ischemic penumbra metabolic demand

Thus, the pretreatment of cells with taurine could reduce oxidative stress [50]. 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. In 2020, Per E. Andrn et al. Rothman D.L., Behar K.L., Hyder F. In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: Implications for brain function. Jackson C.W., Escobar I., Xu J., Perez-Pinzon M.A. Stroke is a leading cause of death and permanent disability, imposing heavy social and family burdens [1,2]. Betti et al. Clinical Imaging of the Penumbra in Ischemic Stroke: From the - PubMed Glutamine importantly regulates this process by providing glutamate and promoting cystine uptake [82]. General description of ischemic preconditioning (IPC), in which several cycles of brief non-lethal ischemia and reperfusion are applied either directly, regionally, or remotely. Measurement of the Ischemic Penumbra With MRI: It's About Time View. Meanwhile, IPC also boosts the PPP, providing an essential redox equivalent for GSH regeneration and enhancing the capacity of antioxidant defense. Brain, tumor, and proliferative tissues have high metabolic activity and energy requirements, necessitating that they have reliable mechanisms to adequately protect their metabolic homeostasis. IPC has been shown to enhance levels of NAD+ in the brain [77]. 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. Regulation of glycogen metabolism: Physiological, pharmacological and pathological aspects. The .gov means its official. 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]. Methods One hundred ten anterior circulation ischemic stroke patients presenting to hospital within 4.5 h of symptom onset and treated with intravenous thrombolysis were studied. Furthermore, the level of glycolytic products of lactate in CSF was found to be decreased following IPC [75]. Metabolic reprogramming during ischemic stroke is also reflected in the large changes of genes and proteins related to carbon and lipid metabolism. Elucidation of these endogenous defense mechanisms against ischemic injury is considered crucial for the development of novel stroke therapies. HHS Vulnerability Disclosure, Help It is common that tumor cells reside in nutrient- and oxygen-poor environments, such that they adapt, through multiple metabolic reprogramming, to meet the energy, macromolecular biosynthesis, and redox needs required for rapid proliferation [63]. official website and that any information you provide is encrypted The ischemic penumbra has been in the center of ischemic stroke research for the last 40 years. 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. In this review, we summarize the metabolic disorder and metabolic plasticity in the incidence and progression of ischemic stroke. Zhang et al. Iron is essential for the accumulation of lipid peroxides and execution of ferroptosis. Hausenloy D.J., Yellon D.M. Mitochondria are major contributors to cellular ROS, and there are multiple antioxidant pathways to neutralize ROS, including superoxide dismutase (SOD2), glutathione, thioredoxin, and peroxiredoxins. The primary aim of current acute stroke . (2014) Multi-parametric imaging of cerebral hemodynamic and metabolic response followed by ischemic injury . energy metabolism might be intermittently compromised within the ischemic penumbra. Bahadoran A., Bezavada L., Smallwood H.S. The Ischemic Penumbra: Correlates in Imaging and Implications for Mouse genetic studies have shown that S1P protects against tissue hypoxia by inducing O2 release. 40.2% ischemic stroke individuals were diagnosed with MetS. See Answer Arrell D.K., Elliott S.T., Kane L.A., Guo Y., Ko Y.H., Pedersen P.L. In addition, recent findings have indicated that mitochondria may represent a useful target to restore CBF after stroke, as it has been shown that ATP, adenosine monophosphate (AMP), and adenosine diphosphate (ADP) can alter cerebrovascular tone via plasmalemmal purinergic receptors [12]. 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. 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. 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. Geng J.L., Aa J.Y., Feng S.Q., Wang S.Y., Wang P., Zhang Y., Ouyang B.C. Brainin M., Feigin V.L., Norrving B., Martins S.C.O., Hankey G.J., Hachinski V. Global prevention of stroke and dementia: The WSO Declaration. 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. 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]. 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. Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. ; funding acquisition and editing, R.H.; funding acquisition, review and editing, B.Z. 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. Protein kinase C epsilon regulates mitochondrial pools of Nampt and NAD following resveratrol and ischemic preconditioning in the rat cortex. Metabolomic Profiling Reveals That Reprogramming of Cerebral Glucose Metabolism is Involved in Ischemic Preconditioning Induced Neuroprotection in a Rodent Model of Ischemic Stroke. Stankovic S., Majkic-Singh N. Genetic aspects of ischemic stroke coagulation homocysteine, and lipoprotein metabolism as potential risk factors Critical Reviews in Clinical Laboratory. Simultaneously, IPC increases regional CBF, in order to enhance the supply of blood glucose and oxygen to maintain metabolic consumption. Geng J.L., Zhang Y., Li S.J., Li S.N., Wang J.K., Wang H., Aa J.Y., Wang G.J. 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. GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling. These data are consistent with the original concepts of the penumbra and core, but recognize the dynamic complex heterogeneous processes involved. 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. Ischemic penumbra is intercalated between normoxic (proximal) and anoxic (distal) fields. Mitochondrial Dysfunction and Mitophagy in Parkinsons Disease: From Mechanism to Therapy. 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 is defined as functionally impaired yet still viable tissue surrounding the ischemic core. Mitochondria in Ischemic Stroke: New Insight and Implications Cellular metabolism is a flexible network to meet homeostasis demands in real-time. Collateral flow predicts response to endovascular therapy for acute ischemic stroke. 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. Regional cerebral blood flow thresholds during cerebral ischemia. 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. ); nc.ude.aaub@9102gnorgnornah (R.H.), 2School of Engineering Medicine, Beihang University, Beijing 100191, China. Frontiers | Clinical Imaging of the Penumbra in Ischemic Stroke: From McIntosh V.J., Lasley R.D. An untargeted metabolomics study has revealed that -hydroxybutyrate (-HB) stands out as highly significantly upregulated after IPC [78], while previous studies have shown that an elevation in the cytosolic NADH/NAD+ ratio would promote -HB formation. Yin J., Han P., Tang Z., Liu Q., Shi J. Sirtuin 3 mediates neuroprotection of ketones against ischemic stroke. 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). Mortality, morbidity, and risk factors in China and its provinces, 19902017: A systematic analysis for the Global Burden of Disease Study 2017. As a library, NLM provides access to scientific literature. 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. At a practical level, however, this definition is unwieldy. Wender R., Brown A.M., Fern R., Swanson R.A., Farrell K., Ransom B.R. Malpartida A.B., Williamson M., Narendra D.P., Wade M.R., Ryan B.J. Sun K., Zhang Y., DAlessandro A., Nemkov T., Song A., Wu H., Liu H., Adebiyi M., Huang A., Wen Y.E., et al. Intravenous thrombolysis and mechanical thrombectomy for selected . Within cells, the selective autophagy of ferritin (abbreviated as ferritinophagy), by modulating iron metabolism and controlling iron availability, occurs to enhance ferroptosis sensitivity [47]. Age, sex, and race/ethnic temporal trends in metabolic syndrome prevalence among individuals with myocardial infarction or stroke in the United States. Pathophysiology of Cerebral Ischemia: Role of Oxidative/Nitrosative Stress. The ischemic protection of IPC has been applied in various organs, such as the heart, brain, kidney, liver, lungs, and intestine. Recently, Yang X. et al. Ischemic stroke is typically caused by blood vessel blockage, which accounts for approximately 87% of all stroke cases. The metabolic characteristics of HBV-related ACLF patients revealed the inhibition of glycolysis, TCA and urea cycle, and the enhancement of fatty acid oxidation and glutamine anaplerosis [70]. 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]. To defend against this ischemic cascade, upon ischemia onset, brain tissues enhance their metabolic plasticity, in order to maintain the cerebral activity transiently, mainly through the regulation of CBF, extraction of oxygen and glucose, energy metabolic reprogramming, antioxidant defense, and mitophagy. Wolf-Dieter Heiss. A new penumbra: transitioning from injury into repair after stroke - Nature Wang G.S., Tong D.M., Chen X.D., Yang T.H., Zhou Y.T., Ma X.B. The vulnerable striatum is enriched in fatty acids, which the mitochondria reprogram to be metabolized as an energy source, but at the cost of ROS accumulation and induced damage. There are two major affected zones in an ischemic brain: The infarct core, surrounded by an ischemic penumbra. 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. Berthet C., Lei H.T., Thevenet J., Gruetter R. Neuroprotective role of lactate after cerebral ischemia. Neuronal regulation of astroglial morphology and proliferation in vitro. 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. In the ischemic penumbra, a further decrease in CBF leads to neuronal electrical silence and a synaptic activity decrease to preserve energy stores, while energy metabolism is partially preserved to transiently sustain tissue viability. Metabolic reprogramming is notably crucial in this regard, especially for energy and redox homeostasis maintenance. Neurons experience mitochondrial dysfunction, shifting the cellular machinery from aerobic to anaerobic metabolism, and a decrease of ATP production, directly resulting in energy failure. Sep 2011. Reduced Nicotinamide Adenine Dinucleotide Phosphate, a Pentose Phosphate Pathway Product, Might Be a Novel Drug Candidate for Ischemic Stroke. Furthermore, IPC treatment also remarkably improves the metabolic disturbances in the TCA cycle during ischemia. These include: NADP+/NADPH. However, the underlying neuroprotective mechanisms of IPC remain elusive. 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 . Hirayama Y., Koizumi S. Astrocytes and ischemic tolerance. 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. This refinement has potential therapeutic implications. 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. 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. Excitingly, emerging evidence from recent research has indicated that metabolic reprogramming may be the crucial neuroprotective mechanism of IPC for ischemia treatment. Up-regulation of the PPP is frequently observed in tumors, in order to increase the production of NADPH and ribulose-5-phosphate, promote glutathione production, and increase nucleic acid and fatty acid synthesis, helping cells to counteract oxidative stress and facilitate DNA damage repairs. 