Dataset Information

Motor Cortex and Hippocampus Display Decreased Heme Oxygenase Activity 2 Weeks After Ventricular Fibrillation Cardiac Arrest in Rats.

ABSTRACT: Heme oxygenase (HO) and biliverdin reductase (BVR) activities are important for neuronal function and redox homeostasis. Resuscitation from cardiac arrest (CA) frequently results in neuronal injury and delayed neurodegeneration that typically affect vulnerable brain regions, primarily hippocampus (Hc) and motor cortex (mC), but occasionally also striatum and cerebellum. We questioned whether these delayed effects are associated with changes of the HO/BVR system. We therefore analyzed the activities of HO and BVR in the brain regions Hc, mC, striatum and cerebellum of rats subjected to ventricular fibrillation CA (6 min or 8 min) after 2 weeks following resuscitation, or sham operation. From all investigated regions, only Hc and mC showed significantly decreased HO activities, while BVR activity was not affected. In order to find an explanation for the changed HO activity, we analyzed protein abundance and mRNA expression levels of HO-1, the inducible, and HO-2, the constitutively expressed isoform, in the affected regions. In both regions we found a tendency for a decreased immunoreactivity of HO-2 using immunoblots and immunohistochemistry. Additionally, we investigated the histological appearance and the expression of markers indicative for activation of microglia [tumor necrosis factor receptor type I (TNFR1) mRNA and immunoreactivity for ionized calcium-binding adapter molecule 1 (Iba1])], and activation of astrocytes [immunoreactivity for glial fibrillary acidic protein (GFAP)] in Hc and mC. Morphological changes were detected only in Hc displaying loss of neurons in the cornu ammonis 1 (CA1) region, which was most pronounced in the 8 min CA group. In this region also markers indicating inflammation and activation of pro-death pathways (expression of HO-1 and TNFR1 mRNA, as well as Iba1 and GFAP immunoreactivity) were upregulated. Since HO products are relevant for maintaining neuronal function, our data suggest that neurodegenerative processes following CA may be associated with a decreased capacity to convert heme into HO products in particularly vulnerable brain regions.

SUBMITTER: Warenits AM

PROVIDER: S-EPMC7511667 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Motor Cortex and Hippocampus Display Decreased Heme Oxygenase Activity 2 Weeks After Ventricular Fibrillation Cardiac Arrest in Rats.

Warenits Alexandra-Maria AM Hatami Jasmin J Müllebner Andrea A Ettl Florian F Teubenbacher Ursula U Magnet Ingrid Anna Maria IAM Bauder Barbara B Janata Andreas A Miller Ingrid I Moldzio Rudolf R Kramer Anne-Margarethe AM Sterz Fritz F Holzer Michael M Högler Sandra S Weihs Wolfgang W Duvigneau Johanna Catharina JC

Frontiers in medicine 20200910

Heme oxygenase (HO) and biliverdin reductase (BVR) activities are important for neuronal function and redox homeostasis. Resuscitation from cardiac arrest (CA) frequently results in neuronal injury and delayed neurodegeneration that typically affect vulnerable brain regions, primarily hippocampus (Hc) and motor cortex (mC), but occasionally also striatum and cerebellum. We questioned whether these delayed effects are associated with changes of the HO/BVR system. We therefore analyzed the activit ...[more]

