Chen W.L., Jin X., Wang M., Liu D., Luo Q., Tian H., Cai L., Meng L., Bi R., Wang L., et al. Glycogen: The metabolism of glycogen is critical for the release of stored glucose. Acute imaging of the penumbra is a critical step toward selection of patients that can best benefit from penumbral-salvaging reperfusion therapies. The study conducted cerebral ischemia and IPC in cultured rodent astrocytes and neurons, revealed that neurons incubated with IPC-treated astrocytes were significantly protected against lethal ischemic injury. Geng J.L., Zhang Y., Li S.J., Li S.N., Wang J.K., Wang H., Aa J.Y., Wang G.J. Furthermore, metabolic reprogramming is a double-edged sword; for example, the enhancement of glucose uptake and glycolysis can provide ATP faster, but the ongoing delivery of large amounts of glucose to the ischemic tissue along with an anaerobic glycolysis shift can adversely promote lactic acidosis, thus leading to tissue necrosis. L-carnitine is the only transporter of fatty acids across the mitochondrial membrane, to be metabolized with the generation of energy, indicating an energetic compensatory mechanism by IPC for neuronal survival. Ying W.H., Wei G.W., Wang D.M., Wang Q., Tang X.N., Shi J., Zhang P., Lu H.F. Intranasal administration with NAD+ profoundly decreases brain injury in a rat model of transient focal ischemia. Betti et al. 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. Ketone. Astrup J, Siesj BK . Zeiger S.L., McKenzie J.R., Stankowski J.N., Martin J.A., Cliffel D.E., McLaughlin B. Neuron specific metabolic adaptations following multi-day exposures to oxygen glucose deprivation. The Ischemic Penumbra: Correlates in Imaging and Implications for Treatment of Ischemic Stroke. Introduction We aimed to assess metabolite profiles in peri-infarct tissue with magnetic resonance spectroscopy (MRS) and correlate these with early and late clinical recovery. Research has found that brain ischemia-refusion (I/R) injury can activate AMPK, which is an adaptive response to stress that plays an essential role in maintaining energy homeostasis, while the overactivation of AMPK accentuates hyperglycolysis, which can lead to serious metabolic distress. revealed that RKIP overexpression markedly reduced the necrotic area after ischemic stroke, mainly reflected in the metabolism of energy, amino acids, and lipids [38]. Simultaneously, the anaplerotic pathway is promoted to refill the macromolecular biosynthesis for rapid proliferation in some cells. Consistent with this data, strategies aimed at increasing astrocyte glycogen have been successfully applied for mitigating neuronal loss [20]. A self-controlled interventional study measured dynamic cerebral autoregulation (dCA) and blood biomarkers at seven time points in healthy participants who had conducted IPC, and found that dCA was significantly increased at 6 h and was sustained for at least 24 h after IPC, while two neuroprotective factors and four inflammation-related biomarkers were significantly elevated, compared with their baseline levels. 40.2% ischemic stroke individuals were diagnosed with MetS. Mitochondria are signaling, bioenergetic, and biosynthetic organelles. Ischemic stroke is the consequence of a sharp reduction of regional cerebral blood flow (CBF), resulting in oxygen and glucose deprivation (OGD). Busija D.W., Rutkai I., Dutta S., Katakam P.V. Meanwhile, IPC also boosts the PPP, providing an essential redox equivalent for GSH regeneration and enhancing the capacity of antioxidant defense. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Preserving pools of NAD+ confers neuroprotection after ischemic stress. Luo L.L., Li Y.F., Shan H.M., Wang L.P., Yuan F., Ma Y.Y., Li W.L., He T.T., Wang Y.Y., Qu M.J., et al. Bahadoran A., Bezavada L., Smallwood H.S. Ischemic stroke occurs most frequently in individuals aged 65 years. Simmons E.C., Scholpa N.E., Schnellmann R.G. Sphingosine 1-phosphate is an important endogenous cardioprotectant released by ischemic pre- and postconditioning. Xu J., Khoury N., Jackson C.W., Escobar I., Stegelmann S.D., Dave K.R., Perez-Pinzon M.A. 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. It should be noted that, due to different synaptic activities, loop connectivity, and functional domains, heterogeneity exists among the spatial distribution of endogenous metabolites; this distribution characteristic has only been noticed in recent years. It was first discovered by Murry et al., in the canine heart, in 1986 [7]. Wang S., Xing Z., Vosler P.S., Yin H., Li W., Zhang F., Signore A.P., Stetler R.A., Gao Y., Chen J. Patients underwent computer tomography . The accumulation of glucose is the primary feature of ischemic stroke, mainly regulated by AMPK, which is a key kinase activated by energy failure which can promote glucose uptake. In-depth research considering these open questions will be valuable for exploring the mechanisms of IPC. Yin, J. et al. Stroke is a leading cause of death and permanent disability, imposing heavy social and family burdens [1,2]. The metabolic syndrome. The authors declare no conflict