Dataset Information

Mild hypothermia improves neurological outcome in mice after cardiopulmonary resuscitation through Silent Information Regulator 1-actviated autophagy.

ABSTRACT: Mild hypothermia treatment (MHT) improves the neurological function of cardiac arrest (CA) patients, but the exact mechanisms of recovery remain unclear. Herein, we generated a CA and cardiopulmonary resuscitation (CPR) mouse model to elucidate such function. Naïve mice were randomly divided into two groups, a normothemia (NT) group, in which animals had normal body temperature, and a MHT group, in which animals had a body temperature of 33 °C (range: 32-34 °C), after the return of spontaneous circulation (ROSC), followed by CA/CPR. MHT significantly improved the survival rate of CA/CPR mice compared with NT. Mechanistically, MHT increased the expression of Silent Information Regulator 1 (Sirt1) and decreased P53 phosphorylation (p-P53) in the cortex of CA/CPR mice, which coincided with the elevated autophagic flux. However, Sirt1 deletion compromised the neuroprotection offered by MHT, indicating that Sirt1 plays an important role. Consistent with the observations obtained from in vivo work, our in vitro study utilizing cultured neurons subjected to oxygen/glucose deprivation and reperfusion (OGD/R) also indicated that Sirt1 knockdown increased OGD/R-induced neuron necrosis and apoptosis, which was accompanied by decreased autophagic flux and increased p-P53. However, the depletion of P53 did not suppress neuron death, suggesting that P53 was not critically involved in MHT-induced neuroprotection. In contrast, the application of autophagic inhibitor 3-methyladenine attenuated MHT-improved neuron survival after OGD/R, further demonstrating that increased autophagic flux significantly contributes to MHT-linked neuroprotection of CA/CRP mice. Our findings indicate that MHT improves neurological outcome of mice after CA/CPR through Sirt1-mediated activation of autophagic flux.

SUBMITTER: Wei H

PROVIDER: S-EPMC6690976 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Hypothermia preconditioning (HPC) improves cardiac function after cardiac arrest, yet the mechanism is unclear. We hypothesized that HPC-activated adenosine monophosphate-activated protein kinase (AMPK) activity may be involved. Adult male Wistar rats were randomly divided into normothermia Control, HPC (cooling to 32-34°C for 30 min), and HPC + Compound C (Compound C 10 mg/kg was injected intraperitoneally 30 min before HPC group). The rats underwent 7 min of untreated ventricular fibrillation (VF) followed by cardiopulmonary resuscitation (CPR). Cardiac function and hemodynamic parameters were evaluated at 4 h after return of spontaneous circulation (ROSC). Survival status was determined 72 h after ROSC. Mechanistically, we further examined the AMPK-Unc-51 Like Autophagy Activating Kinase 1 (ULK1)-mitophagy pathway and autophagic flux in vivo and in vitro. Six of twelve rats in the Control group, 10 of 12 rats in the HPC group, and 7 of 12 rats in HPC + Compound C group were successfully resuscitated. The 72-h survival rates were 1 of 12 Control, 6 of 12 HPC, and 2 of 12 HPC + Compound C rats, respectively (P = 0.043). Rats in the HPC group demonstrated greater cardiac contractility and hemodynamic stability which were compromised by Compound C. Furthermore, HPC increased the protein levels of p-AMPKα and p-ULK1 and promoted the expression of mitochondrial autophagy-related genes. Compound C decreased the expression of mitochondrial autophagy-related genes and reduced autophagic flux. Consistent with the observations obtained in vivo, in vitro experiments in cultured neonatal rat cardiomyocytes (CMs) demonstrated that HPC attenuated simulated ischemia-reperfusion-induced CM death, accompanied by increased AMPK-ULK1-mitophagy pathway activity. These findings suggest that AMPK-ULK1-mitophagy pathway was activated by HPC and has a crucial role in cardioprotection during cardiac arrest. Manipulation of mitophagy by hypothermia may merit further investigation as a novel strategy to prevent cardiac ischemia-reperfusion injury.

Project description:IntroductionMild therapeutic hypothermia (MTH) has been shown to result in better neurological outcome after cardiopulmonary resuscitation. Percutaneous coronary intervention (PCI) may also be beneficial in patients after out-of-hospital cardiac arrest (OHCA).MethodsA selected cohort study of 2,973 prospectively documented adult OHCA patients within the German Resuscitation Registry between 2004 and 2010. Data were analyzed by backwards stepwise binary logistic regression to identify the impact of MTH and PCI on both 24-hour survival and neurological outcome that was based on cerebral performance category (CPC) at hospital discharge. Odds ratios (95% confidence intervals) were calculated adjusted for the following confounding factors: age, location of cardiac arrest, presumed etiology, bystander cardiopulmonary resuscitation, witnessing, first electrocardiogram rhythm, and thrombolysis.ResultsThe Preclinical care dataset included 2,973 OHCA patients with 44% initial return of spontaneous circulation (n = 1,302) and 35% hospital admissions (n = 1,040). Seven hundred and eleven out of these 1,040 OHCA patients (68%) were also registered within the Postresuscitation care dataset. Checking for completeness of datasets required the exclusion of 127 Postresuscitation care cases, leaving 584 patients with complete data for final analysis. In patients without PCI (n = 430), MTH was associated with increased 24-hour survival (8.24 (4.24 to 16.0), P < 0.001) and the proportion of patients with CPC 1 or CPC 2 at hospital discharge (2.13 (1.17 to 3.90), P < 0.05) as an independent factor. In normothermic patients (n = 405), PCI was independently associated with increased 24-hour survival (4.46 (2.26 to 8.81), P < 0.001) and CPC 1 or CPC 2 (10.81 (5.86 to 19.93), P < 0.001). Additional analysis of all patients (n = 584) revealed that 24-hour survival was increased by MTH (7.50 (4.12 to 13.65), P < 0.001) and PCI (3.88 (2.11 to 7.13), P < 0.001), while the proportion of patients with CPC 1 or CPC 2 was significantly increased by PCI (5.66 (3.54 to 9.03), P < 0.001) but not by MTH (1.27 (0.79 to 2.03), P = 0.33), although an unadjusted Fisher exact test suggested a significant effect of MTH (unadjusted odds ratio 1.83 (1.23 to 2.74), P < 0.05).ConclusionsPCI may be an independent predictor for good neurological outcome (CPC 1 or CPC 2) at hospital discharge. MTH was associated with better neurological outcome, although subsequent logistic regression analysis did not show statistical significance for MTH as an independent predictor for good neurological outcome. Thus, postresuscitation care on the basis of standardized protocols including coronary intervention and hypothermia may be beneficial after successful resuscitation. One of the main limitations may be a selection bias for patients subjected to PCI and MTH.

Project description:BACKGROUND:The prognosis in refractory out-of-hospital cardiac arrest (OHCA) with ongoing cardiopulmonary resuscitation (CPR) at hospital arrival is often considered dismal. The use of extracorporeal cardiopulmonary resuscitation (eCPR) for perfusion enhancement during resuscitation has shown variable results. We aimed to investigate outcome in refractory OHCA patients managed conservatively without use of eCPR. METHODS:We included consecutive OHCA patients with refractory arrest or prehospital return of spontaneous circulation (ROSC) in the Copenhagen area in 2002-2011. RESULTS:A total of 3992 OHCA patients with resuscitation attempts were included; in 2599, treatment was terminated prehospital, and 1393 (35%) were brought to the hospital either with ROSC (n?=?1285, 92%) or with refractory OHCA (n?=?108, 8%). Of patients brought in with refractory OHCA, 56 (52%) achieved ROSC in the emergency department. There were no differences between patients with refractory OHCA or prehospital ROSC with regard to age, sex, comorbidities, or etiology of OHCA. Time to emergency medical services (EMS) arrival was similar, whereas time to ROSC (when ROSC was achieved) was longer in refractory OHCA patients (EMS, 6 (5-9] vs. 7 [5-10] min, p?=?0.8; ROSC, 15 [9-22] vs. 27 [20-41] min, p?<?0.001). Independent factors associated with transport with refractory OHCA instead of prehospital termination of therapy were OHCA in public (OR, 3.6 [95% CI, 2.2-5.8]; p?<?0.001), witnessed OHCA (OR, 3.7 [2.0-7.1]; p?<?0.001), shockable rhythm (OR, 3.0 [1.9-4.7]; p?<?0.001), younger age (OR, 1.2 [1.1-1.2]; p?<?0.001), and later calendar year (OR, 1.4 [1.2-1.6]; p?<?0.001). Thirty-day survival was 20% in patients with refractory OHCA compared with 42% in patients with prehospital ROSC (p?<?0.001). Four of 28 refractory OHCA patients with duration of resuscitation >?60 min achieved ROSC. No difference in favorable neurological outcome in patients surviving to discharge was found (prehospital ROSC 84% vs. refractory OHCA 86%; p?=?0.7). CONCLUSIONS:Survival after refractory OHCA with ongoing CPR at hospital arrival was significantly lower than among patients with prehospital ROSC. Despite a lower survival, the majority of survivors with both refractory OHCA and prehospital ROSC were discharged with a similar degree of favorable neurological outcome, indicating that continued efforts in spite of refractory OHCA are not in vain and may still lead to favorable outcome even without eCPR.

Project description:IntroductionHypothermia improves survival and neurological recovery after cardiac arrest. Pro-inflammatory cytokines have been implicated in focal cerebral ischemia/reperfusion injury. It is unknown whether cardiac arrest also triggers the release of cerebral inflammatory molecules, and whether therapeutic hypothermia alters this inflammatory response. This study sought to examine whether hypothermia or the combination of hypothermia with anesthetic post-conditioning with sevoflurane affect cerebral inflammatory response after cardiopulmonary resuscitation.MethodsThirty pigs (28 to 34 kg) were subjected to cardiac arrest following temporary coronary artery occlusion. After seven minutes of ventricular fibrillation and two minutes of basic life support, advanced cardiac life support was started according to the current American Heart Association guidelines. Return of spontaneous circulation was achieved in 21 animals who were randomized to either normothermia at 38 degrees C, hypothermia at 33 degrees C or hypothermia at 33 degrees C combined with sevoflurane (each group: n = 7) for 24 hours. The effects of hypothermia and the combination of hypothermia with sevoflurane on cerebral inflammatory response after cardiopulmonary resuscitation were studied using tissue samples from the cerebral cortex of pigs euthanized after 24 hours and employing quantitative RT-PCR and ELISA techniques.ResultsGlobal cerebral ischemia following resuscitation resulted in significant upregulation of cerebral tissue inflammatory cytokine mRNA expression (mean +/- SD; interleukin (IL)-1beta 8.7 +/- 4.0, IL-6 4.3 +/- 2.6, IL-10 2.5 +/- 1.6, tumor necrosis factor (TNF)alpha 2.8 +/- 1.8, intercellular adhesion molecule-1 (ICAM-1) 4.0 +/- 1.9-fold compared with sham control) and IL-1beta protein concentration (1.9 +/- 0.6-fold compared with sham control). Hypothermia was associated with a significant (P < 0.05 versus normothermia) reduction in cerebral inflammatory cytokine mRNA expression (IL-1beta 1.7 +/- 1.0, IL-6 2.2 +/- 1.1, IL-10 0.8 +/- 0.4, TNFalpha 1.1 +/- 0.6, ICAM-1 1.9 +/- 0.7-fold compared with sham control). These results were also confirmed for IL-1beta on protein level. Experimental settings employing hypothermia in combination with sevoflurane showed that the volatile anesthetic did not confer additional anti-inflammatory effects compared with hypothermia alone.ConclusionsMild therapeutic hypothermia resulted in decreased expression of typical cerebral inflammatory mediators after cardiopulmonary resuscitation. This may confer, at least in part, neuroprotection following global cerebral ischemia and resuscitation.

Dataset Information

Mild hypothermia improves neurological outcome in mice after cardiopulmonary resuscitation through Silent Information Regulator 1-actviated autophagy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets