Preserving pools of NAD+ confers neuroprotection after ischemic stress. Reactive oxygen species (ROS), in the form of superoxide and hydroxyl free radicals, as well as hydrogen peroxide, are produced from multiple physiological reactions, including electron transport by the ETC and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, which are often exacerbated under hypoxic micro-environments. Detailed metabolomics data verification with higher time and tissue-specific resolution will be needed in the future. Stroke is one of the leading causes of death and permanent disability worldwide. Rothman D.L., Behar K.L., Hyder F. In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: Implications for brain function. The MAS has been implicated as potentially dysregulated during cerebral ischemia [31]. In this review, we summarize the metabolic disorder and metabolic plasticity in the incidence and progression of ischemic stroke. Consistent with this data, strategies aimed at increasing astrocyte glycogen have been successfully applied for mitigating neuronal loss [20]. Mortality, morbidity, and risk factors in China and its provinces, 19902017: A systematic analysis for the Global Burden of Disease Study 2017. Furthermore, the accumulation of the TCA intermediate succinate is also responsible for mitochondrial ROS production during ischemic reperfusion [39]. Mitochondrial dysfunction in neurological disorders: Exploring We also elaborate how IPC fully mobilizes the metabolic reprogramming to maintain brain metabolic homeostasis, especially for energy and redox homeostasis, and finally protects brain function in the event of an ischemic stroke. In remote IPC, inflation of a blood-pressure cuff on the arm or leg is used [8]. Current evidence-based . Increasing evidence has shown that IPC takes advantage of brain plasticity and endogenous defense mechanisms for its neuroprotective purposes, among which metabolic reprogramming is crucial to co-ordinate the metabolic imbalance; support demands for body energy, biomass, redox maintenance, and cellular communication; and, finally, affecting pathophysiological alterations in ischemic stroke. In response to the NAD+ decline, NAMPT was upregulated in brain, plasma, and cultured neurons, which is the rate-limiting enzyme in mammalian NAD+ salvage biosynthesis [34]. Brainin M., Feigin V.L., Norrving B., Martins S.C.O., Hankey G.J., Hachinski V. Global prevention of stroke and dementia: The WSO Declaration. Hirayama Y., Ikeda M.Y., Notomi S., Enaida H., Kinouchi H., Koizumi S. Astrocyte-mediated ischemic tolerance. Su L., Zhao H., Zhang X., Lou Z., Dong X. UHPLC-Q-TOF-MS based serum metabonomics revealed the metabolic perturbations of ischemic stroke and the protective effect of RKIP in rat models. Therefore, a fastidious quality control system is important: as is well-known, mitochondrial dysfunction can initiate mitochondrial autophagy, which was first named mitophagy by Lemasters [54]. Early reperfusion aims to save the ischemic penumbra by preventing infarct core expansion and is the mainstay of acute ischemic stroke therapy. This is typical in cancer progression, as primary tumor cells rely on anabolic metabolism to maintain cell proliferation; then, when they enter the circulation, their survival requirement shifts to produce NADPH and GSH, in order to counteract oxidative stress. Dixon S.J., Lemberg K.M., Lamprecht M.R., Skouta R., Zaitsev E.M. Gleason Ferroptosis: An iron-dependent form of nonapoptotic cell death. The metaphor of the ischemic penumbra was coined to describe this intermediate zone of ischemia between functionally normal and dead brain tissue. FOIA MetS patients had a 3.542-fold increased odds ratio (OR) for cognitive impairment. Della Morte D., Abete P., Gallucci F., Scaglione A., DAmbrosio D., Gargiulo G., De Rosa G., Dave K.R., Lin H.W., Cacciatore F., et al. Importantly, in adult neurons, to meet the higher energy requirements, neurons sustain a high rate of oxidative metabolism compared to astrocytes, by which aerobic glycolysis results in the generation of pyruvate, not lactate. All brain cell types are able to uptake ketones; the ketones are then metabolized to acetyl-CoA to support the cell energy [29]. Organic Acids. Vascular and metabolic diseases are common