaining five were sacrificed for the measurement of mitochondrial parameters and cell apoptosis.ResultsCompared with the control group, myocardial function was significantly enhanced in the curcumin group, contributing to a better survival status. Curcumin treatment mitigated the depletion of superoxide dismutase (SOD) and the production of malondialdehyde (MDA). The structural damage of mitochondria was also alleviated, with improved conditions of mPTP and ΔΨm. Curcumin boosted the production of ATP and attenuated myocardial apoptosis. Cytochrome C, caspase-3 and its cleavage were suppressed by curcumin. Proteins closely related to the functional performance of mitochondria, including uncoupling protein 2 (UCP2) and uncoupling protein 3 (UCP3) were downregulated, while mitochondrial transcription factor A (mtTFA) was upregulated.ConclusionCurcumin improves the outcomes of CPR via alleviating myocardial dysfunction induced by I/R injury. It exhibits anti-oxidation properties. Moreover, it is capable of ameliorating mitochondrial structure and energy metabolism, as well as inhibiting the mitochondrial apoptosis pathway. UCP2, UCP3, and mtTFA might also be involved in curcumin mediated protective effects on mitochondria.

Necrosulfonamide improves post-resuscitation myocardial dysfunction via inhibiting pyroptosis and necroptosis in a rat model of cardiac arrest

The systemic inflammatory response following global myocardial ischemia/reperfusion (I/R) injury is a critical driver of poor outcomes. Both pyroptosis and necroptosis are involved in the systemic inflammatory response and contribute to regional myocardial I/R injury. This study aimed to explore the effect of necrosulfonamide (NSA) on post-resuscitation myocardial dysfunction in a rat model of cardiac arrest. Sprague-Dawley rats were randomly categorized to Sham, CPR and CPR-NSA groups. For rats in the latter two groups, ventricular fibrillation was induced without treatment for 6 min, with cardiopulmonary resuscitation (CPR) being sustained for 8 min. Rats were injected with NSA (10 mg/kg in DMSO) or vehicle at 5 min following return of spontaneous circulation. Myocardial function was measured by echocardiography, survival and neurological deficit score (NDS) were recorded at 24, 48, and 72 h after ROSC. Western blotting was used to assess pyroptosis- and necroptosis-related protein expression. ELISAs were used to measure levels of inflammatory cytokine. Rats in the CPR-NSA group were found to exhibit superior post-resuscitation myocardial function, and better NDS values in the group of CPR-NSA. Rats in the group of CPR-NSA exhibited median survival duration of 68 ± 8 h as compared to 34 ± 21 h in the CPR group. After treatment with NSA, NOD-like receptor 3 (NLRP3), GSDMD-N, phosphorylated-MLKL, and phosphorylated-RIP3 levels in cardiac tissue were reduced with corresponding reductions in inflammatory cytokine levels. Administration of NSA significantly improved myocardial dysfunction succeeding global myocardial I/R injury and enhanced survival outcomes through protective mechanisms potentially related to inhibition of pyroptosis and necroptosis pathways.

Electroacupuncture attenuates brain injury through α7 nicotinic acetylcholine receptor-mediated suppression of neuroinflammation in a rat model of asphyxial cardiac arrest

We determined whether electroacupuncture (EA) ameliorated brain injury following asphyxial cardiac arrest (CA) and evaluated the role of the α7 nicotinic acetylcholine receptor (α7nAChR)-mediated anti-inflammatory pathway. In CA-induced rats, EA reduced brain injury and promoted behavioral recovery. Morris water maze escape latency time reduced after Baihui (GV20) and Shuigou (DU26) stimulation. EA reduced α7nAChR downregulation after cardiopulmonary resuscitation (CPR), reducing tumor necrosis factor alpha, interleukin-1, and interleukin-6 expression and ionized calcium binding adapter molecule 1 production. The α7nAChR antagonist methyllycaconitine reversed EA effect. EA stimulation of acupuncture points alleviated brain damage after CPR and reduced the inflammatory response via α7nAChR activation.