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]. Therefore, given the critical role of these organelles in disease onset and progression, strategies . Zong W.X., Rabinowitz J.D., White E. Mitochondria and Cancer. Together, effective IPC metabolic reprogramming may happen and be assumed to sustain during the early and late phases of IPC. Morris-Blanco K.C., Cohan C.H., Neumann J.T., Sick T.J., Perez-Pinzon M.A. Targeting the Ischemic Penumbra | Stroke To maintain the cerebral activity transiently, upon ischemia onset, brain tissues enhance their metabolic plasticity, mainly through energy metabolic reprogramming and antioxidant defense. 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. The authors declare no conflict of interest. Eventually, exogenous lactate administration can significantly increase cell survival in neuronal cultures against lethal oxygen glucose deprivation (OGD) [84]. Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone. 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). Jennifer D. Ischemic preconditioning in 18- to 20-month-old gerbils long-term survival with functional outcome measures. Expanding fascinating horizons in metabolism of other cells under hypoxia or hypoglycemia may promote new inspirations. Bethesda, MD 20894, Web Policies Dawson T.M., Dawson V.L. However, the details of how metabolite coupling between astrocyte and neurons in stroke are still not clear, and the understanding of metabolic pathway regulation during IPC metabolic reprogramming is just beginning. 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. 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]. The ischemic penumbra: From concept to reality Collaterals are demonstrated to be strong predictors of both response to endovascular therapy and functional outcomes [11]. Metabolic reprogramming by ischemic preconditioning (IPC). Yang W.S., Kim K.J., Gaschler M.M., Patel M., Shchepinov M.S., Stockwell B.R. This pathway can produce precursors to synthesize nucleotides and aromatic amino acids, generating cytosolic NADPH simultaneously [30]. The Ischemic Penumbra and Cell Survival | SpringerLink It is well-known that lysine, being an energy-providing amino acid, is necessary for the biosynthesis of L-carnitine. Metabolic reprogramming to maintain metabolic homeostasis, by correcting the metabolic disorder and enhancing metabolic plasticity, serves as an attractive potential therapeutic strategy for ischemic stroke. However, 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. Glycogen: The metabolism of glycogen is critical for the release of stored glucose. Furthermore, there exist some serious contraindications and complications; for example, thrombolytic agents have been associated with symptomatic intracerebral hemorrhage [6]. 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]. utilized MALDI-MSI to observe the intracerebral distribution of neurotransmitters in Parkinsonian rats, primates, and human patients [88]. Sphingosine 1-phosphate (S1P) is a bioactive signaling lipid highly enriched in mature erythrocytes. Efficacy of remote ischemic conditioning on improving WMHs and cognition in very elderly patients with intracranial atherosclerotic stenosis. Exogenous application of nicotinamide mononucleotide (NMN), an intermediate of NAD+ synthesis, mimics the protective effect of IPC under ischemia and reperfusion injury. 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. In remote IPC, inflation of a blood-pressure cuff on the arm or leg is used [8]. Ischemic Penumbra | STROKE MANUAL 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. These studies have indicated the time-specificity of IPC; however, the dynamic change of metabolic reprogramming induced by IPC is still unclear. Licensee MDPI, Basel, Switzerland. Wang P., Miao C.Y. Mech. 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. Furthermore, except for NADPH and GSH, whether there exist some other mechanisms induced by IPC to maintain the redox homeostasis under ischemia is not yet known; especially considering ferroptosis, which has been implicated in the pathological cell death associated with neurodegenerative diseases (i.e., Alzheimers, Huntingtons, and Parkinsons diseases). As the storage form of glucose, the polymer glycogen is entirely located in astrocytes, and the glycogen metabolism rarely occurs in neurons [99]. Dirnagl U., Endres M. Found in translation preclinical stroke research predicts human pathophysiology clinical phenotypes, and therapeutic outcomes. When the CBF is below 10 mL/100 g per minute, irreversible cellular injury will occur, and the infarct core forms [10]. Simultaneously, the anaplerotic pathway is promoted to refill the macromolecular biosynthesis for rapid proliferation in some cells. Bang O.Y., Saver J.L., Kim S.J., Kim G.M., Chung C.S., Ovbiagele B. 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. 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. Early reperfusion aims to save the ischemic penumbra by preventing infarct core expansion and is the mainstay of acute ischemic stroke therapy. Fructose can be readily catabolized to fuel fatty acid synthesis and palmitoleic acid generation by lung cancer cells, as a glucose alternative [65]. MetS patients had a 3.542-fold increased odds ratio (OR) for cognitive impairment. However, the underlying neuroprotection mechanisms of IPC remain elusive. Shariatgorji M., Nilsson A., Fridjonsdottir E., Vallianatou T., Kllback P., Katan L., Svmarker J., Mantas I., Zhang X., Bezard E., et al. 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. Yarian C.S., Toroser D., Sohal R.S. 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. 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.
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