correlates of stroke, and these influences on the balance between cell death and recovery must be understood. Methods One hundred ten anterior circulation ischemic stroke patients presenting to hospital within 4.5 h of symptom onset and treated with intravenous thrombolysis were studied. TCA cycle reactions yield metabolite intermediates and energetic precursors for oxidative phosphorylation. Previous evidence has revealed that IPC diverts excess glucose to oxPPP. This process is named the astrocyteneuron lactate shuttle (ANLS). Efficient ketone metabolism generates relatively abundant energy, which may prevent activation of the hyperglycolytic pathway under oxygen and glucose deprivation [27]. Ketone: Notably, the brain and plasma -hydroxybutyrate (-HB) levels both increase under IPC stimulation, indicating that the brain can increase ketone body oxidation to replenish its energy supply. Lactate: Brain fuel in human traumatic brain injury: A comparison with normal healthy control subjects. official website and that any information you provide is encrypted NAD+ levels and the NAD+/NADH redox couple provide a readout and regulator for cellular energy metabolism [30]. Recent research has shown that metabolic disorders have significant effects, both before and after the onset of ischemic stroke. L-Carnitine: The level of lysine in human CSF increases following IPC [75]. Solved the ischemic penumbra can maintain metabolic demand | Chegg.com Xu J., Khoury N., Jackson C.W., Escobar I., Stegelmann S.D., Dave K.R., Perez-Pinzon M.A. 2 The penumbra includes ischemic areas that recover spontaneously (benign oligemia; Figure 1, area a) and areas that progress to irreversible changes, unless effective treatment is used (referred to as penumbra; Figure 1, area b). Mitochondria lie at the key location for neuronal survival [51]. Suh S.W., Bergher J.P., Anderson C.M., Treadway J.L., Fosgerau K., Swanson R.A. Astrocyte glycogen sustains neuronal activity during hypoglycemia: Studies with the glycogen phosphorylase inhibitor CP-316,819 ([R-R*-S*]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl) propyl]-1H-indole-2-carboxamide). Sun K., Zhang Y., DAlessandro A., Nemkov T., Song A., Wu H., Liu H., Adebiyi M., Huang A., Wen Y.E., et al. There are two major affected zones in an ischemic brain: The infarct core, surrounded by an ischemic penumbra. Altogether, these results imply that subduing postischemic hyperglycolysis and the regulation of brain glucose metabolism play important roles in the neuroprotective aspect of IPC. In acute patients, PET documented areas of decreased 11 C-flumazenil uptake went on to show infarctions, while areas of relative . Magistretti P.J., Martin J.L. 6-8 hours A patient presents to the emergency department with left leg weakness and numbness. Arrell D.K., Elliott S.T., Kane L.A., Guo Y., Ko Y.H., Pedersen P.L. confirmed this: In a Huntington model, they discovered region-specific metabolic reprogramming of astrocytes, which directly induced neuronal susceptibility. electrophysiological/ hemodynamic based definition to the wider metabolic-cellular-therapeutic concept that is managed today by neuroscientists. After ischaemic stroke, brain damage can be curtailed by rescuing the 'ischaemic penumbra' that is, the severely hypoperfused, at-risk but not yet infarcted tissue. Hausenloy D.J., Yellon D.M. To enhance energy reserves, IPC improves mitochondrial efficiency for cellular energy metabolism, boosts glycolysis, and stockpiles and utilizes alternative energy substrates. Sato H., Nomura S., Maebara K., Sato K., Tamba M., Bannai S. Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. Regional cerebral blood flow thresholds during cerebral ischemia. Ischemic penumbra denotes the part of an acute ischemic stroke that is at risk of progressing to infarction but is still salvageable if reperfused. In such tissue, blood flow is decreased below the metabolic demand, but energy metabolism is maintained at a level allowing morphologic preservation of tissue. Changes in the cerebral NAD+ pool under ischemia have been studied in detail. Glutamine importantly regulates this process by providing glutamate and promoting cystine uptake [82]. Awooda H.A. In: Murphy S., editor. Meng R., Asmaro K., Meng L., Liu Y., Ma C., Xi C., Li G., Ren C., Luo Y., Ling F., et al. 40.2% ischemic stroke individuals were diagnosed with MetS. Excessive glutamate release and impeded reuptake of excitatory amino acids result in the activation of NMDARs, AMPARs and KARs. Chen S.Y., Liu J.W., Wang Y.H., Huang J.Y., Chen S.C., Yang S.F., Wang P.H. Careers, Unable to load your collection due to an error. Ketones: Growing evidence has indicated that ketone bodies are beneficial in treating stroke [26], mainly -hydroxybutyrate (-HB) and acetoacetate, which can substitute for glucose under conditions of energy deficiency in the brain for cellular fuel [27]. To defend against this ischemic cascade, upon the onset of ischemia, brain tissues enhance their metabolic plasticity to maintain the cerebral activity transiently, mainly through the regulation of cerebral blood flow (CBF), mitochondrial adaption, and other defense systems; however, with persistent ischemia, irreversible damage can occur in the affected brain areas. First, the availability of cysteine is the limiting link in GSH biosynthesis. Wender et al. The penumbral concept suggests that different areas within the ischemic region evolve into irreversible brain injury over time and that this evolution is most critically linked to the severity . Ischemic Penumbra: Evidence From Functional Imaging in Man Nevertheless, metabolic reprogramming is a relatively new area for understanding the mechanisms of IPC, to the best of our knowledge, no relevant review has yet been published. Proteomic analysis of pharmacological preconditioning. Yarian C.S., Toroser D., Sohal R.S. More glycolytic intermediates divert into the pentosephosphate pathway (PPP), while the entrance of pyruvate for mitochondrial oxidation is downregulated [18]. These preliminary results prompt the research on pathway-specifics alterations in metabolic reprogramming with aging during the stroke and IPC, which will be crucial for precision intervention for individuals of different ages, especially for patients with advanced age and a higher ischemic stroke incidence rate. The authors declare no conflict of interest. Bouzat P., Sala N., Suys T., Zerlauth J.B. Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain. Xi Q., Cheranov S.Y., Jaggar J.H. Metabolic reprogramming to maintain metabolic homeostasis, by correcting the metabolic disorder and enhancing metabolic plasticity, serves as an attractive potential therapeutic strategy for ischemic stroke. However, due to the structural complexity and their specific physiological functions and metabolic patterns, the conclusive details on whether the dynamic metabolic reprogramming behavior accompanied with astrocyte-neuron interaction is induced by ischemia or IPC are still lacking. Ischemic penumbra | Radiology Reference Article | Radiopaedia.org Dirnagl U., Endres M. Found in translation preclinical stroke research predicts human pathophysiology clinical phenotypes, and therapeutic outcomes. revealed that, upon ischemia, the levels of three oxidative stress-related metabolitessuccinate, taurine, and malonatewere dramatically disturbed in the cortex tissues of ischemic mice: taurine decreased, while malonate and succinate increased [16]. The research by Polyzos et al. For blood glucose and oxygen supply, IPC increases regional CBF and regulates the oxygen-delivery ability of erythrocytes through sphingosine 1-phosphate (S1P), in order to maintain glucose and oxygen metabolic consumption. Wang H., He Z., Zhang Y., Zhang J. At the protein level, glutamate oxaloacetate transaminase (GOT), which can metabolize glutamate into TCA intermediates, is induced during acute ischemic stroke (AIS), and may therefore be useful to harness excess neurotoxic extracellular glutamate during AIS [37]. Hence, the abundance and localization of polyunsaturated fatty acids are crucial for the degree of lipid peroxidation that occurs in cells. Katsyuba E., Romani M., Hofer D., Auwerx J. NAD. A field of research that continues to show promise in developing therapies for ischemic stroke is ischemic preconditioning (IPC). An increasing number of studies have shown the time-dependent metabolic changes during IPC or the acute-to-chronic post-stroke phase. Within cells, the selective autophagy of ferritin (abbreviated as ferritinophagy), by modulating iron metabolism and controlling iron availability, occurs to enhance ferroptosis sensitivity [47]. The most famous metabolic reprogramming process is the Warburg effect: Switching the energy metabolism largely to glycolysis, even in the presence of oxygen, implicating an increased rate of glucose uptake by cancer cells. 1Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Interdisciplinary Innovation Institute of Medicine and Engineering, Beihang University, Beijing 100191, China; nc.ude.aaub@9102gnijgnail (J.L. Metabolic syndrome (MetS) is a common metabolic disorder, involving a constellation of insulin resistance, abdominal obesity, hypertension, and dyslipidemia. Show abstract. Guan X., Li X., Yang X., Yan J., Shi P., Ba L., Cao Y., Wang P. The neuroprotective effects of carvacrol on ischemia/reperfusion-induced hippocampal neuronal impairment by ferroptosis mitigation. Accessibility IPC has also demonstrated neuroprotective activity through the activation of Nrf2 both in vivo and in vitro, which is a transcription factor that helps to maintain mitochondrial coupling and antioxidant protein expression [75]. The ischemic penumbra has been in the center of ischemic stroke research for the last 40 years. The ischemic penumbra: From concept to reality Waves of depolarizations, the peri-infarct spreading depres- . In addition, recent findings have indicated that mitochondria may represent a useful target to restore CBF after stroke, as it has been shown that ATP, adenosine monophosphate (AMP), and adenosine diphosphate (ADP) can alter cerebrovascular tone via plasmalemmal purinergic receptors [12]. Chen W.L., Jin X., Wang M., Liu D., Luo Q., Tian H., Cai L., Meng L., Bi R., Wang L., et al. Studies also clearly demonstrate that IPC is quite effective in aged animals: in aged gerbils, IPC provided substantial neuroprotection (>80%) in CA1 neurons ten days after ischemia compared with 6% in ischemic gerbils [95]. revealed that RKIP overexpression markedly reduced the necrotic area after ischemic stroke, mainly reflected in the metabolism of energy, amino acids, and lipids [38]. Other metabolic-related genes in the pathogenesis of ischemic stroke include MTHFR, CBS, and MTR, which are involved in homocysteine metabolism, and apo E, LPL, CETP, ABCA1, apo AI, apo CIII, apo AIV, apo AV, apo B, apo H, apo(a), PON1/2/3, and LDLR/LOX-1, which are involved in lipid metabolism [36]. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Hepatic NADH reductive stress underlies common variation in metabolic traits. Yu Z., Li J., Ren Z., Sun R., Zhou Y., Zhang Q., Wang Q., Cui G., Li J., Li A., et al. Glutamine is the most abundant free amino acid in human blood, which is converted to glutamate in mitochondria by glutaminase (GLS). It should be noted that metabolic reprogramming is a double-edged sword: the overactivation of metabolic reprogramming under ischemia may lead to secondary brain damage (Figure 2). Several studies also showed that transient ischemic attack (TIA) may produce IPC effect in people who have a subsequent stroke [101,102]. Ischemic preconditioning and glucose metabolism during low-flow ischemia: Role of the adenosine a receptor. Consistently, a study showed that neurons benefited from the co-incubated astrocytes, enhancing lactate secretion induced by IPC in astrocytes. In the meantime, free radicals trigger oxidative stress, which further induce damage to nucleic acid bases, lipids, and proteins, ultimately leading to cell death by necrosis or apoptosis. However, the underlying neuroprotection mechanisms of IPC remain elusive. Oxygen is a crucial substrate in metabolism. The adult brain occupies less than 2% of the bodys weight, yet it consumes 25% of the cardiac output at rest and accounts for 20% of the total energy production of the body. The primary definition of the ischemic penumbra is electrical. To test whether acute changes in cardiac workload and metabolic demand impact the redox state of the myocardium and coronary arterial wall in vivo, we used high spatial resolution imaging mass . Does the Mismatch Match the Penumbra? | Stroke . The biochemical control of ferroptosis includes amino acid metabolism, glutathione metabolism, lipid metabolism, iron metabolism, and other metabolic pathways [43].