scholarly journals Featured Article: Pyruvate preserves antiglycation defenses in porcine brain after cardiac arrest

2017 ◽  
Vol 242 (10) ◽  
pp. 1095-1103 ◽  
Author(s):  
Gary F Scott ◽  
Anh Q Nguyen ◽  
Brandon H Cherry ◽  
Roger A Hollrah ◽  
Isabella Salinas ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Glutathione Reductase ◽  
Ischemia Reperfusion ◽  
Protein Glycation ◽  
Carbonyl Stress ◽  
Swine Model ◽  
Glyoxalase 1 ◽  
Cardiocerebral Resuscitation ◽  
The Impact ◽  
The Brain

Cardiac arrest (CA) and cardiocerebral resuscitation (CCR)-induced ischemia–reperfusion imposes oxidative and carbonyl stress that injures the brain. The ischemic shift to anaerobic glycolysis, combined with oxyradical inactivation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), provokes excessive formation of the powerful glycating agent, methylglyoxal. The glyoxalase (GLO) system, comprising the enzymes glyoxalase 1 (GLO1) and GLO2, utilizes reduced glutathione (GSH) supplied by glutathione reductase (GR) to detoxify methylglyoxal resulting in reduced protein glycation. Pyruvate, a natural antioxidant that augments GSH redox status, could sustain the GLO system in the face of ischemia–reperfusion. This study assessed the impact of CA-CCR on the cerebral GLO system and pyruvate’s ability to preserve this neuroprotective system following CA. Domestic swine were subjected to 10 min CA, 4 min closed-chest CCR, defibrillation and 4 h recovery, or to a non-CA sham protocol. Sodium pyruvate or NaCl control was infused (0.1 mmol/kg/min, intravenous) throughout CCR and the first 60 min recovery. Protein glycation, GLO1 content, and activities of GLO1, GR, and GAPDH were analyzed in frontal cortex biopsied at 4 h recovery. CA-CCR produced marked protein glycation which was attenuated by pyruvate treatment. GLO1, GR, and GAPDH activities fell by 86, 55, and 30%, respectively, after CA-CCR with NaCl infusion. Pyruvate prevented inactivation of all three enzymes. CA-CCR sharply lowered GLO1 monomer content with commensurate formation of higher molecular weight immunoreactivity; pyruvate preserved GLO1 monomers. Thus, ischemia–reperfusion imposed by CA-CCR disabled the brain’s antiglycation defenses. Pyruvate preserved these enzyme systems that protect the brain from glycation stress. Impact statement Recent studies have demonstrated a pivotal role of protein glycation in brain injury. Methylglyoxal, a by-product of glycolysis and a powerful glycating agent in brain, is detoxified by the glutathione-catalyzed glyoxalase (GLO) system, but the impact of cardiac arrest (CA) and cardiocerebral resuscitation (CCR) on the brain’s antiglycation defenses is unknown. This study in a swine model of CA and CCR demonstrated for the first time that the intense cerebral ischemia–reperfusion imposed by CA-resuscitation disabled glyoxalase-1 and glutathione reductase (GR), the source of glutathione for methylglyoxal detoxification. Moreover, intravenous administration of pyruvate, a redox-active intermediary metabolite and antioxidant in brain, prevented inactivation of glyoxalase-1 and GR and blunted protein glycation in cerebral cortex. These findings in a large mammal are first evidence of GLO inactivation and the resultant cerebral protein glycation after CA-resuscitation, and identify novel actions of pyruvate to minimize protein glycation in postischemic brain.