PMID: 33015090

Similar Datasets

Project description:Throughout life, stress stimuli act upon the brain leading to morphological and functional changes in advanced age, when it is likely to develop neurodegenerative disorders. There is an increasing need to unveil the molecular mechanisms underlying aging, in a world where populations are getting older. Egr-1 (early growth response 1), a transcriptional factor involved in cell survival, proliferation and differentiation - with a role also in memory, cognition and synaptic plasticity, can be implicated in the molecular mechanism of the aging process. Moreover, Heme Oxygenase-1a (HO), a 32 kDa heat-shock protein that converts heme to iron, carbon monoxide and biliverdin, is a key enzyme with neuroprotective properties. Several in vitro and in vivo studies reported that HO-1 could regulate the metabolism of oxysterols, oxidation products of cholesterol that include markers of oxidative stress. Recently, a link between Egr-1 and HO-1 has been demonstrated in mouse lung cells exposed to cigarette smoke. In view of these data, we wanted to investigate whether Egr-1 can be implicated also in the oxysterol metabolism during brain aging. Our results show that Egr-1 expression is differently expressed in the cortex and hippocampus of old mice, as well as the oxysterol profile between these two brain areas. In particular, we show that the cortex experiences in an age-dependent fashion increasing levels of the Egr-1 protein, and that these correlate with the level of HO-1 expression and oxysterol abundance. Such a situation was not observed in the hippocampus. These results are further strenghtened by our observations made with Egr-1 KO mice, confirming our hypothesis concerning the influence of Egr-1 on oxysterol production and accumulation via regulation of the expression of HO-1 in the cortex, but not the hippocampus, of old mice. It is important to notice that most of the oxysterols involved in this process are those usually stimulated by oxidative stress, which would then represent the triggering factor for this mechanism.

Project description:BackgroundHypothermia has been shown to improve survival and neurological outcomes for ventricular fibrillation (VF) cardiac arrest. The electrophysiological mechanisms of hypothermia are not well-understood, nor are the effects of beginning cooling during the resuscitation.Methods and resultsWe hypothesized that inducing hypothermia prior to the onset of VF would slow the deleterious changes seen in the ECG during VF and that inducing hypothermia at the start of resuscitation would increase the rates of ROSC and short-term survival in a porcine model of prolonged VF. We randomly assigned 42 domestic swine (27.2+/-2.3 kg) to either pretreatment with hypothermia before induction of VF (PRE), normothermic resuscitation (NORM) or intra-resuscitation hypothermia (IRH). During anesthesia, animals were instrumented via femoral cutdown. Lead II ECG was recorded continuously. PRE animals were cooled before the induction of VF, with a rapid infusion of 4 degrees normal saline (30mL/kg). VF was induced electrically, left untreated for 8min, then mechanical CPR began. During CPR the NORM animals got 30mL/kg body-temperature saline and the IRH animals got 30mL/kg 4 degrees saline. In all groups first rescue shocks were delivered after 13min of VF. We calculated the VF scaling exponent (ScE) for the entire 8min period (compared using GEE). ROSC and survival were compared with Fisher's exact test. Mean temperature in degrees C at the onset of VF was PRE=34.7 degrees (+/-0.8), NORM=37.8 (+/-0.9), and IRH=37.9 (+/-0.9). The ScE values over time were significantly lower after 8min in the PRE group (p=0.02). ROSC: PRE=10/14 (71%), NORM=6/14 (43%) and IRH=12/14 (86%); p for IRH vs. NORM=0.02. Survival: PRE=9/14 (64%), NORM=5/14 (36%), IRH 8/14 (57%).ConclusionHypothermia slowed the decay of the ECG waveform during prolonged VF. IRH improved ROSC but not short-term survival compared to NORM. It is possible to rapidly induce mild hypothermia during CPR using an IV infusion of ice-cold saline.

