Pravastatin But Not Simvastatin Improves Survival and Neurofunctional Outcome After Cardiac Arrest and Cardiopulmonary Resuscitation

Bergt, Stefan; Grub, Andrea; Wagner, Steffen; Engelke, Hauke; Nöldge-Schomburg, Gabriele; Vollmar, Brigitte; Roesner, Jan P.; Wagner, Nana-Maria

doi:10.1016/j.jacbts.2017.01.009

Cited by 8 publications

(7 citation statements)

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“…The model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) was conducted as described previously. [16,17] Only female mice were used since male mice almost exclusively presented with urinary outflow obstruction and death from post renal kidney failure between day 4 and 10 after CA/CPR. [16] 53 female C57BL/6J and 37 female B6.B10ScN-Tlr4 lps-del mice (12–16 weeks, 19–22 g) were anaesthetized by intraperitoneal injection of 12μg/g ketamine and 8μg/g xylazine and subjected to oral intubation and mechanical ventilation (0.21 inspired oxygen fraction).…”

Section: Methodsmentioning

confidence: 99%

“…Analysis of neurological function was performed as previously described [16,17]. NeuroScore : Level of consciousness, corneal reflex, respirations, righting reflex, coordination and movement/activity were assessed.…”

Section: Methodsmentioning

confidence: 99%

“…We here propose genetic ablation or pharmacological inhibition of TLR4 augments survival and neurofunctional outcome in mice after CA/CPR. To test this hypothesis we used a previously established, highly standardized model of CA/CPR employing a modified sewing machine to perform CPR after 10min of high potassium-induced cardiac arrest [16,17]. During a 28 day follow up period, we assessed survival and dissected neurofunction by specifically addressing early neurological rehabilitation, motor function, spatial learning ability and memory after CA/CPR.…”

Section: Introductionmentioning

confidence: 99%

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Toll-like receptor 4 deficiency or inhibition does not modulate survival and neurofunctional outcome in a murine model of cardiac arrest and resuscitation

et al. 2019

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Background Patients experiencing cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) often die or suffer from severe neurological impairment. Post resuscitation syndrome is characterized by a systemic inflammatory response. Toll-like receptor 4 (TLR4) is a major mediator of inflammation and TLR4 has been implicated in the pathogenesis of post-resuscitation encephalopathy. The aim of this study was to evaluate whether TLR4 deficiency or inhibition can modulate survival and neurofunctional outcome after CA/CPR. Methods Following intubation and central venous cannulation, CA was induced in wild type (C57Bl/6J, n = 38), TLR4 deficient (TLR4 -/- , n = 37) and TLR4 antibody treated mice (5mg/kg MTS510, n = 15) by high potassium. After 10min, CPR was performed using a modified sewing machine until return of spontaneous circulation (ROSC). Cytokines and cerebral TNFalpha levels were measured 8h after CA/CPR. Survival, early neurological recovery, locomotion, spatial learning and memory were assessed over a period of 28 days. Results Following CA/CPR, all mice exhibited ROSC and 31.5% of wild type mice survived until day 28. Compared to wild type mice, neither TLR4 -/- nor MTS510 treated wild type mice had statistically significant altered survival following CA/CPR (51.3 and 26.7%, P = 0.104 and P = 0.423 vs. WT, respectively). Antibody-treated but not TLR4 -/- mice had higher IL-1β and IL-6 levels and TLR4 -/- mice had higher IL-10 and cerebral TNFalpha levels. No differences existed between mice of all groups in early neurological recovery, locomotion, spatial learning ability or remembrance. Conclusion Therapeutic strategies targeting TLR4 may not be suitable for the reduction of mortality or neurofunctional impairment after CA/CPR.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Toll-like receptor 4 deficiency or inhibition does not modulate survival and neurofunctional outcome in a murine model of cardiac arrest and resuscitation

et al. 2019

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“…Although statins are generally safe, treatment adherence is not optimal in a considerable proportion of patients, resulting in poor cardiovascular outcomes. Among them, the adverse effects of statin-associated muscle symptoms (SAMS) have the greatest health burden ( Thompson et al, 2016 ; Bergt et al, 2017 ; Ward et al, 2019 ), including muscular pain, nocturnal muscle cramping, weakness, rare rhabdomyolysis, and amyotrophic lateral sclerosis (ALS)-like muscle wasting conditions ( Bai et al, 2021 ). To date, there is no therapeutic approach for eliminating the adverse effects of statins, and the molecular mechanism underlying the etiology and pathophysiology of the statin-relative adverse effects still remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin Induces Mitochondria-Dependent Ferroptosis via the Modulation of Nrf2-xCT/GPx4 Axis

Zhang

Chen

et al. 2022

Front. Cell Dev. Biol.

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As one of the cornerstones of clinical cardiovascular disease treatment, statins have an extensive range of applications. However, statins commonly used have side reactions, especially muscle-related symptoms (SAMS), such as muscle weakness, pain, cramps, and severe condition of rhabdomyolysis. This undesirable muscular effect is one of the chief reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. Moreover, the underlying mechanism of muscle cell damage is still unclear. Here, we discovered that ferroptosis, a programmed iron-dependent cell death, serves as a mechanism in statin-induced myopathy. Among four candidates including atorvastatin, lovastatin, rosuvastatin, and pravastatin, only atorvastatin could lead to ferroptosis in human cardiomyocytes (HCM) and murine skeletal muscle cells (C2C12), instead of human umbilical vein endothelial cell (HUVEC). Atorvastatin inhibits HCM and C2C12 cell viability in a dose-dependent manner, accompanying with significant augmentation in intracellular iron ions, reactive oxygen species (ROS), and lipid peroxidation. A noteworthy investigation found that those alterations particularly occurred in mitochondria and resulted in mitochondrial dysfunction. Biomarkers of myocardial injury increase significantly during atorvastatin intervention. However, all of the aforementioned enhancement could be restrained by ferroptosis inhibitors. Mechanistically, GSH depletion and the decrease in nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPx4), and xCT cystine–glutamate antiporter (the main component is SLC7A11) are involved in atorvastatin-induced muscular cell ferroptosis and damage. The downregulation of GPx4 in mitochondria-mediated ferroptosis signaling may be the core of it. In conclusion, our findings explore an innovative underlying pathophysiological mechanism of atorvastatin-induced myopathy and highlight that targeting ferroptosis serves as a protective strategy for clinical application.

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“…Survivors of CA may suffer from brain injury, myocardial dysfunction and systemic ischemia-reperfusion, which are ascribed as post-CA syndrome, even though the CPR-induced restoration of spontaneous circulation (ROSC) is successful. Neurological deficit from brain injury accounts for two-thirds of mortality and is the primary obstacle to rehabilitation of patients after CA/CPR [ 4 ]. The brain injury is probably caused by inadequate cerebral perfusion during CA and consequent cerebral edema [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Melatonin improves neurological outcomes and preserves hippocampal mitochondrial function in a rat model of cardiac arrest

et al. 2018

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Cerebral injury after cardiac arrest (CA)/cardiopulmonary resuscitation (CPR) has been implicated in the poor prognosis of CA survivors. This study was designed to evaluate the impact of melatonin on postresuscitation neurological outcomes and to explore the underlying mechanism. Sprague-Dawley rats were randomly assigned to four groups: sham group, CPR group, melatonin pretreatment group (Pre-M) and posttreatment group (Post-M). For the last 2 groups, daily melatonin gavage was performed for 12 consecutive days before or 24 hours after rat survival from CA/CPR. No statistical differences were observed in heart rate (HR), mean arterial blood pressure (MAP), and end-tidal carbon dioxide (ETCO2) at baseline and after restoration of spontaneous circulation (ROSC) among groups. However, melatonin pretreatment or posttreatment significantly improved neurological deficit score and memory and spatial learning ability after CA/CPR. Further studies demonstrated that the complex I- and complex-II supported mitochondrial respiration were greatly increased under melatonin treatment. In addition, melatonin treatment preserved the mitochondrial-binding hexokinase II (HKII) and ATP levels and suppressed the upregulated protein lysine acetylation in hippocampus after CA/CPR. In conclusion, using a rat asphyxial CA model we have demonstrated that treatment with melatonin either before or after CA/CPR provides a promising neuroprotective effect, and this protection was mediated by increasing mitochondrial HKII expression, suppressing protein acetylation and improving mitochondrial function in hippocampus.

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Pravastatin But Not Simvastatin Improves Survival and Neurofunctional Outcome After Cardiac Arrest and Cardiopulmonary Resuscitation

Abstract: Visual Abstract

Cited by 8 publications

References 51 publications

Toll-like receptor 4 deficiency or inhibition does not modulate survival and neurofunctional outcome in a murine model of cardiac arrest and resuscitation

Toll-like receptor 4 deficiency or inhibition does not modulate survival and neurofunctional outcome in a murine model of cardiac arrest and resuscitation

Atorvastatin Induces Mitochondria-Dependent Ferroptosis via the Modulation of Nrf2-xCT/GPx4 Axis

Melatonin improves neurological outcomes and preserves hippocampal mitochondrial function in a rat model of cardiac arrest

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