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. The translation of experimental . 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. 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. Lactate levels have been shown to decrease 24 h after IPC treatment in MCAO rats, indicating that the glycolytic pathway is downregulated by IPC; meanwhile, the activity of fructose-2,6-biphosphatase 3 (PFKFB3) was inhibited by IPC. These include: NADP+/NADPH. Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. utilized MALDI-MSI to observe the intracerebral distribution of neurotransmitters in Parkinsonian rats, primates, and human patients [88]. Betti et al. and transmitted securely. The astrocytic glycolysis is also stimulated by neuronal activation, giving neurons the capacity of tight control over astrocyte metabolism. 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]. Expanding fascinating horizons in metabolism of other cells under hypoxia or hypoglycemia may promote new inspirations. Lekoubou A., Ovbiagele B., Markovic D., Sanossian N., Towfighi A. Neurons experience mitochondrial dysfunction, shifting the cellular machinery from aerobic to anaerobic metabolism, and a decrease of ATP production, directly resulting in energy failure. Mitophagy is also essential in sustaining mitochondrial homeostasis, biogenesis, and the total number and quality of mitochondria. Marchiq I., Pouyssgur J. Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H+ symporters. the ischemic penumbra can maintain metabolic demand with marginal blood flow from collateral circulation for a maximum of __ before increasing in size? Ischemic heterogeneity is also demonstrated by recent PET studies. ischemic penumbra as a biochemical target (intermittent bioenergetic compromise); (3) the ischemic penumbra as a . Jaggar et al. Consistent with this data, strategies aimed at increasing astrocyte glycogen have been successfully applied for mitigating neuronal loss [20]. Advance in this active research field will stimulate a promising new direction in precision intervention and drug target discovery for ischemic stroke. 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. Sphingosine 1-phosphate is an important endogenous cardioprotectant released by ischemic pre- and postconditioning. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immune metabolism. 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. The https:// ensures that you are connecting to the Sphingosine 1-phosphate (S1P) is a bioactive signaling lipid highly enriched in mature erythrocytes. In acute patients, PET documented areas of decreased 11 C-flumazenil uptake went on to show infarctions, while areas of relative . Katayama H., Hama H., Nagasawa K., Kurokawa H., Sugiyama M., Ando R., Funata M., Yoshida N., Homma M., Nishimura T., et al. . Lactate: Studies in the past two decades have indicated that lactate is also an efficient energy substrate for maintaining neuronal integrity and functioning during cerebral ischemia [21]. Consistently, a study showed that neurons benefited from the co-incubated astrocytes, enhancing lactate secretion induced by IPC in astrocytes. found that ketone treatment in mice at 30 min after ischemia enhanced mitochondrial function, reduced oxidative stress and, therefore, reduced infarct volume [49]. 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. Metabolic reprogramming during ischemic stroke is also reflected in the large changes of genes and proteins related to carbon and lipid metabolism. The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression. The primary aim of current acute stroke . It has been found that metabolic disorder is a determinant of the incidence and progression of stroke. 1 and represented an important milestone for understanding the temporal and spatial evolution of focal ischemic brain injury. In the mammalian brain, neurons are outnumbered 10:1 by astrocytes in most regions. Identify the blocked artery that could potentially cause these symptoms. Jackson C.W., Escobar I., Xu J., Perez-Pinzon M.A. Metabolic reprogramming for metabolic homeostasis maintenance. NAMPT as a Therapeutic Target against Stroke. 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. 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. All authors have read and agreed to the published version of the manuscript. The ischemic penumbra: operationally . 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). Collateral flow predicts response to endovascular therapy for acute ischemic stroke. 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. 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. sharing sensitive information, make sure youre on a federal The ischemic penumbra has been in the center of ischemic stroke research for the last 40 years. In: Murphy S., editor. Finally, the NAD+ pool declines by approximately 3550%. L-Carnitine: The level of lysine in human CSF increases following IPC [75]. View. Yang W.S., Kim K.J., Gaschler M.M., Patel M., Shchepinov M.S., Stockwell B.R. Astrup J, Siesj BK . 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. 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). Amino acids: To sustain fuel oxidation by the tricarboxylic acid (TCA) cycle, nerve cells upregulate glutaminolysis and use of fatty acids and branched chain amino acids. Awooda H.A. 