of interest. Excitingly, emerging evidence from recent research has indicated that metabolic reprogramming may be the crucial neuroprotective mechanism of IPC for ischemia treatment. However, the complex connection between the neuroprotective function of IPC and cerebral metabolic reprogramming is still an exciting area of investigation, especially with respect to their spatiotemporal variation in consideration of the brain metabolic compartmentalization and time dependence. As the brain NADPH level decreases during ischemia, boosting the PPP activity may serve as a potential neuroprotective strategy for the regulation of the cellular redox environment [81]. Together, these findings reveal the biological activity of S1P in erythrocyte oxygen delivery, indicating that IPC may enhance erythrocyte oxygen delivery through S1P, thereby enhancing cerebral metabolism to defend against ischemic stress. Mitochondrial Dysfunction and Mitophagy in Parkinsons Disease: From Mechanism to Therapy. IPC has been shown to enhance levels of NAD+ in the brain [77]. Wender et al. Ischemic Neuroprotectant PKCepsilon Restores Mitochondrial Glutamate Oxaloacetate Transaminase in the Neuronal NADH Shuttle after Ischemic Injury. However, the underlying neuroprotection mechanisms of IPC remain elusive. Writingoriginal draft preparation, editing, J.L. Previous research has revealed that S1P is an important endogenous protectant against ischemia, where the increased release of S1P from myocytes in response to IPC has been observed [86]. 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]. Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia. Ischaemic conditioning and reperfusion injury. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. MetS prevalence was 61.2% in stroke survivors. Wolf-Dieter Heiss. This refinement has potential therapeutic implications. Effects of ischemic preconditioning on mitochondrial and metabolic neruoprotection: 5 adenosine monophosphate-activated protein kinase and sirtuins. At the onset of ischemia, NAD+ levels decrease within 30 min, a second depletion occurs at 6 h of reperfusion (when necrosis is prominent), and a third depletion of NAD+ happens at 24 h (when apoptosis is prominent). Overall, metabolic reprogramming is a stress-protectant mechanism for brain tissues under ischemia, which can sustain cerebral cell survival in specified period, but will be invalidated if no effective interventions to recover glucose and oxygen supply are implemented for a prolonged stage. It will be a further explanation that the pathophysiological mechanisms in ischemic stroke are closely related to metabolic disorder. It has been found that metabolic disorders are a determinant of the incidence and progression of stroke. FOIA Narayanan S.V., Perez-Pinzon M.A. Mech. Morawetz R.B., Crowell R.H., De Girolami U. As a library, NLM provides access to scientific literature. Metabolic disorder and metabolic plasticity in ischemic stroke: Upon ischemia onset, a sharp reduction of regional CBF results in oxygen and glucose deprivation, followed by excess excitatory and bloodbrain barrier dysfunction. Proteomic analysis of pharmacological preconditioning. Chen S.Y., Liu J.W., Wang Y.H., Huang J.Y., Chen S.C., Yang S.F., Wang P.H. The normal CBF in healthy normal men is 54 mL/100 g per minute. NADP+ is an essential cofactor for the rate-limiting step of the pentosephosphate pathway (PPP). Furthermore, as IPC not only can salvage the stroke patient at the acute period, but can also provide effective solutions for stroke rehabilitation during the chronic period, determination of the underlying metabolic regulation mechanism, which is still unclear, should be actively pursued. Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. Goodman R.P., Markhard A.L., Shah H., Sharma R., Skinner O.S., Clish C.B., Deik A., Patgiri A., Hsu Y.H., Masia R., et al. Reduced Nicotinamide Adenine Dinucleotide Phosphate, a Pentose Phosphate Pathway Product, Might Be a Novel Drug Candidate for Ischemic Stroke. It was shown that free and protein-bound NADH differs regarding lifetime. The relaxation of VSM can also be indirectly regulated by the action of NO and other vasoactive agents. sharing sensitive information, make sure youre on a federal However, the underlying biological mechanisms of ischemic preconditioning are still confusing. Research has found that L-glutamine reduced brain infarct volume and promoted neurobehavioral recovery in cerebral ischemic mice [25]. Advance in this active research field will stimulate a promising new direction in precision intervention and drug target discovery for ischemic stroke. quences as drastically increase d metabolic demand cannot be satisfied in regions with critically reduced blood supply. 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 . If the ischemic penumbra is characterized by these approaches, then a reduction of CBF to levels between a lower threshold of 10-15 mL/100 g/min and an upper threshold of approximately 25 mL/100 g/min is likely to identify penumbral tissue. Magistretti P.J., Martin J.L. 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]. Note incursions of preferentially-oxygenated peri-arterial cells across planar hypoxic (ht) and anoxic (at) pO 2 thresholds. the ischemic penumbra can maintain metabolic demand with marginal blood flow from collateral circulation for a maximum of __ before increasing in size? Simultaneously, IPC increases regional CBF, in order to enhance the supply of blood glucose and oxygen to maintain metabolic consumption. Other significant changes in amino acid metabolic pathways have also been confirmed upon ischemia: the levels of some well-known energy-providing amino acids, such as leucine, isoleucine, valine, tyrosine, and lysine, increased significantly in brain tissues of mice treated by IPC, indicating that proteolysis was up-regulated [16]. 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. Mechanistically, S1P enhances the release of membrane-bound glycolytic enzymes to the cytosol, which promotes glycolysis and, thus, increases the production of 2,3-bisphosphoglycerate (2,3-BPG). Thus, there is an urgent need to develop new treatment strategies for ischemic stroke. Erythrocytes are the only cell type responsible for delivering oxygen. Metabolic reprogramming during ischemic stroke is also reflected in the large changes of genes and proteins related to carbon and lipid metabolism. Glutamate can be exchanged for cystine in a 1:1 ratio, such that the accumulation of extracellular glutamate could trigger ferroptosis in physiological contexts [44]. Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases. Another critical concern is the proper time window for IPC metabolic reprogramming in sustaining the neuroprotection effects for the forthcoming ischemia stroke. In this review, we summarize the metabolic disorder and metabolic plasticity in the incidence and progression of ischemic stroke. In response to ischemia, there exists a cerebral vessel autoregulatory mechanism, inducing the enhancement of cerebral collateral circulation and vasodilation, in order to stabilize or increase the CBF and oxygen/glucose extraction for viable neurons. The pathophysiology of MetS seems to be largely attributable to the metabolic disorder caused by insulin resistance, with glucose intolerance and excessive flux of fatty acids also being implicated [57]. the contents by NLM or the National Institutes of Health. Remote ischaemic conditioningA new paradigm of self-protection in the brain. Furthermore, IPC treatment also remarkably improves the metabolic disturbances in the TCA cycle during ischemia. The ischemic penumbra is defined as the severely hypoperfused, functionally impaired, at-risk but not yet infarcted tissue that will be progressively recruited into the infarct core. Accumulating evidence has suggested that IPC regulates the cerebral metabolism by providing alternative energy substrates, which partly reduce the dependence of the brain on a continuous supply of glucose, therefore improving the brains resistance to ischemia. Meanwhile, IPC-treated astrocytes significantly enhanced lactate secretion into the extracellular media. Rapid NAD+ depletion inevitably disrupts intracellular energy homeostasis. . Here we provide a summary of metabolic mechanism of ischemic preconditioning when it is applied to ischemic stroke. Banks M.A., Porter D.W., Martin W.G., Castranova V. Ozone-induced lipid-peroxidation and membrane leakage in isolated rat alveolar macrophages- protective effects of taurine. Though glycolysis is advantageous for rapidly producing ATP to meet the high energy demands, hyperglycolysis can aggravate the brain damage caused by lactic acidosis and ROS overproduction [76]. Yang Q., Guo M., Wang X., Zhao Y.X., Zhao Q., Ding H.Y., Dong Q., Cui M. Ischemic preconditioning with a ketogenic diet improves brain ischemic tolerance through increased extracellular adenosine levels and hypoxia-inducible factors. Zong W.X., Rabinowitz J.D., White E. Mitochondria and Cancer. Metabolic reprogramming for metabolic homeostasis maintenance. Objectively, the study on metabolic reprogramming of ischemic preconditioning is still in its infancy, such as, there are extremely few studies on the spatiotemporal variation, aging influence, and astrocyte-neuron interactions in metabolic reprogramming of ischemic preconditioning. Dirnagl U., Endres M. Found in translation preclinical stroke research predicts human pathophysiology clinical phenotypes, and therapeutic outcomes. Krebs H.A., Williamson D.H., Bates M.W., Page M.A., Hawkins R.A. Though the information about IPC-mediated metabolic reprogramming in older adults is scant, these promising findings drive the hypothesis that IPC-mediated metabolomic reprogramming may have a subtle susceptibility to aging. Iron-Deficiency and Estrogen Are Associated with Ischemic Stroke by Up-Regulating Transferrin to Induce Hypercoagulability. Notably, neurons and astrocytes preferentially use quite different metabolic pathways in physiological conditions [98]. Mouse genetic studies have shown that S1P protects against tissue hypoxia by inducing O2 release. However, in response to changes in the micro-environment, metabolic reprogramming is notably crucial to maintaining metabolic homeostasis. In addition, age-related alterations in TCA cycle enzyme activities will likely contribute to the decline of mitochondrial bioenergetics [96]. In such tissue, blood flow is decreased below the metabolic demand, but energy metabolism is maintained at a level allowing morphologic preservation of tissue. found that, after 60 min of glucose deprivation, astrocytes in the rat optic nerve (a CNS white matter tract) drove glycogen to be broken down to lactate, which was then transferred to fuel axons [19]. Baranovicova E., Grendar M., Kalenska D., Tomascova A., Cierny D., Lehotsky J. 