Hydrogen therapy after resuscitation improves myocardial injury involving inhibition of autophagy in an asphyxial rat model of cardiac arrest

Hydrogen (H2) therapy is a therapeutic strategy using molecular H2. Due to its ability to regulate cell homeostasis, H2 therapy has exhibited marked therapeutic effects on a number of oxidative stress-associated diseases. The present study investigated the effectiveness of H2 therapy in protecting against myocardial injury in a rat model of asphyxial cardiac arrest and cardiopulmonary resuscitation. Rats underwent 10-min asphyxia-induced cardiac arrest (CA) and cardiopulmonary resuscitation (CPR), and were randomly divided into control and H2 therapy groups. After resuscitation, the H2 therapy group was administered room air mixed with 2% H2 gas for respiration. During CA/CPR, the arterial pressure and heart rate were measured every minute. Survival rate, cardiac function, myocardial injury biomarkers creatine kinase-MB and cardiac troponin-T, and histopathological changes were evaluated to determine the protective effects of H2 therapy in CA/CPR. Immunohistochemistry and western blot analysis were used to determine the expression levels of autophagy-associated proteins. In vitro, H9C2 cells were subjected to hypoxia/reoxygenation and H2-rich medium was used in H2 treatment groups. Western blotting and immunofluorescence were used to observe the expression levels of autophagy-associated proteins. Moreover, an adenovirus-monomeric red fluorescent protein-green fluorescent protein-LC3 construct was used to explore the dynamics of autophagy in the H9C2 cells. The results showed that H2 therapy significantly improved post-resuscitation survival and cardiac function. H2 therapy also improved mitochondrial mass and decreased autophagosome numbers in cardiomyocytes after resuscitation. The treatment inhibited autophagy activation, with lower expression levels of autophagy-associated proteins and decreased autophagosome formation in vivo and vitro. In conclusion, H2 gas inhalation after return of spontaneous circulation improved cardiac function via the inhibition of autophagy.

Effects of Different Hypothermia on the Results of Cardiopulmonary Resuscitation in a Cardiac Arrest Rat Model.

Objective To investigate the optimal temperature of hypothermia treatment in rats with cardiac arrest caused by ventricular fibrillation (VF) after the return of spontaneous circulation (ROSC). Methods A total of forty-eight male Sprague-Dawley rats were induced by VF through the guidewire with a maximum of 5 mA current and untreated for 8 min. Cardiopulmonary resuscitation (CPR) was performed for 8 min followed by defibrillation (DF). Resuscitated rats were then randomized into the normothermia (37°C) group, milder (35°C) group, mild (33°C) group, or moderate (28°C) group. Hypothermia was immediately induced with surface cooling. The target temperature was maintained for 4 h before rewarming to 37 ± 0.5°C. Moreover, at the end of the 4 h, a rat in each group was randomly selected to be sacrificed for the cerebral cortex electron microscopy observation (n = 1). The other resuscitated animals were observed for up to 72 h after ROSC (n = 7). Left ventricular ejection fraction (LVEF) and left ventricular end diastolic volume (LVEDV) were measured. Survival time, survival rate, and neurological deficit score (NDS) were recorded for 72 h. Results During hypothermia, higher LVEF was observed in the hypothermia groups when compared with normothermia group (35°C vs. 37°C, p < 0.05, 33°C and 28°C vs. 37°C, p < 0.01). Among the hypothermia groups, LVEF was higher in the 28°C group than that of 35°C (p < 0.05). However, both the heart rate (HR) (p < 0.01) and LVEDV (28°C vs. 35°C, p < 0.01, 28°C vs. 37°C and 33°C, p < 0.05) were lowest in the 28°C group when compared with the other groups. There were no significant differences of LVEF and LVEDV between the group 35°C and 33°C (p > 0.05). After rewarming, the LVEF of 35°C group was higher than that of group 37°C, 33°C, and 28°C (35°C vs. 37°C and 28°C, p < 0.01, 35°C vs. 33°C, p < 0.05). Group 35°C and 33°C resulted in longer survival (p < 0.01), higher survival rate (p < 0.01), and lower NDS (35°C vs. 37°C and 28°C, p < 0.01, 33°C vs. 37°C and 28°C, p < 0.05) compared with the group 37°C and 28°C. The extent of damage to cerebral cortex cells in group of 35°C and 33°C was lighter than that in group of 37°C and 28°C. The 35°C group spent less time in the process of cooling and rewarming than the group 33°C and 28°C (p < 0.01). Conclusions An almost equal protective effect of milder hypothermia (35°C) and mild hypothermia (33°C) in cardiac arrest (CA) rats was achieved with more predominant effect than moderate hypothermia (28°C) and normothermia (37°C). More importantly, shorter time spent in cooling and rewarming was required in the 35°C group, indicating its potential clinical application. These findings support the possible use of milder hypothermia (35°C) as a therapeutic agent for postresuscitation.

Carbon monoxide-releasing molecule-2 protects intestinal mucosal barrier function by reducing epithelial tight-junction damage in rats undergoing cardiopulmonary resuscitation

BackgroundIschemia-reperfusion injury (IRI) to the small intestine is associated with the development of systemic inflammation and multiple organ failure after cardiopulmonary resuscitation (CPR). It has been reported that exogenous carbon monoxide (CO) reduces IRI. This study aimed to assess the effects of carbon monoxide-releasing molecule-2 (CORM-2) on intestinal mucosal barrier function in rats undergoing CPR. MethodsWe established a rat model of asphyxiation-induced cardiac arrest (CA) and resuscitation to study intestinal IRI, and measured the serum levels of intestinal fatty acid-binding protein. Morphological changes were investigated using light and electron microscopes. The expression levels of claudin 3 (CLDN3), occludin (OCLN), zonula occludens 1 (ZO-1), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), and nuclear factor kappa B (NF-κB) p65 were detected by western blotting. ResultsCompared with the sham-operated group, histological changes and transmission electron microscopy revealed severe intestinal mucosal injury in the CPR and inactive CORM-2 (iCORM-2) groups. In contrast, CORM-2 alleviated intestinal IRI. CORM-2, unlike iCORM-2, markedly decreased the Chiu's scores (2.38 ± 0.38 vs. 4.59 ± 0.34; P < 0.05) and serum intestinal fatty acid-binding protein level (306.10 ± 19.22 vs. 585.64 ± 119.84 pg/mL; P < 0.05) compared with the CPR group. In addition, CORM-2 upregulated the expression levels of tight junction proteins (CLDN3, OCLN, and ZO-1) (P < 0.05) and downregulated those of IL-10, TNF-α, and NF-кB p65 (P < 0.05) in the ileum tissue of rats that received CPR. ConclusionsCORM-2 prevented intestinal mucosal damage as a result of IRI during CPR. The underlying protective mechanism was associated with inhibition of ischemia-reperfusion-induced changes in intestinal epithelial permeability and inflammation in intestinal tissue.

Preserving Brain LPC-DHA by Plasma Supplementation Attenuates Brain Injury after Cardiac Arrest.

Cardiac arrest (CA) is a major health burden with brain damage being a significant contributor to mortality. We found lysophosphatidylcholine (LPC), including a species containing docosahexaenoic acid (LPC-DHA), was significantly decreased in plasma post-CA, supplementation of which significantly improved neurological outcomes. The aim of this study is to understand the protective role of LPC-DHA supplementation on the brain post-CA. We first evaluated associations between the plasma level of LPC-DHA and neurological injury and outcomes of human patients with CA. We then utilized a rat CA model and cell cultures to investigate therapeutic and mechanistic aspects of plasma LPC-DHA supplementation. We found that decreased plasma LPC-DHA was strongly associated with neurological outcomes and disappearance of the difference between gray and white matter in the brain after CA in human patients. In rats, the decreased plasma LPC-DHA was associated with decreased levels of brain LPC-DHA after CA, and supplementing plasma LPC-DHA normalized brain levels of LPC-DHA and alleviated neuronal cell death, activation of astrocytes, and expression of various inflammatory and mitochondrial dynamics genes. We also observed deceased severity of metabolic alterations with LPC-DHA supplementation using untargeted metabolomics analysis. Furthermore, LPC treatment showed a similar protective effect for neurons and astrocytes in mixed primary brain cell cultures. The observed neuroprotection accompanied with normalized brain LPC-DHA level by plasma supplementation implicate the importance of preventing the decrease of brain LPC-DHA post-CA for attenuating brain injury. Furthermore, the data supports the causative role of decreased plasma LPC-DHA for brain damage after CA. ANN NEUROL 2022;91:389-403.

Rapid Treatment with Intramuscular Magnesium Sulfate During Cardiopulmonary Resuscitation Does Not Provide Neuroprotection Following Cardiac Arrest.

Brain injury is the most common cause of death for patients resuscitated from cardiac arrest. Magnesium is an attractive neuroprotective compound which protects neurons from ischemic injury by reducing neuronal calcium overload via NMDA receptor modulation and preventing calcium-induced mitochondrial permeability transition. Intramuscular (IM) delivery of MgSO4 during CPR has the potential to target these mechanisms within an early therapeutic window. We hypothesize that IM MgSO4 administrated during CPR could achieve therapeutic serum magnesium levels within 15min after ROSC and improve neurologic outcomes in a rat model of asphyxial cardiac arrest. Male Long Evans rats were subjected to 8-min asphyxial cardiac arrest and block randomized to receive placebo, 107mg/kg, 215mg/kg, or 430mg/kg MgSO4 IM at the onset of CPR. Serum magnesium concentrations increased rapidly with IM delivery during CPR, achieving twofold to fourfold increase by 15min after ROSC in all magnesium dose groups. Rats subjected to cardiac arrest or sham surgery were block randomized to treatment groups for assessment of neurological outcomes. We found that IM MgSO4 during CPR had no effect on ROSC rate (p > 0.05). IM MgSO4 treatment had no statistically significant effect on 10-day survival with good neurologic function or hippocampal CA1 pyramidal neuron survival compared to placebo treatment. In conclusion, a single dose IM MgSO4 during CPR achieves up to fourfold baseline serum magnesium levels within 15min after ROSC; however, this treatment strategy did not improve survival, recovery of neurologic function, or neuron survival. Future studies with repeated dosing or in combination with hypothermic targeted temperature management may be indicated.