Abstract 273: Noninvasive Mitochondrial Modulation: Neuroprotection in a Translational Model of Cardiac Arrest and Resuscitation

Circulation ◽  
2019 ◽  
Vol 140 (Suppl_2) ◽  
Author(s):  
Joseph M Wider ◽  
Erin Gruley ◽  
Jennifer Mathieu ◽  
Emma Murphy ◽  
Rachel Mount ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Brain Injury ◽  
Near Infrared ◽  
Small Animal ◽  
Spontaneous Circulation ◽  
Infrared Light ◽  
Swine Model ◽  
Treatment Groups ◽  
The Brain ◽  
Neuroprotective Therapies

Background: Mitochondrial dysfunction contributes to cardiac arrest induced brain injury and has been a target for neuroprotective therapies. An emerging concept suggests that hyperactivation of neuronal mitochondria following resuscitation results in hyperpolarization of the mitochondrial membrane during reperfusion, which drives generation of excess reactive oxygen species. Previous studies from our group demonstrated that limiting mitochondrial hyperactivity by non-invasively modulating mitochondrial function with specific near infrared light (NIR) wavelengths can reduce brain injury in small animal models of global and focal ischemia. Hypothesis: Inhibitory wavelengths of NIR will reduce neuronal injury and improve neurocognitive outcome in a clinically relevant swine model of cardiac arrest. Methods: Twenty-eight male and female adult swine were enrolled (3 groups: Sham, CA/CPR, and CA/CPR + NIR). Cardiac arrest (8 minutes) was induced with a ventricular pacing wire and followed by manual CPR with defibrillation and epinephrine every 30 seconds until return of spontaneous circulation (ROSC), 2 of the 20 swine that underwent CA did not achieve ROSC and were not enrolled. Treatment groups were randomized prior to arrest and blinded to the CPR team. Treatment was applied at onset of ROSC by irradiating the scalp with 750 nm and 950 nm LEDs (5W) for 2 hours. Results: Sham-operated animals all survived (8/8), whereas 22% of untreated animals subjected to cardiac arrest died within 45 min of ROSC (CA/CPR, n= 7/9). All swine treated with NIR survived the duration of the study (CA/CPR + NIR, n=9/9). Four days following cardiac arrest, neurological deficit score was improved in the NIR treatment group (50 ± 21 CA/CPR vs. 0.8 ± 0.8 CA/CPR + NIR, p < 0.05). Additionally, neuronal death in the CA1/CA3 regions of the hippocampus, assessed by counting surviving neurons with stereology, was attenuated by treatment with NIR (17917 ± 5534 neurons/mm 3 CA/CPR vs. 44655 ± 5637 neurons/mm 3 CA/CPR + NIR, p < 0.05). All data is reported as mean ± SEM. Conclusions: These data provide evidence that noninvasive modulation of mitochondria, achieved by transcranial irradiation of the brain with NIR, mitigates post-cardiac arrest brain injury.

Abstract P790: Landiolol Attenuates Global Cerebral Edema Following Experimental Cardiac Arrest in Mice

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Tomoyuki Iwai ◽  
Shin Nakayama
Keyword(s):  
Cardiac Arrest ◽  
Water Content ◽  
Cerebral Edema ◽  
Ischemia Reperfusion ◽  
Control Group ◽  
P Value ◽  
Brain Water Content ◽  
Arterial Blood ◽  
The Brain ◽  
Brain Water

Introduction: Cerebral edema following cardiac arrest and cardiopulmonary resuscitation (CA/CPR) is associated with unfavorable neurologic outcome. The Na + -K + -2Cl - water cotransporter NKCC1 is suspected to be a critical mediator of edema formation after ischemia. It is reported that β1 adrenoreceptor antagonists protect neurons following brain ischemia in rodents. β1 adrenoreceptor antagonists inhibit the Na + -K + -ATPase, which can inhibit driving force of NKCC1 that theoretically reduces cerebral edema following ischemia-reperfusion injury. In this study, we examined whether landiolol, a selective β1 adrenoreceptor antagonist, attenuates cerebral edema following CA/CPR. Methods: Isoflurane-anesthetized adult male mice (C57BL/6J, 25-30g) were randomized into landiolol group or control group. After 7-min CA followed by CPR, landiolol (0.5ml, 830μg/ml) was administered by continuous infusion intravenously for 4 hours. Animals in control group were given normal saline (0.5ml) in the same manner. Twenty-four hours after CA/CPR, the brain was removed to assess brain water content using wet-to-dry method. The primary outcome was measurement of the brain water content. Heart rate and arterial blood pressure were recorded. Measured parameters were analyzed by one-way ANOVA with post hoc Tukey-Kramer test using SPSS® statistics 25. Differences were considered statistically significant at a P value < 0.05. Results: Brain water contents was increased in control group mice after CA/CPR (n=10) compared with those in sham operated mice (n=5) (79.5±0.85% vs 78.3±0.14%, P=0.003). Compared with control group, landiolol treatment significantly reduced brain water content in mice subjected to CA/CPR (n=12) (78.9±0.51% vs 79.5±0.85%, P=0.04). Conclusion: Landiolol attenuated brain edema following CA/CPR. These results may suggest selective β1-blocker could be alternative treatment for neuroprotection in patients who suffered CA/CPR.

Abstract 328: Hemodynamic Comparison of Zucker Diabetic Fatty Rats to Their Lean Littermates After Asphyxial Cardiac Arrest

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Claudius Balzer ◽  
Franz Baudenbacher ◽  
Michele M Salzman ◽  
William J Cleveland ◽  
Susan Eagle ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Cardiac Arrest ◽  
Ejection Fraction ◽  
Ischemia Reperfusion ◽  
Diabetic Rats ◽  
Arterial Blood ◽  
Zucker Diabetic Fatty Rats ◽  
Zdf Rats ◽  
The Impact

Patients with metabolic syndrome are at higher risk for cardiac arrest (CA), and also have worse neurologic outcome after CA related to their comorbidities (e.g., Type 2 Diabetes Mellitus [T2DM]). Using Zucker Diabetic Fatty (ZDF) rats as a new and relevant model with common comorbidities for CA and cardiopulmonary resuscitation (CPR), we hypothesized that T2DM is associated with a lower chance for return of spontaneous circulation (ROSC) and/or a worse outcome regarding heart function after asphyxial CA compared to their lean littermates. Two groups of rats (8 ZDF, 7 lean) were monitored for 37±2 weeks. The rats were anesthetized and intubated; heart rate was monitored by subcutaneous ECG needles. Femoral artery and vein were cannulated for continuous blood pressure measurement and delivery of fluids and medications, respectively. Before ventilation was stopped to initiate asphyxial CA, rocuronium was given. After 8 minutes of CA, ventilation was re-initiated with FiO 2 1.0, epinephrine and sodium-bicarbonate were administered, and pneumatic chest compression were started with 200 compressions per minute. Chest compressions were stopped when a systolic blood pressure of 120 mmHg was achieved. During 4 hours of observation, vital parameters were closely monitored, blood gases were measured, and ejection fraction (EF %) was assessed with ultrasound. Data are mean ± SD. Statistics: Unpaired student’s t-test (two-tailed), α.05. At baseline, ZDF rats showed significantly higher blood glucose levels (504±52 vs 174±14 mg/dl) compared to their lean littermates. All ZDF and lean rats achieved ROSC, and measurements taken directly after ROSC and after the first hour showed no relevant differences. After four hours, there was no difference in heart rate between ZDF and lean rats. However, diabetic rats had a significantly higher mean arterial blood pressure (142±24vs. 107±19 mmHg) and ejection fraction (42±16%vs 20±8%) compared to their lean littermates. The hypothesis that ROSC-rate in diabetic rats would be lower could not be proven. Conversely, the ZDF rats showed a significantly higher blood pressure related to an increased EF%. Further analysis in this study will focus on the impact of T2DM on cardiac and neurological ischemia-reperfusion injury.

scholarly journals The Responses of Tissues from the Brain, Heart, Kidney, and Liver to Resuscitation following Prolonged Cardiac Arrest by Examining Mitochondrial Respiration in Rats

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Junhwan Kim ◽  
José Paul Perales Villarroel ◽  
Wei Zhang ◽  
Tai Yin ◽  
Koichiro Shinozaki ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Mitochondrial Respiration ◽  
Ischemia Reperfusion ◽  
Liver Mitochondria ◽  
Brain Mitochondria ◽  
Heart Mitochondria ◽  
Whole Body ◽  
Sprague Dawley ◽  
Respiration Activity ◽  
The Brain

Cardiac arrest induces whole-body ischemia, which causes damage to multiple organs. Understanding how each organ responds to ischemia/reperfusion is important to develop better resuscitation strategies. Because direct measurement of organ function is not practicable in most animal models, we attempt to use mitochondrial respiration to test efficacy of resuscitation on the brain, heart, kidney, and liver following prolonged cardiac arrest. Male Sprague-Dawley rats are subjected to asphyxia-induced cardiac arrest for 30 min or 45 min, or 30 min cardiac arrest followed by 60 min cardiopulmonary bypass resuscitation. Mitochondria are isolated from brain, heart, kidney, and liver tissues and examined for respiration activity. Following cardiac arrest, a time-dependent decrease in state-3 respiration is observed in mitochondria from all four tissues. Following 60 min resuscitation, the respiration activity of brain mitochondria varies greatly in different animals. The activity after resuscitation remains the same in heart mitochondria and significantly increases in kidney and liver mitochondria. The result shows that inhibition of state-3 respiration is a good marker to evaluate the efficacy of resuscitation for each organ. The resulting state-3 respiration of brain and heart mitochondria following resuscitation reenforces the need for developing better strategies to resuscitate these critical organs following prolonged cardiac arrest.

Abstract 296: Adult Swine Model of Ventricular Fibrillation Arrest for Resuscitation with Perfluorocarbon Emulsions

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_4) ◽  
Author(s):  
Travis W Murphy ◽  
Jiepei Zhu ◽  
Travis Parsons ◽  
Bruce D Spiess ◽  
Torben K Becker
Keyword(s):  
Cardiac Arrest ◽  
Ventricular Fibrillation ◽  
Minimally Invasive ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Circulatory Arrest ◽  
Spontaneous Circulation ◽  
Blood Levels ◽  
Swine Model ◽  
Initial Attempt

Background: The purpose of this study was to develop a model of ventricular fibrillation arrest with reliable outcomes and minimally invasive methods to study the use of perfluorocarbon emulsions (PFC) as agents to prevent ischemia-reperfusion injury after cardiac arrest as quantified by known biomarkers. Methods: Female Yorkshire swine underwent anesthesia and minimally invasive instrumentation for monitoring under ultrasound. Cardiac arrest was induced with spinal needle insertion at the apex and right parasternal space. Ventricular fibrillation was reliably obtained in all animals on initial attempts. A three-minute circulatory arrest state was observed. Administration of PFC was concurrent with resuscitation including closed chest compressions, epinephrine, amiodarone, and defibrillation at 1J/kg. Primary endpoint was induction of cardiac arrest and tolerance of PFC with return of spontaneous circulation. Blood levels of glial fibrillary acidic protein (GFAP) and ubiquitin C-Terminal Hydrolase-L1 (UCLH1) were secondary end points for three animals. Results: Six of six animals were induced into ventricular fibrillation on initial attempt and two of three survival experiments were able to obtain spontaneous circulation. PFC with pretreatment was tolerated well and no signs of increased pulmonary pressures. GFAP, UCHL1 were significantly lower in intervention animals compared to controls. Conclusions: The results obtained from this preliminary study and technical refinements via additional donated animals have allowed us to make modifications in the choice of PFC, vascular access, and anticoagulation plan. This model provides a consistent method for inducing ventricular fibrillation with minimally invasive techniques. The PFC tested was well tolerated. More robust evaluation of PFC as resuscitative agents is needed with appropriately powered studies.

scholarly journals Forebrain Ischemia-Reperfusion Simulating Cardiac Arrest in Mice Induces Edema and DNA Fragmentation in the Brain

2007 ◽  
Vol 6 (3) ◽  
pp. 7290.2007.00011 ◽  
Author(s):  
Christina H. Liu ◽  
Shuning Huang ◽  
Young R. Kim ◽  
Bruce R. Rosen ◽  
Philip K. Liu
Keyword(s):  
Cardiac Arrest ◽  
Dna Fragmentation ◽  
Ischemia Reperfusion ◽  
Forebrain Ischemia ◽  
The Brain

scholarly journals Activation of the ATF6 (Activating Transcription Factor 6) Signaling Pathway in Neurons Improves Outcome After Cardiac Arrest in Mice

