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Metformin Improves Neurologic Outcome Via AMP-Activated Protein Kinase-Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation.

ABSTRACT: BACKGROUND:Sudden cardiac arrest (CA) often results in severe injury to the brain, and neuroprotection after CA has proved to be difficult to achieve. Herein, we sought to investigate the effects of metformin pretreatment on brain injury secondary to CA and cardiopulmonary resuscitation. METHODS AND RESULTS:Rats were subjected to 9-minute asphyxial CA after receiving daily metformin treatment for 2 weeks. Survival rate, neurologic deficit scores, neuronal loss, AMP-activated protein kinase (AMPK), and autophagy activation were assessed at indicated time points within the first 7 days after return of spontaneous circulation. Our results showed that metformin pretreatment elevated the 7-day survival rate from 55% to 85% and significantly reduced neurologic deficit scores. Moreover, metformin ameliorated CA-induced neuronal degeneration and glial activation in the hippocampal CA1 region, which was accompanied by augmented AMPK phosphorylation and autophagy activation in affected neuronal tissue. Inhibition of AMPK or autophagy with pharmacological inhibitors abolished metformin-afforded neuroprotection, and augmented autophagy induction by metformin treatment appeared downstream of AMPK activation. CONCLUSIONS:Taken together, our data demonstrate, for the first time, that metformin confers neuroprotection against ischemic brain injury after CA/cardiopulmonary resuscitation by augmenting AMPK-dependent autophagy activation.

SUBMITTER: Zhu J

PROVIDER: S-EPMC6220525 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Metformin Improves Neurologic Outcome Via AMP-Activated Protein Kinase-Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation.

Zhu Juan J Liu Kewei K Huang Kaibin K Gu Yong Y Hu Yafang Y Pan Suyue S Ji Zhong Z

Journal of the American Heart Association 20180612 12

<h4>Background</h4>Sudden cardiac arrest (CA) often results in severe injury to the brain, and neuroprotection after CA has proved to be difficult to achieve. Herein, we sought to investigate the effects of metformin pretreatment on brain injury secondary to CA and cardiopulmonary resuscitation.<h4>Methods and results</h4>Rats were subjected to 9-minute asphyxial CA after receiving daily metformin treatment for 2 weeks. Survival rate, neurologic deficit scores, neuronal loss, AMP-activated prote ...[more]

PMID: 29895585

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Project description:BACKGROUND:Cardiac arrest (CA) is associated with high morbidity and mortality, even after spontaneous circulation is re-established. This dire situation is partly due to post-CA syndrome for which no specific and effective intervention is available. One key component of post-CA syndrome is sterile inflammation, which affects various organs including the brain. A major effector of sterile inflammation is activated NLRP3 inflammasome, which leads to increased release of interleukin (IL)-1?. However, how NLRP3 inflammasome impacts neuroinflammation and neurologic outcome after CA is largely undefined. METHODS:Mice were subjected to a potassium-based murine CA and cardiopulmonary resuscitation (CPR) model. MCC950 was used to suppress activation of NLRP3 inflammasome after CA/CPR. Levels of protein and mRNA were examined by Western blotting and quantitative PCR, respectively. Immunologic changes were assessed by measuring cytokine expression and immune cell compositions. CA outcomes, including neurologic deficits, bacterial load in the lung, and survival rate, were evaluated. RESULTS:Using our CA/CPR model, we found that NLRP3 inflammasome was activated in the post-CA brain, and that pro-inflammatory cytokine levels, including IL-1?, were increased. After treatment with MCC950, a potent and selective NLRP3 inflammasome inhibitor, mice exhibited improved functional recovery and survival rate during the 14-day observational period after CA/CPR. In line with these findings, IL-1? mRNA levels in the post-CA brain were significantly suppressed after MCC950 treatment. Interestingly, we also found that in MCC950- vs. vehicle-treated CA mice, immune homeostasis in the spleen was better preserved and bacterial load in the lung was significantly reduced. CONCLUSIONS:Our data demonstrate that activation of NLRP3 inflammasome could be a key event shaping the post-CA immuno- and neuro-pathology, and identify this pathway as a unique and promising therapeutic target to improve outcomes after CA/CPR.

Project description:OBJECTIVES:Laboratory studies suggest elevated blood pressure after resuscitation from cardiac arrest may be protective; however, clinical data are limited. We sought to test the hypothesis that elevated postresuscitation mean arterial blood pressure is associated with neurologic outcome. DESIGN:Preplanned analysis of a prospective cohort study. SETTING:Six academic hospitals in the United States. PATIENTS:Adult, nontraumatic cardiac arrest patients treated with targeted temperature management after return of spontaneous circulation. INTERVENTIONS:Mean arterial blood pressure was measured noninvasively after return of spontaneous circulation and every hour during the initial 6 hours after return of spontaneous circulation. MEASURES AND MAIN RESULTS:We calculated the mean arterial blood pressure and a priori dichotomized subjects into two groups: mean arterial blood pressure 70-90 and greater than 90?mm Hg. The primary outcome was good neurologic function, defined as a modified Rankin Scale less than or equal to 3. The modified Rankin Scale was prospectively determined at hospital discharge. Of the 269 patients included, 159 (59%) had a mean arterial blood pressure greater than 90?mm Hg. Good neurologic function at hospital discharge occurred in 30% of patients in the entire cohort and was significantly higher in patients with a mean arterial blood pressure greater than 90?mm Hg (42%) as compared with mean arterial blood pressure 70-90?mm Hg (15%) (absolute risk difference, 27%; 95% CI, 17-37%). In a multivariable Poisson regression model adjusting for potential confounders, mean arterial blood pressure greater than 90?mm Hg was associated with good neurologic function (adjusted relative risk, 2.46; 95% CI; 2.09-2.88). Over ascending ranges of mean arterial blood pressure, there was a dose-response increase in probability of good neurologic outcome, with mean arterial blood pressure greater than 110?mm Hg having the strongest association (adjusted relative risk, 2.97; 95% CI, 1.86-4.76). CONCLUSIONS:Elevated blood pressure during the initial 6 hours after resuscitation from cardiac arrest was independently associated with good neurologic function at hospital discharge. Further investigation is warranted to determine if targeting an elevated mean arterial blood pressure would improve neurologic outcome after cardiac arrest.

Project description:PurposePrevious clinical studies have suggested an effect of gender on outcome after out-of-hospital cardiac arrest, but the results are conflicting and there is no uniform agreement regarding gender differences in survival and prognosis. The present study was aimed to investigate the interaction between gender and post resuscitation interventions on neurological outcome in an asphyxial rat model of cardiac arrest.MethodsAsphyxia was induced by blocking the endotracheal tube in 120 adult Sprague-Dawley rats (60 males and 60 females) at the same age. Cardiopulmonary resuscitation (CPR) was started after 5 min of untreated cardiac arrest. Animals were randomized into one of the three post resuscitation care intervention groups (n = 40, 20 males) immediately after resuscitation: (1) normothermic control (NC): ventilated with 2% N2/98% O2 for 1 h under normothermia; (2) targeted temperature management (TTM): ventilated with 2% N2/98% O2 for 1 h under hypothermia; (3) hydrogen inhalation (HI): ventilated with 2% H2/98% O2 for 1 h under normothermia. Physiological variables were recorded during the 5 h post resuscitation monitoring period. Neurological deficit score (NDS) and accumulative survival were used to assess 96 h outcomes. Mutual independence analysis and Mantel-Haenszel stratified analysis were used to explore the associations among gender, intervention and survival.ResultsThe body weights of female rats were significantly lighter than males, but CPR characteristics did not differ between genders. Compared with male rats, females had significantly lower mean arterial pressure, longer onset time of the electroencephalogram (EEG) burst and time to normal EEG trace (TTNT) in the NC group; relatively longer TTNT in the TTM group; and substantially longer TTNT, lower NDSs, and higher survival in the HI group. Mutual independence analysis revealed that both gender and intervention were associated with neurological outcome. Mantel-Haenszel stratified analysis demonstrated that female rats had significantly higher survival rate than males when adjusted for the confounder intervention.ConclusionIn this rat model cardiac arrest and CPR, gender did not affect resuscitation but associated with neurological outcome. The superiority of female rats in neurological recovery was affected by post resuscitation interventions and female rats were more likely to benefit from hydrogen therapy.

Project description:ObjectivesLess than half of the thousands of children who suffer in-hospital cardiac arrests annually survive, and neurologic injury is common among survivors. Hemodynamic-directed cardiopulmonary resuscitation improves short-term survival, but its impact on longer term survival and mitochondrial respiration-a potential neurotherapeutic target-remains unknown. The primary objectives of this study were to compare rates of 24-hour survival with favorable neurologic outcome after cardiac arrest treated with hemodynamic-directed cardiopulmonary resuscitation versus standard depth-guided cardiopulmonary resuscitation and to compare brain and heart mitochondrial respiration between groups 24 hours after resuscitation.DesignRandomized preclinical large animal trial.SettingA large animal resuscitation laboratory at a large academic children's hospital.SubjectsTwenty-eight 4-week-old female piglets (8-11 kg).InterventionsTwenty-two swine underwent 7 minutes of asphyxia followed by ventricular fibrillation and randomized treatment with either hemodynamic-directed cardiopulmonary resuscitation (n = 10; compression depth titrated to aortic systolic pressure of 90 mm Hg, vasopressors titrated to coronary perfusion pressure ≥ 20 mm Hg) or depth-guided cardiopulmonary resuscitation (n = 12; depth 1/3 chest diameter, epinephrine every 4 min). Six animals (sham group) underwent anesthesia and instrumentation without cardiac arrest. The primary outcomes were favorable neurologic outcome (swine Cerebral Performance Category ≤ 2) and mitochondrial maximal oxidative phosphorylation utilizing substrate for complex I and complex II (OXPHOSCI+CII) in the cerebral cortex and hippocampus.Measurements and main resultsFavorable neurologic outcome was more likely with hemodynamic-directed cardiopulmonary resuscitation (7/10) than depth-guided cardiopulmonary resuscitation (1/12; p = 0.006). Hemodynamic-directed cardiopulmonary resuscitation resulted in higher intra-arrest coronary perfusion pressure, aortic pressures, and brain tissue oxygenation. Hemodynamic-directed cardiopulmonary resuscitation resulted in higher OXPHOSCI+CII (pmol oxygen/s × mg/citrate synthase) in the cortex (6.00 ± 0.28 vs 3.88 ± 0.43; p < 0.05) and hippocampus (6.26 ± 0.67 vs 3.55 ± 0.65; p < 0.05) and higher complex I respiration (pmol oxygen/s × mg) in the right (20.62 ± 1.06 vs 15.88 ± 0.81; p < 0.05) and left ventricles (20.14 ± 1.40 vs 14.17 ± 1.53; p < 0.05).ConclusionsIn a model of asphyxia-associated pediatric cardiac arrest, hemodynamic-directed cardiopulmonary resuscitation increases rates of 24-hour survival with favorable neurologic outcome, intra-arrest hemodynamics, and cerebral and myocardial mitochondrial respiration.

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Metformin Improves Neurologic Outcome Via AMP-Activated Protein Kinase-Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation.

Publications

Metformin Improves Neurologic Outcome Via AMP-Activated Protein Kinase-Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation.

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