IPC has been reported to exhibit a significant neuroprotective effect, remarkably reducing the incidence of ischemic stroke and improving the prognosis in patients with stroke [9]. Ischemic penumbra | Radiology Reference Article | Radiopaedia.org Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. Recently, Yang X. et al. Studies have shown that IPC upregulates NAMPT protein, and the protective effect of IPC against ischemia (30 min) and reperfusion (24 h) was attenuated in NAMPT knockdown mice, suggesting that NAMPT is essential in mediating the protective effect of IPC [80]. Metabolomic Profiling Reveals That Reprogramming of Cerebral Glucose Metabolism is Involved in Ischemic Preconditioning Induced Neuroprotection in a Rodent Model of Ischemic Stroke. To maintain the cerebral activity transiently, upon ischemia onset, brain tissues enhance their metabolic plasticity, mainly through energy metabolic reprogramming and antioxidant defense. 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. After hypoxic-ischemic insult, the perturbation of mitochondrial homeostasis can profoundly alter the ATP production and intracellular cellular energy status, leading to apoptotic cell death in the presence of increased ROS production, calcium accumulation, opening of mitochondrial permeability transition pores (mPTPs), and releasing cytochrome C [52,53]. Mortality, morbidity, and risk factors in China and its provinces, 19902017: A systematic analysis for the Global Burden of Disease Study 2017. Zong W.X., Rabinowitz J.D., White E. Mitochondria and Cancer. 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. 6-8 hours A patient presents to the emergency department with left leg weakness and numbness. Bang O.Y., Saver J.L., Kim S.J., Kim G.M., Chung C.S., Ovbiagele B. More glycolytic intermediates divert into the pentosephosphate pathway (PPP), while the entrance of pyruvate for mitochondrial oxidation is downregulated [18]. Lactate: Brain fuel in human traumatic brain injury: A comparison with normal healthy control subjects. 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. Bethesda, MD 20894, Web Policies The Ischemic Penumbra and the Ischemic Core The metabolic syndrome. Phosphocreatine (PCr): In addition, the protective effect of IPC on metabolic recovery has been demonstrated by a notably increased level of creatine, observed both in rat plasma and human CSF [27,75], suggesting an improvement in the neuroenergetic status. Identifying and utilizing the ischemic penumbra | Neurology the contents by NLM or the National Institutes of Health. 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. Fructose can be readily catabolized to fuel fatty acid synthesis and palmitoleic acid generation by lung cancer cells, as a glucose alternative [65]. Significantly lower levels of glutamine and glycine in CSF following IPC have been observed [75], indicating that the replenishment of GSH is accelerated, eventually imposing reductive stress in the ischemic brain tissue. Shariatgorji M., Nilsson A., Fridjonsdottir E., Vallianatou T., Kllback P., Katan L., Svmarker J., Mantas I., Zhang X., Bezard E., et al. Therefore, given the critical role of these organelles in disease onset and progression, strategies . utilized MALDI-MSI to observe the intracerebral distribution of neurotransmitters in Parkinsonian rats, primates, and human patients [88]. (Stroke. 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. Ischemic stroke occurs most frequently in individuals aged 65 years. 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. and transmitted securely. 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]. Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia. 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. Several studies also showed that transient ischemic attack (TIA) may produce IPC effect in people who have a subsequent stroke [101,102]. Simultaneously, the anaplerotic pathway is promoted to refill the macromolecular biosynthesis for rapid proliferation in some cells. 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. The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression. However, research on metabolic reprogramming in the neuroscience field is still in its infancy. 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]. All authors have read and agreed to the published version of the manuscript. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. 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. Remote ischaemic conditioningA new paradigm of self-protection in the brain. The concept of the ischemic penumbra was initially proposed by Astrup et al. A comprehensive analysis of metabolic changes in the salvaged penumbra Furthermore, the level of glycolytic products of lactate in CSF was found to be decreased following IPC [75]. Jaggar et al. Efficacy of remote ischemic conditioning on improving WMHs and cognition in very elderly patients with intracranial atherosclerotic stenosis. The relaxation of VSM can also be indirectly regulated by the action of NO and other vasoactive agents. 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]. 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. Metabolic reprogramming is notably crucial in this regard, especially for energy and redox homeostasis maintenance. Age, sex, and race/ethnic temporal trends in metabolic syndrome prevalence among individuals with myocardial infarction or stroke in the United States. 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. Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immune metabolism. Preservation of the IPC phenotype implicated a unifying endogenous mechanism, possibly involving energy and redox homeostasis maintenance. 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). Over the past few decades, considerable progress has been made in ischemic stroke treatment, typically in intravenous thrombolysis and mechanical thrombectomy. In biosynthetic pathways, cancer cells require that intermediate pools are maintained. Ischemic stroke is typically caused by blood vessel blockage, which accounts for approximately 87% of all stroke cases. -ketoglutarate, produced by glutaminolysis, is vital for alternatively M2-activated macrophages [69]. A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. 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. MetS prevalence was 61.2% in stroke survivors. 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. Efficient ketone metabolism generates relatively abundant energy, which may prevent activation of the hyperglycolytic pathway under oxygen and glucose deprivation [27]. Geng J.L., Aa J.Y., Feng S.Q., Wang S.Y., Wang P., Zhang Y., Ouyang B.C. . Exogenous application of nicotinamide mononucleotide (NMN), an intermediate of NAD+ synthesis, mimics the protective effect of IPC under ischemia and reperfusion injury. Most ketones are generated in the liver, while the transport of ketone bodies across the blood-brain barrier (BBB) is the limiting step. First, the availability of cysteine is the limiting link in GSH biosynthesis. Stroke is a leading cause of death and permanent disability, imposing heavy social and family burdens [1,2]. 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]. ischemic penumbra as a biochemical target (intermittent bioenergetic compromise); (3) the ischemic penumbra as a . Current evidence-based . (1)H NMR metabolic signature of cerebrospinal fluid following repetitive lower-limb remote ischemia preconditioning. (2014) Multi-parametric imaging of cerebral hemodynamic and metabolic response followed by ischemic injury . 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. Xi Q., Cheranov S.Y., Jaggar J.H. 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]. 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. Consistently, a study showed that neurons benefited from the co-incubated astrocytes, enhancing lactate secretion induced by IPC in astrocytes. Furthermore, the accumulation of the TCA intermediate succinate is also responsible for mitochondrial ROS production during ischemic reperfusion [39]. However, with persistent ischemia, irreversible damage may occur in the affected brain areas. and increases energy demand and neurotransmitter effluxes, Coincidentally, a clinical study has implicated the effectiveness of IPC in preventing the progression of white matter hyperintensities (WMHs) and in ameliorating cognitive impairment of very elderly patients (83.5 2.3 year) with ICAS [94]. One study showed that neurons made specific metabolic adaptations following IPC (transient OGD) with the regulation of oxygen utilization and lactate production [100]. However, in response to changes in the micro-environment, metabolic reprogramming is notably crucial to maintaining metabolic homeostasis. 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. As IPC is innocuous, cost-effective, and has fewer or no contraindications, and has exciting new prospects in the broader management of ischemic stroke (Figure 1). 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. (2) Excitotoxicity. In the mammalian brain, neurons are outnumbered 10:1 by astrocytes in most regions. 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. Li P., Quan W., Lu D., Wang Y., Zhang H.H., Liu S., Jiang R.C., Zhou Y.Y. Previous studies reported that when MCAO is applied during the early IPC phase, the brain is ischemia-tolerant. 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. The latter form is informative in energy metabolism than free NADH. Jackson C.W., Escobar I., Xu J., Perez-Pinzon M.A. 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. John P. Cooke, in Stem Cell and Gene Therapy for Cardiovascular Disease, 2016 Functional Response to Metabolic Demand Vascular response to metabolic demand involves a closely orchestrated set of hormonal, neuronal, endothelial, and metabolic mechanisms. Ischemic Penumbra | STROKE MANUAL 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 research by Polyzos et al. Glenn T.C., Martin N.A., Horning M.A. Faubert B., Solmonson A., DeBerardinis R.J. Metabolic reprogramming and cancer progression. Mitochondria in Ischemic Stroke: New Insight and Implications found that ketone treatment in mice at 30 min after ischemia enhanced mitochondrial function, reduced oxidative stress and, therefore, reduced infarct volume [49]. Excessive glutamate release and impeded reuptake of excitatory amino acids result in the activation of NMDARs, AMPARs and KARs. 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. Research has found that L-glutamine reduced brain infarct volume and promoted neurobehavioral recovery in cerebral ischemic mice [25]. Bouzat P., Sala N., Suys T., Zerlauth J.B. Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain. 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. 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. Meanwhile, although restoring blood flow by thrombolysis and thrombectomy is essential in limiting ischemic neuronal damage, substantial neuronal, glial, and neurovascular damages may still occur, particularly due to reperfusion injury of the penumbra [5]. energy metabolism might be intermittently compromised within the ischemic penumbra. Consistent with IPC may effectively reprogram mitochondrial energy metabolism and benefit stroke. Bahadoran A., Bezavada L., Smallwood H.S. . Inclusion in an NLM database does not imply endorsement of, or agreement with, 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. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. 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. In the brain, astrocytes can also generate ketone bodies from fatty acid -oxidation. Ischemic preconditioning treatment of astrocytes transfers ischemic tolerance to neurons. The https:// ensures that you are connecting to the Visualizing and Modulating Mitophagy for Therapeutic Studies of Neurodegeneration. 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. Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute-On-Chronic Liver Failure. These include: NADP+/NADPH. Eckel R.H., Grundy S.M., Zimmet P.Z. The normal CBF in healthy normal men is 54 mL/100 g per minute. Vascular and metabolic diseases are common correlates of stroke, and these influences on the balance between cell death and recovery must be understood. https://creativecommons.org/licenses/by/4.0/, Cohort study of 5398 adults aged 35 years or older followed for 10 years. Geng J.L., Zhang Y., Li S.J., Li S.N., Wang J.K., Wang H., Aa J.Y., Wang G.J. A diagram showing metabolism in the ischemic, penumbra and distant 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]. The Ischemic Penumbra: Correlates in Imaging and Implications for 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 Advance in this active research field will stimulate a promising new direction in precision intervention and drug target discovery for ischemic stroke. Heterogeneity in the penumbra - SAGE Journals 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. Irreversible injury to mitochondria is a cornerstone of pathogenesis of neurological diseases. Yarian C.S., Toroser D., Sohal R.S. It has been found that metabolic disorder is a determinant of the incidence and progression of stroke. Here we provide a summary of metabolic mechanism of ischemic preconditioning when it is applied to ischemic stroke. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. 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. Additionally, GSH is synthesized from glutamate, cysteine, and glycine. Marchiq I., Pouyssgur J. Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H+ symporters. Simmons E.C., Scholpa N.E., Schnellmann R.G. 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]. Ischemic penumbra is intercalated between normoxic (proximal) and anoxic (distal) fields. 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. In this review, we summarize the metabolic disorder and metabolic plasticity in the incidence and progression of ischemic stroke. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Meanwhile, exogenous supplementation of lactate has shown remarkable effects in traumatic brain injury therapy [23]. Mech. Identify the blocked artery that could potentially cause these symptoms. Excitingly, emerging evidence from recent research has indicated that metabolic reprogramming may be the crucial neuroprotective mechanism of IPC for ischemia treatment. A new penumbra: transitioning from injury into repair after stroke - Nature Stroke Education Flashcards | Quizlet 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. Accessibility Hirayama Y., Koizumi S. Astrocytes and ischemic tolerance. Hence, the abundance and localization of polyunsaturated fatty acids are crucial for the degree of lipid peroxidation that occurs in cells. 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. Brain, tumor, and proliferative tissues have high metabolic activity and energy requirements, necessitating that they have reliable mechanisms to adequately protect their metabolic homeostasis. The accumulation of glucose and glycolytic intermediates is a prominent feature of brain ischemia-induced metabolic disturbance in rodents. The pathway mainly involves glycolysis, TCA cycle, PPP, and glutaminolysis to maintain the energy and redox homeostasis, which are the most primary demands for cells under the deprivation or limitation of nutrients and oxygen. Metabolic reprogramming by ischemic preconditioning (IPC). During ischemia, the depletion of GSH and NADPH causes an iron-dependent accumulation of lipid hydroperoxides to lethal levels, thus inducing cell death, which is defined as ferroptosis [42]. 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. 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. Such emerging evidence of the metabolic reprogramming involved in metabolic homeostasis on the progression of different diseases has revealed that metabolic reprogramming is an important stress-protective mechanism, which plays a key role in many biological activities. Protecting the ischaemic penumbra as an adjunct to - Nature 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. Ischemic penumbra denotes the part of an acute ischemic stroke that is at risk of progressing to infarction but is still salvageable if reperfused. 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). 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].
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