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). Lactate: Previous research has suggested that astrocytes play a pivotal role in the induction of ischemic tolerance [83], during which lactate is extremely crucial. Eventually, exogenous lactate administration can significantly increase cell survival in neuronal cultures against lethal oxygen glucose deprivation (OGD) [84]. TCA cycle reactions yield metabolite intermediates and energetic precursors for oxidative phosphorylation. Metabolomic Profiling Reveals That Reprogramming of Cerebral Glucose Metabolism is Involved in Ischemic Preconditioning Induced Neuroprotection in a Rodent Model of Ischemic Stroke. The malateaspartate shuttle (MAS) is considered the most important NAD+/NADH shuttle in neurons, playing a prominent role in neuronal mitochondrial respiration. 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. The ischemic protection of IPC has been applied in various organs, such as the heart, brain, kidney, liver, lungs, and intestine. First, the availability of cysteine is the limiting link in GSH biosynthesis. Efficacy of remote ischemic conditioning on improving WMHs and cognition in very elderly patients with intracranial atherosclerotic stenosis. The complex underlying mechanisms responsible for the neuroprotection against IPC remain elusive. Ischemic stroke is typically caused by blood vessel blockage, which accounts for approximately 87% of all stroke cases. Sep 2011. 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. 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]. Yarian C.S., Toroser D., Sohal R.S. 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. 6-8 hours A patient presents to the emergency department with left leg weakness and numbness. 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. Association between Metabolic Syndrome and Cognitive Impairment after Acute Ischemic Stroke: A Cross-Sectional Study in a Chinese Population. Excitingly, emerging evidence from recent research has indicated that metabolic reprogramming may be the crucial neuroprotective mechanism of IPC for ischemia treatment. 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. Reduced nicotinamide adenine dinucleotide(NADH)/nicotinamide adenine dinucleotide (NAD+): The NAD+ and NADH redox couple is essential for a variety of electron exchange-dependent biochemical reactions, and serves as a cofactor for enzymes involved in glycolysis, the oxidative decarboxylation of pyruvate to acetyl-CoA, fatty acid -oxidation, and TCA cycle. Effects of ischemic preconditioning on mitochondrial and metabolic neruoprotection: 5 adenosine monophosphate-activated protein kinase and sirtuins. Xi Q., Cheranov S.Y., Jaggar J.H. 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. Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. Patients underwent computer tomography . 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. Therefore, it can be seen that mitochondrial mechanism is an important, but underutilized, target for improving CBF and decreasing brain injury in stroke patients [14]. 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. As a library, NLM provides access to scientific literature. However, the underlying neuroprotective mechanisms of IPC remain elusive. Mitochondrial Dysfunction and Mitophagy in Parkinsons Disease: From Mechanism to Therapy. Thus, there is an urgent need to develop new treatment strategies for ischemic stroke. Age, sex, and race/ethnic temporal trends in metabolic syndrome prevalence among individuals with myocardial infarction or stroke in the United States. Before Eckel R.H., Grundy S.M., Zimmet P.Z. In 2020, Per E. Andrn et al. Sarrafzadegan N., Gharipour M., Sadeghi M., Nezafati P., Talaie M., Oveisgharan S., Nouri F., Khosravi A. Metabolic Syndrome and the Risk of Ischemic Stroke. Altogether, these results imply that subduing postischemic hyperglycolysis and the regulation of brain glucose metabolism play important roles in the neuroprotective aspect of IPC. Research has found that L-glutamine reduced brain infarct volume and promoted neurobehavioral recovery in cerebral ischemic mice [25]. 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. Metabolic disorder and metabolic plasticity are salient features triggered by ischemia. 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. Ischemic stroke is the consequence of a sharp reduction of regional cerebral blood flow (CBF), resulting in oxygen and glucose deprivation (OGD). 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. 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. Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases. It is the para-ischemic zone which loses electrical excitability, as measured by EEG and SEP, but maintains the membrane potential of the neurons within it. 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. Ischemic preconditioning and glucose metabolism during low-flow ischemia: Role of the adenosine a receptor. The ischemic penumbra (defined as local cerebral blood flow (LCBF) of 20-40% of control) forms an irregular rim around the ischemic core and tends to be greatest in frontal and occipital cortex . Glutamine is the most abundant free amino acid in human blood, which is converted to glutamate in mitochondria by glutaminase (GLS). In-depth research considering these open questions will be valuable for exploring the mechanisms of IPC. PPFKFB3 controls glycolytic flux by synthesizing fructose-2,6-bisphosphate (F2,6BP), a potent allosteric activator of phosphofructokinase 1 (PFK-1), which is a master regulator of glycolysis [18]. The Ischemic Penumbra: Correlates in Imaging and Implications . In remote IPC, inflation of a blood-pressure cuff on the arm or leg is used [8]. Direct IPC is conducted by brief, direct, repetitive clamping of the target artery, while regional IPC involves a repetitive occlusion of the circumflex artery, which is near to the target artery. 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. Interestingly, IPC has exhibited significant time-window effects in both basic and clinical research, where two phases have been observed. Berthet C., Lei H.T., Thevenet J., Gruetter R. Neuroprotective role of lactate after cerebral ischemia. Zong W.X., Rabinowitz J.D., White E. Mitochondria and Cancer. Ischemic penumbra denotes the part of an acute ischemic stroke that is at risk of progressing to infarction but is still salvageable if reperfused. Ischemic stroke occurs most frequently in individuals aged 65 years. However, research on metabolic reprogramming in the neuroscience field is still in its infancy. Article. Raf kinase inhibitory protein (RKIP) is involved in the protective effect against stroke: Li et al. To date, IPC has been replicated in humans and other species, and applied to other organs and tissues (e.g., the brain and kidney). GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling. 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]. The brain is an unusual organ, having the highest metabolic activity and energy requirement by mass. Two activities that provide compensatory fluxes to refill the TCA cycle, respectively, are glutaminolysis (which produces -ketoglutarate from glutamine) and oxidation of the branched-chain amino acids and fatty acids [66,67]. Timely interventions are effective for avoiding the progression of the penumbra into infarction. Further study focus on ischemic preconditioning metabolic reprogramming is needed, and it will be valuable for exploring the mechanisms of ischemic preconditioning, and will be greatly beneficial for the understanding of ischemic stroke treatment and standardized application of ischemic preconditioning. Jennifer D. Ischemic preconditioning in 18- to 20-month-old gerbils long-term survival with functional outcome measures. Cells adapt to environmental changes through metabolic remodeling, in order to maintain cellular homeostasis, which is an important stress-protective mechanism that plays a key role in many biological activities (see Figure 3). 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. 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. Bang O.Y., Saver J.L., Kim S.J., Kim G.M., Chung C.S., Ovbiagele B. It has been found that metabolic disorders are a determinant of the incidence and progression of stroke. Chen W.L., Jin X., Wang M., Liu D., Luo Q., Tian H., Cai L., Meng L., Bi R., Wang L., et al. Collectively, these findings suggest IPC could specify metabolic reprogramming in neurons and astrocytes and contribute to functional homeostasis. Tang X., Fang M., Cheng R., Zhang Z., Wang Y., Shen C., Han Y., Lu Q., Du Y., Liu Y., et al. 8600 Rockville Pike The site is secure. Mitochondria are signaling, bioenergetic, and biosynthetic organelles. The relaxation of VSM can also be indirectly regulated by the action of NO and other vasoactive agents. 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. 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. 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. Visualizing and Modulating Mitophagy for Therapeutic Studies of Neurodegeneration. Simmons E.C., Scholpa N.E., Schnellmann R.G. Furthermore, such heterogeneous distribution of metabolic substrates may be exploited by different brain regions, in order to regulate their cellular metabolic homeostasis during mitochondrial dysfunction. Upregulation of pentose phosphate pathway and preservation oftricarboxylic acid cycle flux after experimental brain injury. 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). The ischemic penumbra is defined as functionally impaired yet still viable tissue surrounding the ischemic core. Federal government websites often end in .gov or .mil. HHS Vulnerability Disclosure, Help Simultaneously, the anaplerotic pathway is promoted to refill the macromolecular biosynthesis for rapid proliferation in some cells. Furthermore, IPC treatment also remarkably improves the metabolic disturbances in the TCA cycle during ischemia. Oxygen is a crucial substrate in metabolism. Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Meng R., Asmaro K., Meng L., Liu Y., Ma C., Xi C., Li G., Ren C., Luo Y., Ling F., et al. 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. Therefore, how to accurately and effectively utilize the metabolic reprogramming strategy is crucial, with which we anticipate its broad application in the prevention and treatment of ischemic stroke. Accessibility Ischemic preconditioning treatment of astrocytes transfers ischemic tolerance to neurons. Shariatgorji M., Nilsson A., Fridjonsdottir E., Vallianatou T., Kllback P., Katan L., Svmarker J., Mantas I., Zhang X., Bezard E., et al. Additionally, GSH is synthesized from glutamate, cysteine, and glycine. Mitochondria lie at the key location for neuronal survival [51]. Furthermore, acute-on-chronic liver failure (ACLF) induces hyperammonemia and hypoxia in hepatocytes. Metabolic reprogramming is notably crucial in this regard, especially for energy and redox homeostasis maintenance. It will be a further explanation that the pathophysiological mechanisms in ischemic stroke are closely related to metabolic disorder. https://creativecommons.org/licenses/by/4.0/, Cohort study of 5398 adults aged 35 years or older followed for 10 years. Second, polyunsaturated fatty acids are susceptible to lipid peroxidation and are necessary for ferroptosis [45]. 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)
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