The Selective NLRP3-inflammasome inhibitor MCC950 Mitigates Post-resuscitation Myocardial Dysfunction and Improves Survival in a Rat Model of Cardiac Arrest and Resuscitation

PurposeTo investigate the effects of the selective NLRP3 inflammasome inhibitor MCC950 on post-resuscitation myocardial function and survival in a rat model of cardiopulmonary resuscitation (CPR).MethodsThirty-six Sprague Dawley rats were randomized into three groups: (1) MCC950, (2) control, and (3) sham. Each group consisted of a 6 h non-survival subgroup (n = 6) and a 48 h survival subgroup (n = 6). Ventricular fibrillation (VF) was induced and untreated for 6 min. CPR was initiated and continued for 8 min. Resuscitation was attempted with a 4 J defibrillation. MCC950 (10 mg/kg) or vehicle was administered via intraperitoneal injection immediately after the return of spontaneous circulation (ROSC). Myocardial function and sublingual microcirculation were measured after ROSC in the non-survival subgroups. Plasma levels of interleukin Iβ (IL-1β) and cardiac troponin I (cTnI) were measured at baseline and 6 h in the non-survival subgroups. Heart tissue was harvested to measure the NLRP3 inflammasome constituents, including NLRP3, apoptosis-associated speck-like protein (ASC), Caspase-1, and IL-1β. Survival duration and neurologic deficit score (NDS) were recorded and evaluated among survival groups.ResultsPost-resuscitation myocardial function and sublingual microcirculation were improved in MCC950 compared with control (p < 0.05). IL-1β and cTnI were decreased in MCC950 compared to control (p < 0.01). The MCC950 treated groups showed significantly reduced ASC, caspase-1, and IL-1β compared with the control group (p < 0.05). Survival at 48 h after ROSC was greater in MCC950 (p < 0.05) with improved NDS (p < 0.05).ConclusionAdministration of MCC950 following ROSC mitigates post-resuscitation myocardial dysfunction and improves survival.

Histopathology and Tumor Necrosis Factor-α Expression in The Kidney of an Asphyxial Cardiac Arrest Rat Model

Histopathology and Tumor Necrosis Factor-α Expression in The Kidney of an Asphyxial Cardiac Arrest Rat Model

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.

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.

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

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.

Retraction of: Abstract 03: High-Dose Intranasal Insulin During CPR Improves Neurological Outcomes in a Rat Model of Cardiac Arrest

Retraction of: Abstract 03: High-Dose Intranasal Insulin During CPR Improves Neurological Outcomes in a Rat Model of Cardiac Arrest

Effect of therapeutic hypothermia against renal injury in a rat model of asphyxial cardiac arrest: Α focus on the survival rate, pathophysiology and antioxidant enzymes.

Although multi-organ dysfunction is associated with the survival rate following cardiac arrest (CA), the majority of studies to date have focused on hearts and brains, and few studies have considered renal failure. The objective of the present study, therefore, was to examine the effects of therapeutic hypothermia on the survival rate, pathophysiology and antioxidant enzymes in rat kidneys following asphyxial CA. Rats were sacrificed one day following CA. The survival rate, which was estimated using Kaplan-Meier analysis, was 42.9% one day following CA. However, hypothermia, which was induced following CA, significantly increased the survival rate (71.4%). In normothermia rats with CA, the serum blood urea nitrogen level was significantly increased one day post-CA. In addition, the serum creatinine level was significantly increased one day post-CA. However, in CA rats exposed to hypothermia, the levels of urea nitrogen and creatinine significantly decreased following CA. Histochemical staining revealed a significant temporal increase in renal injury after the normothermia group was subjected to CA. However, renal injury was significantly decreased in the hypothermia group. Immunohistochemical analysis of the kidney revealed a significant decrease in antioxidant enzymes (copper-zinc superoxide dismutase, manganese superoxide dismutase, glutathione peroxidase and catalase) with time in the normothermia group. However, in the hypothermia group, these enzymes were significantly elevated following CA. Collectively, the results revealed that renal dysfunction following asphyxial CA was strongly associated with the early survival rate and therapeutic hypothermia reduced renal injury via effective antioxidant mechanisms.