Project description:IntroductionBesides therapeutic hypothermia or targeted temperature management no novel therapies have been developed to improve outcomes of patients after cardiac arrest (CA). Recent studies suggest that nitrite reduces neurological damage after asphyxial CA. Nitrite is also implicated as a new mediator of remote post conditioning produced by tourniquet inflation-deflation, which is under active investigation in CA. However, little is known about brain penetration or pharmacokinetics (PK). Therefore, to define the optimal use of this agent, studies on the PK of nitrite in experimental ventricular fibrillation (VF) are needed. We tested the hypothesis that nitrite administered after resuscitation from VF is detectable in cerebrospinal fluid (CSF), brain and other organ tissues, produces no adverse hemodynamic effects, and improves neurologic outcome in rats.MethodsAfter return of spontaneous circulation (ROSC) of 5 min untreated VF, adult male Sprague-Dawley rats were given intravenous nitrite (8 μM, 0.13 mg/kg) or placebo as a 5 min infusion beginning at 5 min after CA. Additionally, sham groups with and without nitrite treatment were also studied. Whole blood nitrite levels were serially measured. After 15 min, CSF, brain, heart and liver tissue were collected. In a second series, using a randomized and blinded treatment protocol, rats were treated with nitrite or placebo after arrest. Neurological deficit scoring (NDS) was performed daily and eight days after resuscitation, fear conditioning testing (FCT) and brain histology were assessed.ResultsIn an initial series of experiments, rats (n = 21) were randomized to 4 groups: VF-CPR and nitrite therapy (n = 6), VF-CPR and placebo therapy (n = 5), sham (n = 5), or sham plus nitrite therapy (n = 5). Whole blood nitrite levels increased during drug infusion to 57.14 ± 10.82 μM at 11 min post-resuscitation time (1 min after dose completion) in the VF nitrite group vs. 0.94 ± 0.58 μM in the VF placebo group (p < 0.001). There was a significant difference between the treatment and placebo groups in nitrite levels in blood between 7.5 and 15 min after CPR start and between groups with respect to nitrite levels in CSF, brain, heart and liver. In a second series (n = 25 including 5 shams), 19 out of 20 animals survived until day 8. However, NDS, FCT and brain histology did not show any statistically significant difference between groups.ConclusionsNitrite, administered early after ROSC from VF, was shown to cross the blood brain barrier after a 5 min VF cardiac arrest. We characterized the PK of intravenous nitrite administration after VF and were able to demonstrate nitrite safety in this feasibility study.

Project description:BACKGROUND:Quantitative measures of the ventricular fibrillation (VF) ECG waveform can assess myocardial physiology and predict cardiac arrest outcomes, making these measures a candidate to help guide resuscitation. Chest compressions are typically paused for waveform measure calculation because compressions cause ECG artifact. However, such pauses contradict resuscitation guideline recommendations to minimize cardiopulmonary resuscitation interruptions. We evaluated a comprehensive group of VF measures with and without ongoing compressions to determine their performance under both conditions for predicting functionally-intact survival, the study's primary outcome. METHODS:Five-second VF ECG segments were collected with and without chest compressions before 2755 defibrillation shocks from 1151 out-of-hospital cardiac arrest patients. Twenty-four individual measures and 3 combination measures were implemented. Measures were optimized to predict functionally-intact survival (Cerebral Performance Category score ?2) using 460 training cases, and their performance evaluated using 691 independent test cases. RESULTS:Measures predicted functionally-intact survival on test data with an area under the receiver operating characteristic curve ranging from 0.56 to 0.75 (median, 0.73) without chest compressions and from 0.53 to 0.75 (median, 0.69) with compressions ( P<0.001 for difference). Of all measures evaluated, the support vector machine model ranked highest both without chest compressions (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.73-0.78) and with compressions (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.72-0.78; P=0.75 for difference). CONCLUSIONS:VF waveform measures predict functionally-intact survival when calculated during chest compressions, but prognostic performance is generally reduced compared with compression-free analysis. However, support vector machine models exhibited similar performance with and without compressions while also achieving the highest area under the receiver operating characteristic curve. Such machine learning models may, therefore, offer means to guide resuscitation during uninterrupted cardiopulmonary resuscitation.

Dataset Information

Motor Cortex and Hippocampus Display Decreased Heme Oxygenase Activity 2 Weeks After Ventricular Fibrillation Cardiac Arrest in Rats.

Publications

Motor Cortex and Hippocampus Display Decreased Heme Oxygenase Activity 2 Weeks After Ventricular Fibrillation Cardiac Arrest in Rats.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets