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

Bergt, Stefan; Grub, Andrea; Mueller, Melanie; Bajorat, Rika; Barilar, Ivan; Vollmar, Brigitte; Roesner, Jan P.; Wagner, Nana-Maria

doi:10.1371/journal.pone.0220404

Cited by 3 publications

(7 citation statements)

References 36 publications

(55 reference statements)

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“…Only female mice were used in this resuscitation model, as male mice were shown to regularly develop urinary outflow obstruction and death from post-renal kidney failure between Days 4 and 10 after CA-CPR [ 25 ]. Therefore, in all subsequent studies with this model, only female mice were used [ 16 , 26 , 27 ]. Animals were housed in a temperature-controlled environment (22 °C) under a 12/12 h dark/light cycle with free access to water and food.…”

Section: Methodsmentioning

confidence: 99%

“…A standardized, well-established mouse model of cardiac arrest and resuscitation was used in this study [ 16 , 25 , 26 , 27 ]. During the experimental time, the animals had free access to water and food.…”

Section: Methodsmentioning

confidence: 99%

“…The CA-CPR model was conducted as described previously [ 16 , 26 , 27 ]. Briefly, the anesthetized and mechanically ventilated (inspiratory oxygen fraction (FiO 2 ) 0.21) mice were placed on an auto-regulated heating plate to prevent hypothermia.…”

Section: Methodsmentioning

confidence: 99%

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The Effect of Early Application of Synthetic Peptides 19-2.5 and 19-4LF to Improve Survival and Neurological Outcome in a Mouse Model of Cardiac Arrest and Resuscitation

et al. 2023

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The synthetic antimicrobial peptides (sAMPs) Pep19-2.5 and Pep19-4LF have been shown in vitro and in vivo to reduce the release of pro-inflammatory cytokines, leading to the suppression of inflammation and immunomodulation. We hypothesized that intervention with Pep19-2.5 and Pep19-4LF immediately after cardiac arrest and resuscitation (CA-CPR) might attenuate immediate systemic inflammation, survival, and long-term outcomes in a standardized mouse model of CA-CPR. Long-term outcomes up to 28 days were assessed between a control group (saline) and two peptide intervention groups. Primarily, survival as well as neurological and cognitive parameters were assessed. In addition, systemic inflammatory molecules and specific biomarkers were analyzed in plasma as well as in brain tissue. Treatment with sAMPs did not provide any short- or long-term benefits for either survival or neurological outcomes, and no significant benefit on inflammation in the CA-CPR animal model. While no difference was found in the plasma analysis of early cytokines between the intervention groups four hours after resuscitation, a significant increase in UCH-L1, a biomarker of neuronal damage and blood–brain barrier rupture, was measured in the Pep19-4LF-treated group. The theoretical benefit of both sAMPs tested here for the treatment of post-cardiac arrest syndrome could not be proven.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The Effect of Early Application of Synthetic Peptides 19-2.5 and 19-4LF to Improve Survival and Neurological Outcome in a Mouse Model of Cardiac Arrest and Resuscitation

et al. 2023

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“…The model of CA-CPR was conducted as described previously [ 24 , 35 ]. Briefly, CA was induced by injection of 80 µg/g potassium chloride via a central venous catheter inserted into the right jugular vein, and mechanical ventilation was interrupted.…”

Section: Methodsmentioning

confidence: 99%

Early Post-ischemic Brain Glucose Metabolism Is Dependent on Function of TLR2: a Study Using [18F]F-FDG PET-CT in a Mouse Model of Cardiac Arrest and Cardiopulmonary Resuscitation

et al. 2021

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Purpose The mammalian brain glucose metabolism is tightly and sensitively regulated. An ischemic brain injury caused by cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) affects cerebral function and presumably also glucose metabolism. The majority of patients who survive CA suffer from cognitive deficits and physical disabilities. Toll-like receptor 2 (TLR2) plays a crucial role in inflammatory response in ischemia and reperfusion (I/R). Since deficiency of TLR2 was associated with increased survival after CA-CPR, in this study, glucose metabolism was measured using non-invasive [18F]F-FDG PET-CT imaging before and early after CA-CPR in a mouse model comparing wild-type (WT) and TLR2-deficient (TLR2−/−) mice. The investigation will evaluate whether FDG-PET could be useful as an additional methodology in assessing prognosis. Procedures Two PET-CT scans using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]F-FDG) tracer were carried out to measure dynamic glucose metabolism before and early after CPR. To achieve this, anesthetized and ventilated adult female WT and TLR2−/− mice were scanned in PET-CT. After recovery from the baseline scan, the same animals underwent 10-min KCL-induced CA followed by CPR. Approximately 90 min after CA, measurements of [18F]F-FDG uptake for 60 min were started. The [18F]F-FDG standardized uptake values (SUVs) were calculated using PMOD-Software on fused FDG-PET-CT images with the included 3D Mirrione-Mouse-Brain-Atlas. Results The absolute SUVmean of glucose in the whole brain of WT mice was increased about 25.6% after CA-CPR. In contrast, the absolute glucose SUV in the whole brain of TLR2−/− mice was not significantly different between baseline and measurements post CA-CPR. In comparison, baseline measurements of both mouse strains show a highly significant difference with regard to the absolute glucose SUV in the whole brain. Values of TLR2−/− mice revealed a 34.6% higher glucose uptake. Conclusions The altered mouse strains presented a different pattern in glucose uptake under normal and ischemic conditions, whereby the post-ischemic differences in glucose metabolism were associated with the function of key immune factor TLR2. There is evidence for using early FDG-PET-CT as an additional diagnostic tool after resuscitation. Further studies are needed to use PET-CT in predicting neurological outcomes.

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“…The model of CA-CPR was conducted as described previously (20,28). Briefly, the anesthetized and mechanically ventilated mice were placed on an auto-regulated heating plate to prevent cooling.…”

Section: Cardiac Arrest and Resuscitationmentioning

confidence: 99%

Early post-ischemic glucose metabolism is dependent on function of TLR2: a study using [18F]FDG PET-CT in a mouse model of cardiac arrest and cardiopulmonary resuscitation

Bajorat

Kurth

Stenzel

et al. 2021

Preprint

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Purpose: An ischemic brain injury caused by cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) affects cerebral function and presumably also brain glucose metabolism. The majority of patients who survive CA suffer from cognitive deficits and physical disabilities. Toll-like receptor 2 (TLR2) plays a cruical role in inflammatory response in ischemia and reperfusion (I/R). Since deficiency of TLR2 was associated with increased survival after CA-CPR, in this study glucose metabolism was measured using non-invasive [18F]FDG PET-CT imaging before and early after CA-CPR in a mouse model comparing wild type (WT) and TLR2-deficient (TLR2-/-) mice. Methods: Two PET-CT scans using [18F]FDG tracer were carried out to measure dynamic glucose metabolism before and early after CPR. To achieve this, anesthetized and ventilated adult female WT and TLR2-/- mice were scanned in PET-CT. After recovery from the baseline scan, the same animals underwent 10-minute CA followed by CPR and approximately 90 min after CA measurements of [18F]FDG uptake were started. The [18F]FDG standardized uptake values (SUVs) were calculated using PMOD-Software on fused FDG-PET-CT images with the included 3D Mirrione-Mouse-Brain-Atlas. Results: The absolute SUV of glucose in the whole brain of WT mice was increased after CA-CPR. In contrast, the absolute glucose SUV in the whole brain of TLR2-/- mice was not significantly different between basal and measurements after CA-CPR. In comparison, basal measurements of both mouse strains show a significant difference in the whole brain absolute glucose SUVs, whereby TLR2-/- mice revealed 34.6% higher values. The altered mouse strains presented a different pattern in glucose uptake under normal and ischemic conditions. Conclusion: There is evidence that the post-ischemic differences in glucose metabolism were associated with the function of TLR2 and that PET-CT imaging could be useful as an additional methodology in assessing diagnosis and prognosis during post-cardiac arrest care. Further studies are needed.

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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

Cited by 3 publications

References 36 publications

The Effect of Early Application of Synthetic Peptides 19-2.5 and 19-4LF to Improve Survival and Neurological Outcome in a Mouse Model of Cardiac Arrest and Resuscitation

The Effect of Early Application of Synthetic Peptides 19-2.5 and 19-4LF to Improve Survival and Neurological Outcome in a Mouse Model of Cardiac Arrest and Resuscitation

Early Post-ischemic Brain Glucose Metabolism Is Dependent on Function of TLR2: a Study Using [18F]F-FDG PET-CT in a Mouse Model of Cardiac Arrest and Cardiopulmonary Resuscitation

Early post-ischemic glucose metabolism is dependent on function of TLR2: a study using [18F]FDG PET-CT in a mouse model of cardiac arrest and cardiopulmonary resuscitation

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