Metabolic Changes Induced by Cerebral Ischemia, the Effect of Ischemic Preconditioning, and Hyperhomocysteinemia

Abstract

1H Nuclear Magnetic Resonance (NMR) metabolomics is one of the fundamental tools in the fast-developing metabolomics field. It identifies and quantifies the most abundant metabolites, alterations of which can describe energy metabolism, activated immune response, protein synthesis and catabolism, neurotransmission, and many other factors. This paper summarizes our results of the 1H NMR metabolomics approach to characterize the distribution of relevant metabolites and their alterations induced by cerebral ischemic injury or its combination with hyperhomocysteinemia in the affected tissue and blood plasma in rodents. A decrease in the neurotransmitter pool in the brain tissue likely follows the disordered feasibility of post-ischemic neurotransmission. This decline is balanced by the increased tissue glutamine level with the detected impact on neuronal health. The ischemic injury was also manifested in the metabolomic alterations in blood plasma with the decreased levels of glycolytic intermediates, as well as a post-ischemically induced ketosis-like state with increased plasma ketone bodies. As the 3-hydroxybutyrate can act as a likely neuroprotectant, its post-ischemic increase can suggest its supporting role in balancing ischemic metabolic dysregulation. Furthermore, the 1H NMR approach revealed post-ischemically increased 3-hydroxybutyrate in the remote organs, such as the liver and heart, as well as decreased myocardial glutamate. Ischemic preconditioning, as a proposed protective strategy, was manifested in a lower extent of metabolomic changes and/or their faster recovery in a longitudinal study. The paper also summarizes the pre- and post-ischemic metabolomic changes in the rat hyperhomocysteinemic models. Animals are challenged with hyperglycemia and ketosis-like state. A decrease in several amino acids in plasma follows the onset and progression of hippocampal neuropathology when combined with ischemic injury. The 1H NMR metabolomics approach also offers a high potential for metabolites in discriminatory analysis in the search for potential biomarkers of ischemic injury. Based on our results and the literature data, this paper presents valuable findings applicable in clinical studies and suggests the precaution of a high protein diet, especially foods which are high in Met content and low in B vitamins, in the possible risk of human cerebrovascular neuropathology.