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. Once ischemic stroke occurs, the PPP is boosted and more glycolytic intermediates are diverted into the PPP to sustain NADPH production [18]. Li M., Zhou Z.P., Sun M., Cao L., Chen J., Qin Y.Y., Gu J.H., Han F., Sheng R., Wu J.C., et al. Expanding fascinating horizons in metabolism of other cells under hypoxia or hypoglycemia may promote new inspirations. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (, ischemic stroke, ischemic preconditioning (IPC), metabolic reprogramming. As we showed in Section 1.2 and Section 1.3, under oxygen and glucose deprivation (OGD), the brain experiences a shift of the cerebral metabolism from glucose pathways to compensatory pathways, taking energy from other metabolic substrates, such as ketones, amino acids, endogenous carbohydrates, and lactate, in order to sustain energy and redox homeostasis. Amarenco P., Kim J.S., Labreuche J., Charles H., Abtan J., Bejot Y., Cabrejo L., Cha J.K., Ducrocq G., Giroud M., et al. An increasing number of studies have shown that epidemiologic changes are likely responsible for the observed rise of stroke incidence (Table 1). In: Murphy S., editor. These data are consistent with the original concepts of the penumbra and core, but recognize the dynamic complex heterogeneous processes involved. Visualizing and Modulating Mitophagy for Therapeutic Studies of Neurodegeneration. However, the underlying neuroprotective mechanisms of IPC remain elusive. These include: NADP+/NADPH. 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. Iron is essential for the accumulation of lipid peroxides and execution of ferroptosis. There is also a beneficial role of erythrocyte S1P in hypertensive CKD, where S1P also induces 2,3-BPG production and oxygen delivery [72]. Bethesda, MD 20894, Web Policies In biosynthetic pathways, cancer cells require that intermediate pools are maintained. Since astrocytes play an integral role in inducing ischemic tolerance [97], the traditional view of astrocytes as passive supporters of neurons is revised, and the survival of neurons tightly associated with astrocytes is recognized. 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. 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]. For ischemic stroke, IPC can reduce the infarct size and improve prognosis, which is supported by increasing the cerebral blood flow (CBF), protecting mitochondrial function, and maintaining neuronal activity. The concept of the ischemic penumbra was formulated 30 years ago based on experiments in animal models showing functional impairment and electrophysiological disturbances with decreasing flow to the brain below defined values (the threshold for function) and irreversible tissue damage with the blood The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression. To defend against this, the brain shifts the cellular machinery from aerobic to anaerobic metabolism. -HB is a biomarker of the cytosolic NADH/NAD+ ratio [79], indicating that IPC can regulate the NADH/NAD+ ratio. de Jonge R., de Jong J.W. Timely interventions are effective for avoiding the progression of the penumbra into infarction. It has been found that metabolic disorder is a determinant of the incidence and progression of stroke. 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. When ischemic stroke occurred, patients who had a target LDL cholesterol level of 90110 mg per deciliter had a higher risk of subsequent cardiovascular events than those who had a target range of less than 70 mg per deciliter. Therefore, given the critical role of these organelles in disease onset and progression, strategies . Considering these results, we may be able to predict the spatial properties of ischemic stroke metabolic disorders and IPC-mediated metabolic remodeling; however, there is still a lack of relevant research. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. government site. When the CBF is below 10 mL/100 g per minute, irreversible cellular injury will occur, and the infarct core forms [10]. Meanwhile, exogenous supplementation of lactate has shown remarkable effects in traumatic brain injury therapy [23]. An official website of the United States government. Glenn T.C., Martin N.A., Horning M.A. 