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

Abstract

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.

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

“…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.…”

“…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.…”

“…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.…”