2021 ◽  
Author(s):  
Yuntian Shen ◽  
Ran Li ◽  
Shu Yu ◽  
Qiang Zhao ◽  
Zhuoran Wang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Cardiac Arrest ◽  
Cardiopulmonary Resuscitation ◽  
Short Form ◽  
Ischemia Reperfusion ◽  
Sequencing Analysis ◽  
Activating Transcription Factor ◽  
The Brain

Background Ischemia/reperfusion injury impairs proteostasis, and triggers adaptive cellular responses, such as the unfolded protein response (UPR), which functions to restore endoplasmic reticulum homeostasis. After cardiac arrest (CA) and resuscitation, the UPR is activated in various organs including the brain. However, the role of the UPR in CA has remained largely unknown. Here we aimed to investigate effects of activation of the ATF6 (activating transcription factor 6) UPR branch in CA. Methods and Results Conditional and inducible sATF6‐KI (short‐form ATF6 knock‐in) mice and a selective ATF6 pathway activator 147 were used. CA was induced in mice by KCl injection, followed by cardiopulmonary resuscitation. We first found that neurologic function was significantly improved, and neuronal damage was mitigated after the ATF6 pathway was activated in neurons of sATF6‐KI mice subjected to CA/cardiopulmonary resuscitation. Further RNA sequencing analysis indicated that such beneficial effects were likely attributable to increased expression of pro‐proteostatic genes regulated by ATF6. Especially, key components of the endoplasmic reticulum–associated degradation process, which clears potentially toxic unfolded/misfolded proteins in the endoplasmic reticulum, were upregulated in the sATF6‐KI brain. Accordingly, the CA‐induced increase in K48‐linked polyubiquitin in the brain was higher in sATF6‐KI mice relative to control mice. Finally, CA outcome, including the survival rate, was significantly improved in mice treated with compound 147. Conclusions This is the first experimental study to determine the role of the ATF6 UPR branch in CA outcome. Our data indicate that the ATF6 UPR branch is a prosurvival pathway and may be considered as a therapeutic target for CA.

scholarly journals Mild Hypothermia Inhibits Systemic and Cerebral Complement Activation in a Swine Model of Cardiac Arrest

2015 ◽  
Vol 35 (8) ◽  
pp. 1289-1295 ◽  
Author(s):  
Ping Gong ◽  
g Zhao ◽  
Rong Hua ◽  
Mingyue Zhang ◽  
Ziren Tang ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Complement Activation ◽  
Ischemia Reperfusion Injury ◽  
Mild Hypothermia ◽  
Ischemia Reperfusion ◽  
Spontaneous Circulation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Swine Model ◽  
Factor Α ◽  
Necrosis Factor

Complement activation has been implicated in ischemia/reperfusion injury. This study aimed to determine whether mild hypothermia (HT) inhibits systemic and cerebral complement activation after resuscitation from cardiac arrest. Sixteen minipigs resuscitated from 8 minutes of untreated ventricular fibrillation were randomized into two groups: HT group ( n = 8), treated with HT (33 °C) for 12 hours; and normothermia group ( n = 8), treated similarly as HT group except for cooling. Blood samples were collected at baseline and 0.5, 6, 12, and 24 hours after return of spontaneous circulation (ROSC). The brain cortex was harvested 24 hours after ROSC. Complement and pro-inflammatory markers were detected using enzyme-linked immunosorbent assay. Neurologic deficit scores were evaluated 24 hours after ROSC. C1q, Bb, mannose-binding lectin (MBL), C3b, C3a, C5a, interleukin-6, and tumor necrosis factor- α levels were significantly increased under normothermia within 24 hours after ROSC. However, these increases were significantly reduced by HT. Hypothermia decreased brain C1q, MBL, C3b, and C5a contents 24 hours after ROSC. Hypothermic pigs had a better neurologic outcome than normothermic pigs. In conclusion, complement is activated through classic, alternative, and MBL pathways after ROSC. Hypothermia inhibits systemic and cerebral complement activation, which may provide an additional mechanism of cerebral protection.

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