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]. Ischemic penumbra denotes the part of an acute ischemic stroke that is at risk of progressing to infarction but is still salvageable if reperfused. Astrocytes state in a particular position to both sense neuronal signaling and capture glucose directly from the capillary and permit them to govern astrocyte-neurons cooperation. Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice. The Ischemic Penumbra: Correlates in Imaging and Implications . Together, effective IPC metabolic reprogramming may happen and be assumed to sustain during the early and late phases of IPC. See Answer Recently, Yang X. et al. investigated genomic DNA from 501 ischemic stroke patients and 1211 comparable controls, and identified significant genetic associations between premature ischemic stroke in BHMT, CBS, FOLH1, MTR, PON2, TCN2, and TYMS genes, which are involved in methionine metabolism [35]. Eckel R.H., Grundy S.M., Zimmet P.Z. The research by Polyzos et al. 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. This problem has been solved! In delayed IPC, those protein kinases activate transcription factors, which facilitate the synthesis of distal mediators, such as cyclooxygenase-2 (COX-2) and heat shock protein (Hsp72), to induce the protective effect 1224 h after IPC. L-Carnitine: The level of lysine in human CSF increases following IPC [75]. This necessitates that the brain has reliable mechanisms to adequately protect its metabolic homeostasis. A previous study has demonstrated that cerebral ischemia caused a ketogenic response, shown through the enhancement of hepatic free fatty acids -oxidation and increasement of serum and brain -hydroxybutyrate levels [28]. This feature determines that the metabolic homeostasis of neurons is related to their brain micro-environment, which may provide different substrates to fuel the neurons. The ischemic penumbra can maintain metabolic demand with marginal blood flow from collateral circulation for a maximum of _____ before increasing in size. (Stroke. Excessive glutamate release and impeded reuptake of excitatory amino acids result in the activation of NMDARs, AMPARs and KARs. Moreover, the brain utilizes metabolic plasticity, a protective response to stroke injury. There are two major affected zones in an ischemic brain: The infarct core, surrounded by an ischemic penumbra. Mechanisms underlying neuronal death in ischemic stroke (1) Mitochondrial response, including excessive ROS production, mitochondrial calcium overloading, and disrupted mitochondria quality control. Exploring the neuroprotective effects of ginkgolides injection in a rodent model of cerebral ischemia-reperfusion injury by GC-MS based metabolomic profiling. Background and Purpose In ischemic stroke, diffusion-weighted (DW) and perfusion-weighted (PW) magnet resonance imaging (MRI) is used to define the mismatch as the therapeutic target. Remarkably, specific neurotransmitters and neuromodulators could dictate astrocytes glycogenolysis. 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. Under high altitude or chronic kidney disease, hypoxia-responsive sphingosine-1-phosphate (S1P) promotes erythrocyte glycolysis, channeling glucose metabolism toward RapoportLuebering Shunt and inducing 2,3-bisphosphoglycerate (2,3-BPG) production for O2 delivery [71,72]. The ischemic penumbra: operationally . utilized MALDI-MSI to observe the intracerebral distribution of neurotransmitters in Parkinsonian rats, primates, and human patients [88]. Servick K. Reprogrammed cells could tackle brain damage. 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. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Association between Metabolic Syndrome and Cognitive Impairment after Acute Ischemic Stroke: A Cross-Sectional Study in a Chinese Population. Murry C.E., Jennings R.B., Reimer K.A. Energy failure leads to the depolarization of neurons and activation of specific glutamate receptors dramatically, which further induce the failure of the transmembrane electrochemical gradient established by the Na+, K+-ATPase pump. One study showed that neurons made specific metabolic adaptations following IPC (transient OGD) with the regulation of oxygen utilization and lactate production [100]. Metabolic syndrome (MetS) increases stroke incidence. Both studies revealed that the metabolites have inhomogeneous distributions in the brain, with high levels of spatial specificity. Long-term metabolic disorders, such as metabolic syndrome (MetS), increase the probability of occurrence of ischemic stroke. Mortality, morbidity, and risk factors in China and its provinces, 19902017: A systematic analysis for the Global Burden of Disease Study 2017. Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute-On-Chronic Liver Failure. View. The primary definition of the ischemic penumbra is electrical. Upon ischemic stroke, cerebral glycolysis exhibits an increasing trend. Tang X., Fang M., Cheng R., Zhang Z., Wang Y., Shen C., Han Y., Lu Q., Du Y., Liu Y., et al. Mitochondria lie at the key location for neuronal survival [51]. 2011;42 . National Library of Medicine Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging.