ischemic penumbra metabolic demand

These multifaceted functions make them important cellular stress sensors, and they drive metabolic reprogramming for cellular adaptation to harsh environments, such as nutrient depletion or hypoxia [15]. confirmed this: In a Huntington model, they discovered region-specific metabolic reprogramming of astrocytes, which directly induced neuronal susceptibility. 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 occurs, a rapid increase in the production of ROS rapidly overwhelms the antioxidant defenses, which are inadequate to completely clear the ROS. Visualizing and Modulating Mitophagy for Therapeutic Studies of Neurodegeneration. It is usually located around an infarct core which represents the tissue which has already infarcted or is going to infarct regardless of reperfusion. Mitochondria are major contributors to cellular ROS, and there are multiple antioxidant pathways to neutralize ROS, including superoxide dismutase (SOD2), glutathione, thioredoxin, and peroxiredoxins. Recent research has shown that metabolic disorders have significant effects, both before and after the onset of ischemic stroke. 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. Both studies revealed that the metabolites have inhomogeneous distributions in the brain, with high levels of spatial specificity. It was shown that free and protein-bound NADH differs regarding lifetime. Furthermore, there exist some serious contraindications and complications; for example, thrombolytic agents have been associated with symptomatic intracerebral hemorrhage [6]. It has been implied that the neuroprotective ability of IPC may be related with the promotion of ANLS, where lactate serves as a potential agent to protect neurons against lethal ischemic injury. Eventually, exogenous lactate administration can significantly increase cell survival in neuronal cultures against lethal oxygen glucose deprivation (OGD) [84]. It has been found that direct administration of NADPH can significantly reduce infarct volume, improving post-stroke survival and neurological function recovery in mouse and rat stroke models, with a remarkable increase in the level of the reduced form of glutathione (GSH), while decreasing ROS levels [41]. 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. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. All brain cell types are able to uptake ketones; the ketones are then metabolized to acetyl-CoA to support the cell energy [29]. Direct intracerebroventricular or intravenous administration of lactate protected mouse brains against ischemic injury [22]. The .gov means its official. Rapid NAD+ depletion inevitably disrupts intracellular energy homeostasis. 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. 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. Thus, there is an urgent need to develop new treatment strategies for ischemic stroke. In short, understanding the mechanism of metabolic reprogramming is expected to be greatly beneficial for our understanding of ischemic stroke treatment and for the standardized application of IPC. Under these circumstances, oxidative stress occurs, which further induces damage to nucleic acid bases, lipids, and proteins, ultimately leading to cell death by necrosis or apoptosis [40]. Busija D.W., Rutkai I., Dutta S., Katakam P.V. Upon ischemic stroke, cerebral glycolysis exhibits an increasing trend. Upregulation of pentose phosphate pathway and preservation oftricarboxylic acid cycle flux after experimental brain injury. Zhang et al. Geng J.L., Zhang Y., Li S.J., Li S.N., Wang J.K., Wang H., Aa J.Y., Wang G.J. It will be a further explanation that the pathophysiological mechanisms in ischemic stroke are closely related to metabolic disorder. Growing evidence suggests that ischemic preconditioning takes advantage of brain plasticity for its neuroprotective purposes, among which, metabolic reprogramming is crucial to co-ordinate the metabolic imbalance, especially for energy and redox homeostasis. 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. 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]. 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]. The ischemic penumbra: operationally . However, the underlying biological mechanisms of ischemic preconditioning are still confusing. ischemic injury develops heterogeneously, and with time coalesces dynamically into a homogenous core. sharing sensitive information, make sure youre on a federal Lactate: Brain fuel in human traumatic brain injury: A comparison with normal healthy control subjects. The latter form is informative in energy metabolism than free NADH. -HB is a biomarker of the cytosolic NADH/NAD+ ratio [79], indicating that IPC can regulate the NADH/NAD+ ratio. We can see that antioxidant defense plays an important role in the redox control, which may promote new therapeutic strategies for ischemic stroke in the future. However, continuing ischemic stress, or additional energy demanding episodes, or both, will exhaust this limited capacity and transform penumbra into necrotic tissue. Krebs H.A., Williamson D.H., Bates M.W., Page M.A., Hawkins R.A. GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling. Collateral flow predicts response to endovascular therapy for acute ischemic stroke. Intriguing, the protective effect of IPC can be mimicked pharmacologically. Stockwell B.R., Friedmann Angeli J.P., Bayir H., Bush A.I., Conrad M., Dixon S.J., Fulda S., Gascon S., Hatzios S.K., Kagan V.E., et al. Wang P., Miao C.Y. The Conditions Under Which Piracetam Is Used and the Factors That Can Improve National Institute of Health Stroke Scale Score in Ischemic Stroke Patients and the Importance of Previously Unnoticed Factors from a Hospital-Based Observational Study in Taiwan. Sarrafzadegan N., Gharipour M., Sadeghi M., Nezafati P., Talaie M., Oveisgharan S., Nouri F., Khosravi A. Metabolic Syndrome and the Risk of Ischemic Stroke. However, these conventional therapies have a narrow therapeutic window: the effective intravenous thrombolytic therapy is within 4.5 h of onset, and that of intra-arterial thrombectomy is within 6 h of onset [3], resulting in only a minority (35%) of stroke patients being able to receive these therapies [4]. These studies have indicated the time-specificity of IPC; however, the dynamic change of metabolic reprogramming induced by IPC is still unclear. Shariatgorji M., Nilsson A., Fridjonsdottir E., Vallianatou T., Kllback P., Katan L., Svmarker J., Mantas I., Zhang X., Bezard E., et al. Advance in this active research field will stimulate a promising new direction in precision intervention and drug target discovery for ischemic stroke. 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). Collectively, these findings suggest IPC could specify metabolic reprogramming in neurons and astrocytes and contribute to functional homeostasis. Meanwhile, IPC-treated astrocytes significantly enhanced lactate secretion into the extracellular media. Chen W.L., Jin X., Wang M., Liu D., Luo Q., Tian H., Cai L., Meng L., Bi R., Wang L., et al. This enhanced glycolysis drives the generation of energy-rich molecules (e.g., ATP, NADH, and NADPH) and the supply of carbon pool for the synthesis of amino acids, nucleotides, and lipids [64]. Erythrocytes are the only cell type responsible for delivering oxygen. Ischemic preconditioning and glucose metabolism during low-flow ischemia: Role of the adenosine a receptor. In addition, age-related alterations in TCA cycle enzyme activities will likely contribute to the decline of mitochondrial bioenergetics [96]. 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. Oxygen is a crucial substrate in metabolism. Yin J., Han P., Tang Z., Liu Q., Shi J. Sirtuin 3 mediates neuroprotection of ketones against ischemic stroke. Effects of ischemic preconditioning on mitochondrial and metabolic neruoprotection: 5 adenosine monophosphate-activated protein kinase and sirtuins. Liu P.S., Wang H., Li X., Chao T., Teav T., Christen S., Di Conza G., Cheng W.C., Chou C.H., Vavakova M., et al. Malpartida A.B., Williamson M., Narendra D.P., Wade M.R., Ryan B.J. 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. 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. There are two major affected zones in an ischemic brain: The infarct core, surrounded by an ischemic penumbra. Vessey D.A., Li L., Honbo N., Karliner J.S. Hu S., Dong H., Zhang H., Wang S., Hou L., Chen S. Noninvasive limb remote ischemic preconditioning contributes neuroprotective effects via activation of adenosine a1 receptor and redox status after transient focal cerebral ischemia in rats. Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Sato H., Nomura S., Maebara K., Sato K., Tamba M., Bannai S. Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. Mortality, morbidity, and risk factors in China and its provinces, 19902017: A systematic analysis for the Global Burden of Disease Study 2017. More glycolytic intermediates divert into the pentosephosphate pathway (PPP), while the entrance of pyruvate for mitochondrial oxidation is downregulated [18]. The astrocytic glycolysis is also stimulated by neuronal activation, giving neurons the capacity of tight control over astrocyte metabolism. Giusti B., Saracini C., Bolli P., Magi A., Martinelli I. Early-onset Ischaemic Stroke: Analysis of 58 Polymorphisms in 17 Genes Involved in Methionine Metabolism. Excitingly, emerging evidence from recent research has indicated that metabolic reprogramming may be the crucial neuroprotective mechanism of IPC for ischemia treatment. ROS is not elevated and, so, this region sustains little damage [89]. Then, the accumulated free radicals damage cell membranes, mitochondria, and DNA, thus triggering caspase-mediated cell death. Berthet C., Lei H.T., Thevenet J., Gruetter R. Neuroprotective role of lactate after cerebral ischemia. Murry C.E., Jennings R.B., Reimer K.A. Erythrocyte Metabolic Reprogramming by Sphingosine 1-Phosphate in Chronic Kidney Disease and Therapies. Zhou D., Ding J.Y., Ya J.Y., Pan L.Q., Bai C.B., Guan J.W., Wang Z.G., Jin K.X., Yang Q., Ji X.M., et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Wender R., Brown A.M., Fern R., Swanson R.A., Farrell K., Ransom B.R. Hess D.C., Blauenfeldt R.A., Andersen G., Hougaard K.D., Hoda M.N., Ding Y., Ji X. Therefore, the provision of a summary on the progress of the metabolic regulation in ischemic stroke and IPC will serve to provide new ideas for ischemic stroke therapies. 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 authors declare no conflict of interest. Rink C., Gnyawali S., Peterson L., Khanna S. Oxygen-inducible glutamate oxaloacetate transaminase as protective switch transforming neurotoxic glutamate to metabolic fuel during acute ischemic stroke. Goyal M., Menon B.K., van Zwam W.H., Dippel D.W., Mitchell P.J., Demchuk A.M., Dvalos A., Majoie C.B., van der Lug A., de Miquel M.A., et al. Laursen M.R., Hansen J., Elkjaer C., Stavnager N., Nielsen C.B., Pryds K., Johnsen J., Nielsen J.M., Botker H.E., Johannsen M. Untargeted metabolomics reveals a mild impact of remote ischemic conditioning on the plasma metabolome and alpha-hydroxybutyrate as a possible cardioprotective factor and biomarker of tissue ischemia. Metabolomic Profiling Reveals That Reprogramming of Cerebral Glucose Metabolism is Involved in Ischemic Preconditioning Induced Neuroprotection in a Rodent Model of Ischemic Stroke. Increased pools of NAMPT and NAD+ are protective against oxygenglucose deprivation, as well as playing a crucial role in cell energy maintenance. Mitochondria are signaling, bioenergetic, and biosynthetic organelles. Consistent with this data, strategies aimed at increasing astrocyte glycogen have been successfully applied for mitigating neuronal loss [20]. and transmitted securely. In remote IPC, inflation of a blood-pressure cuff on the arm or leg is used [8]. 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. 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. The ischemic penumbra has been in the center of ischemic stroke research for the last 40 years. 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. However, continuing ischemic stress, or additional energy demanding episodes, or both, will exhaust this limited capacity and transform penumbra into necrotic tissue. 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. Ischemic penumbra is intercalated between normoxic (proximal) and anoxic (distal) fields. Cellular NAD replenishment confers marked neuroprotection against ischemic cell death: Role of enhanced DNA repair. Sep 2011. Faubert B., Solmonson A., DeBerardinis R.J. Metabolic reprogramming and cancer progression. 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]. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. The ischemic penumbra is defined as functionally impaired yet still viable tissue surrounding the ischemic core. Cellular metabolism is a flexible network to meet homeostasis demands in real-time. 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. 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. 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 stroke occurs most frequently in individuals aged 65 years. Altogether, these results imply that subduing postischemic hyperglycolysis and the regulation of brain glucose metabolism play important roles in the neuroprotective aspect of IPC. Mounting evidence has shown that brain metabolic plasticity and IPC metabolic reprogramming are crucial for ischemic defense, typically through maintaining cellular energy and redox homeostasis. The malateaspartate shuttle (MAS) is considered the most important NAD+/NADH shuttle in neurons, playing a prominent role in neuronal mitochondrial respiration. The more we understand the underlying metabolic reprogramming mechanisms manipulated by IPC affecting its efficiency and function against ischemic stroke, the more we will be able to experimentally (and, eventually, clinically) utilize the metabolic homeostasis to confer protection against the ischemic insult. 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. Ischemic penumbra denotes the part of an acute ischemic stroke that is at risk of progressing to infarction but is still salvageable if reperfused. Katsyuba E., Romani M., Hofer D., Auwerx J. NAD. 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. Timely interventions are effective for avoiding the progression of the penumbra into infarction. Exogenous application of nicotinamide mononucleotide (NMN), an intermediate of NAD+ synthesis, mimics the protective effect of IPC under ischemia and reperfusion injury. In 2014, Gary used laser desorptionionization mass (LDI/MS) spectrometry to create maps of the spatial distributions of glutamine, DHA, and other metabolites across the brain and within each sub-region [87]. 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. Reduced Nicotinamide Adenine Dinucleotide Phosphate, a Pentose Phosphate Pathway Product, Might Be a Novel Drug Candidate for Ischemic Stroke. Hou W., Xie Y., Song X., Sun X., Lotze M.T., Zeh H.J., Tang D. Autophagy promotes ferroptosis by degradation of ferritin. The metabolic syndrome. Metabolic reprogramming during ischemic stroke is also reflected in the large changes of genes and proteins related to carbon and lipid metabolism. Amarenco P., Kim J.S., Labreuche J., Charles H., Abtan J., Bejot Y., Cabrejo L., Cha J.K., Ducrocq G., Giroud M., et al. 2,3-BPG is an erythrocyte-specific glycolytic intermediate that facilitates O2 release [71]; concurrently, hypoxia promotes renal damage and progression of chronic kidney disease (CKD). Stroke is a leading cause of death and permanent disability, imposing heavy social and family burdens [1,2]. Likewise, as the most difficult challenge in ischemic stroke is energy failure, whether some other new energetic substrates are mobilized by IPC (e.g., fructose), in addition to the glucose and common alternative energy substrates, should be determined. NAD+ levels and the NAD+/NADH redox couple provide a readout and regulator for cellular energy metabolism [30]. A previous study has shown ketone bodies to reduce ROS by using NADH as an electron donor. Mech. Lekoubou A., Ovbiagele B., Markovic D., Sanossian N., Towfighi A. Consistently, a study showed that neurons benefited from the co-incubated astrocytes, enhancing lactate secretion induced by IPC in astrocytes. Waves of depolarizations, the peri-infarct spreading depres- . Direct NAD+ repletion, either in animal or in cultured neurons, markedly reduced ischemic cell death and DNA damage [32,33]. During glycolysis, NAD+ is reduced to NADH, which is then oxidized by complex I of the mitochondrial electron transport chain (ETC) to supply the necessary proton gradient for ATP production. Li P., Quan W., Lu D., Wang Y., Zhang H.H., Liu S., Jiang R.C., Zhou Y.Y. Related studies have mainly focused on the processes of humoral and neuronal factors interacting to initiate and transmit signals, in order to increase the cerebral blood flow and protect mitochondria to reduce oxidative stress [73], as well as several key enzymes and regulatory factors, such as AMP-activated protein kinase (AMPK), SIRT1, and SIRT574. NADP+ and its reduced counterpart, NADPH, are mainly required for anabolic reactions and cellular oxidative-stress defense. 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]. Another critical concern is the proper time window for IPC metabolic reprogramming in sustaining the neuroprotection effects for the forthcoming ischemia stroke. At a practical level, however, this definition is unwieldy. 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. An increased understanding of the pathogenic mechanisms of stroke and IPC serves to highlight the importance of metabolic reprogramming. Magistretti P.J., Martin J.L. Ischemic stroke is typically caused by blood vessel blockage, which accounts for approximately 87% of all stroke cases. It is well-known that lysine, being an energy-providing amino acid, is necessary for the biosynthesis of L-carnitine. The biochemical control of ferroptosis includes amino acid metabolism, glutathione metabolism, lipid metabolism, iron metabolism, and other metabolic pathways [43]. 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 major function of mitochondria is ATP production, but they perform many other roles as well, including biosynthetic metabolism, generation of ROS, redox molecules and metabolites, and regulation of cell signaling and cell death. It has been demonstrated that mitochondria are a major target in ischemic injury. Xi Q., Cheranov S.Y., Jaggar J.H. 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. However, a controversial finding has been observed in the plasma of ischemic rats and the CSF of humans after IPC: Both of their glucose levels increased significantly [74], indicating the metabolic regulation of IPC may be metabolic compartmentalization. They showed erythrocyte S1P levels rapidly increased in 21 healthy lowland volunteers at 5260 m altitude, with a concurrent elevation of hemoglobin and oxygen release capacity. 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. 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. Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone. 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. Mechanisms underlying neuronal death in ischemic stroke (1) Mitochondrial response, including excessive ROS production, mitochondrial calcium overloading, and disrupted mitochondria quality control. Servick K. Reprogrammed cells could tackle brain damage. TCA cycle reactions yield metabolite intermediates and energetic precursors for oxidative phosphorylation. Moreover, the brain utilizes metabolic plasticity, a protective response to stroke injury. Morris-Blanco K.C., Cohan C.H., Neumann J.T., Sick T.J., Perez-Pinzon M.A. Bahadoran A., Bezavada L., Smallwood H.S. The normal CBF in healthy normal men is 54 mL/100 g per minute. However, the underlying neuroprotection mechanisms of IPC remain elusive. Jaggar et al. First, the availability of cysteine is the limiting link in GSH biosynthesis. Though emerging studies have shown that metabolic reprogramming is especially critical in IPC, the study of metabolic reprogramming conducted by IPC is still in its infancy (Figure 4). Geng J.L., Aa J.Y., Feng S.Q., Wang S.Y., Wang P., Zhang Y., Ouyang B.C. At the onset of ischemic stroke, in order to maintain the energy demand, compensatory pathways are initiated, comprising a major metabolic reprogramming strategy including glycogen metabolism, lactate metabolism, amino acid metabolism, and lipid metabolism. Stroke incidence rates for those with and without MetS were 2.6% and 1.1%, respectively. Expanding fascinating horizons in metabolism of other cells under hypoxia or hypoglycemia may promote new inspirations. Yin, J. et al. Concept of ischemic penumbra the extent of brain damage during a stroke depends on the severity and duration of the cerebral blood flow (CBF) disorder there are two major zones of injury within the ischemic area: core penumbra as blood flow decreases, there is an initial loss of function with structural integrity intact ( functional threshold) Baron, Donnan, Heiss, and others have re-explored the penumbra concept using PET markers [].The benzodiazepine 11 C-flumazenil binds to the intact GABA-A receptors of presumably intact neural tissue. Ischemic preconditioning triggers endogenous neuroprotection to defend against subsequent, more severe cerebral ischemia. . The translation of experimental . A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. Wang H., He Z., Zhang Y., Zhang J. Intravenous thrombolysis and mechanical thrombectomy for selected . Wu Y., Zhang S., Gong X., Tam S., Xiao D., Liu S., Tao Y. Previous studies reported that when MCAO is applied during the early IPC phase, the brain is ischemia-tolerant. 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]. Raf B., Rishi S., Annick W. Evaluation of lactate as a marker of metabolic stress and cause of secondary damage in acute ischemic stroke or TIA. Writingoriginal draft preparation, editing, J.L. Metabolic syndrome (MetS) is a common metabolic disorder, involving a constellation of insulin resistance, abdominal obesity, hypertension, and dyslipidemia. However, the importance of PCr in energy homeostasis is underestimated by the fact that the total creatine pool (as creatine and PCr) in the brain is at least three-fold larger than the adenosine nucleotide pool (consisting of AMP, ADP, and ATP). This process is named the astrocyteneuron lactate shuttle (ANLS). (2014) Multi-parametric imaging of cerebral hemodynamic and metabolic response followed by ischemic injury . Notably, neurons and astrocytes preferentially use quite different metabolic pathways in physiological conditions [98]. This research was funded by National Natural Science Foundation of China [No.81971198]; Beijing Municipal Natural Science Foundation [No.7192103]; Chinese Ministry of science and Technology [No.2019YFA0508603]; and the China Postdoctoral Science Foundation (2020M670103). In such tissue, blood flow is decreased below the metabolic demand, but energy metabolism is maintained at a level allowing morphologic preservation of tissue. With positron emission tomography (PET), we characterized the metabolic patterns of tissue compartments identified by MRI and compared the volumes of mismatch to those of PET-defined penumbra. Early reperfusion aims to save the ischemic penumbra by preventing infarct core expansion and is the mainstay of acute ischemic stroke therapy. Previous evidence has revealed that IPC diverts excess glucose to oxPPP. Mitochondria-derived reactive oxygen species dilate cerebral arteries by activating Ca. 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. Paez D.T., Garces M., Calabro V., Bin E.P., DAnnunzio V., Del Mauro J. Adenosine a1 receptors and mitochondria: Targets of remote ischemic preconditioning. 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.

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