NMR metabolomic study of blood plasma in ischemic and ischemically preconditioned rats: an increased level of ketone bodies and decreased content of glycolytic products 24 h after global cerebral ischemia

Abstract

Cardiac arrest is one of the leading causes of death among adults in older age. Understanding mechanisms how organism responds to ischemia at global level is essential for the prevention and ischemic patient's treatment. In this study, we used a global cerebral ischemia induced by four-vessel occlusion as an established animal model for ischemic stroke to investigate metabolic changes after 24 h reperfusion, when transitions occur due to the onset of delayed neuronal death. We also focused on the endogenous phenomenon known as ischemic tolerance by the pre-ischemic treatment. The experiments were carried out on blood plasma samples as easily available and metabolically reflecting the overall changes in injured organism. Our results imply that disturbed glycolysis pathway, as a consequence of ischemic injury, leads to the increased level of ketone bodies (acetone, acetoacetate and β-hydroxybutyrate) along with increased utilization of triacylglycerols in plasma of ischemic and ischemically preconditioned rats. Complementary to, a decreased level of glycolytic intermediates (lactate, pyruvate, acetate) with increased level of glucose was found in ischemic and preconditioned animals. The protective effect of ischemic preconditioning on metabolome recovery was demonstrated by significantly increased level of creatine compared to ischemic, non-preconditioned rats. We also document that acetoacetate, pyruvate, lactate, and leucine have the best discriminatory power between ischemic and control plasma. Conclusively, our results provide evidence that NMR spectra analysis can identify specific group of metabolites present in plasma with the capability for discrimination between individual groups of animals. In addition, an excellent feasibility for the statistical discrimination among ischemic, preconditioned, and control rats can be applied regardless of native or deproteinated plasma and also regardless of noesy or cpmg NMR acquisition.

Metabolomic profiling of blood plasma of patients with lung cancer and malignant tumors with metastasis in the lungs showed similar features and promising statistical discrimination against controls

“…It is remarkable that observed metabolomic changes, in particular increased glucose and decreased pyruvate and alanine, tryptophane and tyrosine balanced with increased ketone bodies are very similar to those found in rats after ischemia [36][37][38] and in patients after myocardial infarction [39].…”

Metabolomic profiling of blood plasma in patients with primary brain tumours: Basal plasma metabolites correlated with tumour grade and plasma biomarker analysis predicts feasibility of the successful statistical discrimination from healthy subjects – a preliminary study

“…Five hundres and fifty microlitre of the final mixture were transferred into 5 mm NMR tube. A similar protocol for sample preparation has been already used in previous studies …”

The metabolic signatures of cardiometabolic diseases: Does the shared metabotype offer new therapeutic targets?

“…Abbreviations: HOMA‐IR, homeostatic model assessment of insulin resistance, T2DM, Type 2 diabetes mellites, CVDs, cardiovascular diseases, IHD, ischemic heart disease, CAD, Coronary artery disease, MI, Myocardial infarction, CI, cerebral ischemia, TIA, Transient Ischemic attack, Carotid‐Athero, Carotid atherosclerosis, HF, Heart failure, BCAAs, Branched chain amino acids, DMG, dimethylglycine, TMAO, Trimethylamine oxide 124,150,151,141,152,153,31,154 . .…”

“…Similarly, ceramides which are metabolic biomarkers of CVDs incidences, stroke, and T2DM 123,87,145 are indicative of IR, inflammation, and mitochondrial dysfunction 123,146–148,87 . Ketone body metabolites such as acetone, acetoacetic acid, and 3‐hydroxybutyrate (β‐hydroxybutyrate) are metabolic biomarkers of CMDs 149,68,124,150,151,141,152,153,31,154 . β‐Hydroxybutyrate may elevate in CVDs as a compensatory mechanism, which may have a potential cardioprotective role 155 .…”