Numerous in vitro, in vivo, and clinical studies have indicated that influenza infection induces hyperglycolysis in infected cells, activated immune cells, foci, and lymph nodes [68]. 2 The penumbra includes ischemic areas that recover spontaneously (benign oligemia; Figure 1, area a) and areas that progress to irreversible changes, unless effective treatment is used (referred to as penumbra; Figure 1, area b). The ischemic core . Bartnik B.L., Sutton R.L., Fukushima M., Harris N.G., Hovda D.A., Lee S.M. Exogenous application of nicotinamide mononucleotide (NMN), an intermediate of NAD+ synthesis, mimics the protective effect of IPC under ischemia and reperfusion injury. The .gov means its official. 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. Neuronal regulation of astroglial morphology and proliferation in vitro. 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. Identifying and utilizing the ischemic penumbra | Neurology 2011;42 . (2) Excitotoxicity. Vascular and metabolic diseases are common correlates of stroke, and these influences on the balance between cell death and recovery must be understood. Protecting the ischaemic penumbra as an adjunct to - Nature In the early phase, tissues benefit within minutes of IPC intervention, lasting for 23 h, while the late phase occurs at 1224 h and lasts for 23 days. Xie T., Chen C., Peng Z., Brown B.C., Reisz J.A., Xu P., Zhou Z., Song A., Zhang Y., Bogdanov M.V., et al. Mortality, morbidity, and risk factors in China and its provinces, 19902017: A systematic analysis for the Global Burden of Disease Study 2017. Hirayama Y., Ikeda M.Y., Notomi S., Enaida H., Kinouchi H., Koizumi S. Astrocyte-mediated ischemic tolerance. Narayanan S.V., Perez-Pinzon M.A. 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). 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. The MAS has been implicated as potentially dysregulated during cerebral ischemia [31]. 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. However, continuing ischemic stress, or additional energy demanding episodes, or both, will exhaust this limited capacity and transform penumbra into necrotic tissue. GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling. The accumulation of glucose is the primary feature of ischemic stroke, mainly regulated by AMPK, which is a key kinase activated by energy failure which can promote glucose uptake. 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. Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Collaterals are demonstrated to be strong predictors of both response to endovascular therapy and functional outcomes [11]. Meanwhile, glucose-6-phosphate dehydrogenase (G6PD) activity was notably increased by IPC in both normal and ischemic brains, which is the key rate-limiting enzyme responsible for regulating the flux of glucose into the PPP. As the main product of the oxidative PPP (oxPPP), NADPH provides the essential redox equivalent for GSH regeneration, enhancing the antioxidant defense capacity. One study showed that neurons made specific metabolic adaptations following IPC (transient OGD) with the regulation of oxygen utilization and lactate production [100]. 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. Mitochondrial Dysfunction and Mitophagy in Parkinsons Disease: From Mechanism to Therapy. 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]. Krebs H.A., Williamson D.H., Bates M.W., Page M.A., Hawkins R.A. Simmons E.C., Scholpa N.E., Schnellmann R.G. Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia. Mechanistically, S1P enhances the release of membrane-bound glycolytic enzymes to the cytosol, which promotes glycolysis and, thus, increases the production of 2,3-bisphosphoglycerate (2,3-BPG). Hence, the abundance and localization of polyunsaturated fatty acids are crucial for the degree of lipid peroxidation that occurs in cells. 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]. 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. ROS is not elevated and, so, this region sustains little damage [89]. To defend against this, the brain shifts the cellular machinery from aerobic to anaerobic metabolism. Meanwhile, exogenous supplementation of lactate has shown remarkable effects in traumatic brain injury therapy [23]. 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. Iron-Deficiency and Estrogen Are Associated with Ischemic Stroke by Up-Regulating Transferrin to Induce Hypercoagulability. However, in response to changes in the micro-environment, metabolic reprogramming is notably crucial to maintaining metabolic homeostasis. 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. Clinical Imaging of the Penumbra in Ischemic Stroke: From the - PubMed Simultaneously, IPC increases regional CBF, in order to enhance the supply of blood glucose and oxygen to maintain metabolic consumption. Cerebral Blood Flow Threshold of Ischemic Penumbra and Infarct - Stroke Transient ischemic attack before nonlacunar ischemic stroke in the elderly. 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. Xi Q., Cheranov S.Y., Jaggar J.H. 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. A previous study has demonstrated that cerebral ischemia caused a ketogenic response, shown through the enhancement of hepatic free fatty acids -oxidation and increasement of serum and brain -hydroxybutyrate levels [28]. Another critical concern is the proper time window for IPC metabolic reprogramming in sustaining the neuroprotection effects for the forthcoming ischemia stroke. Cellular metabolism is a flexible network to meet homeostasis demands in real-time. 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. 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. Furthermore, IPC treatment also remarkably improves the metabolic disturbances in the TCA cycle during ischemia. 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]. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. These include: NADP+/NADPH. Berthet C., Castillo X., Magistretti P.J., Hirt L. New evidence of neuroprotection by lactate after transient focal cerebral ischaemia: Extended benefit after intracerebroventricular injection and efficacy of intravenous administration. Iron is essential for the accumulation of lipid peroxides and execution of ferroptosis. In this review, we summarize the metabolic disorder and metabolic plasticity in the incidence and progression of ischemic stroke. Ischemic penumbra in retina endures: vascular neuropathology is Glycogen: The metabolism of glycogen is critical for the release of stored glucose. General description of ischemic preconditioning (IPC), in which several cycles of brief non-lethal ischemia and reperfusion are applied either directly, regionally, or remotely. In subsequent hours after IPC, the brain regresses to its nave state. Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice. Association between Metabolic Syndrome and Cognitive Impairment after Acute Ischemic Stroke: A Cross-Sectional Study in a Chinese Population. Rothman D.L., Behar K.L., Hyder F. In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: Implications for brain function. 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. You'll get a detailed solution from a subject matter expert that helps you learn core concepts. The latter form is informative in energy metabolism than free NADH. 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. In: Murphy S., editor. Dawson T.M., Dawson V.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. Elucidation of these endogenous defense mechanisms against ischemic injury is considered crucial for the development of novel stroke therapies. U.S. National Health and Nutrition Examination Surveys of 12,502 adults during 19992010. These studies have indicated the time-specificity of IPC; however, the dynamic change of metabolic reprogramming induced by IPC is still unclear. 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. Durukan A., Tatlisumak T. Preconditioning-induced ischemic tolerance: A window into endogenous gearing for cerebroprotection. Timely interventions are effective for avoiding the progression of the penumbra into infarction. It has been noted that a minimal CBF of 18 mL/100 g per minute is needed to maintain normal electroencephalographic (EEG) activity. The ischemic penumbra: From concept to reality These data are consistent with the original concepts of the penumbra and core, but recognize the dynamic complex heterogeneous processes involved. 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]. At the onset of ischemia, NAD+ levels decrease within 30 min, a second depletion occurs at 6 h of reperfusion (when necrosis is prominent), and a third depletion of NAD+ happens at 24 h (when apoptosis is prominent). An official website of the United States government. 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. Shariatgorji M., Nilsson A., Fridjonsdottir E., Vallianatou T., Kllback P., Katan L., Svmarker J., Mantas I., Zhang X., Bezard E., et al. Studies have revealed that inhibitors of ferroptosis, such as ferrostatins, carvacrol, and liproxstatins, could protect against cerebral ischemic injury in rodent models [43,48]. Ischemic Neuroprotectant PKCepsilon Restores Mitochondrial Glutamate Oxaloacetate Transaminase in the Neuronal NADH Shuttle after Ischemic Injury. We designed a prospective study to investigate the metabolic changes in the ischemic penumbra for patients with ICA flow lesions and cerebral infarct (or ischemia) before and after CEA using localized in vivo proton magnetic resonance spectroscopy ( (1)H-MRS). electrophysiological/ hemodynamic based definition to the wider metabolic-cellular-therapeutic concept that is managed today by neuroscientists. To enhance energy reserves, IPC improves mitochondrial efficiency for cellular energy metabolism, boosts glycolysis, and stockpiles and utilizes alternative energy substrates. It was shown that free and protein-bound NADH differs regarding lifetime. 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. The Ischemic Penumbra: Correlates in Imaging and Implications . 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). Stroke Education Flashcards | Quizlet When the CBF is below 10 mL/100 g per minute, irreversible cellular injury will occur, and the infarct core forms [10]. The ischemic penumbra: operationally . The authors declare no conflict of interest. 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]. In such tissue, blood flow is decreased below the metabolic demand, but energy metabolism is maintained at a level allowing morphologic preservation of tissue. Metabolic reprogramming for metabolic homeostasis maintenance. 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. 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. 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. 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]. Amarenco P., Kim J.S., Labreuche J., Charles H., Abtan J., Bejot Y., Cabrejo L., Cha J.K., Ducrocq G., Giroud M., et al. In 2020, Per E. Andrn et al. The ischemic penumbra can maintain metabolic demand with marginal blood flow from collateral circulation for a maximum of _____ before increasing in size. Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone. L-Carnitine: The level of lysine in human CSF increases following IPC [75]. official website and that any information you provide is encrypted Mitochondrial Mechanisms of Neuronal Cell Death: Potential Therapeutics. Identify the blocked artery that could potentially cause these symptoms. Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immune metabolism. The ischemic protection of IPC has been applied in various organs, such as the heart, brain, kidney, liver, lungs, and intestine. Astrup J, Siesj BK . NADP+ and its reduced counterpart, NADPH, are mainly required for anabolic reactions and cellular oxidative-stress defense. 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 . National Library of Medicine 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. https://creativecommons.org/licenses/by/4.0/, Cohort study of 5398 adults aged 35 years or older followed for 10 years. -HB is a biomarker of the cytosolic NADH/NAD+ ratio [79], indicating that IPC can regulate the NADH/NAD+ ratio. Intravenous thrombolysis and mechanical thrombectomy for selected . Zeiger S.L., McKenzie J.R., Stankowski J.N., Martin J.A., Cliffel D.E., McLaughlin B. Neuron specific metabolic adaptations following multi-day exposures to oxygen glucose deprivation. 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. 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. found that ketone treatment in mice at 30 min after ischemia enhanced mitochondrial function, reduced oxidative stress and, therefore, reduced infarct volume [49]. A field of research that continues to show promise in developing therapies for ischemic stroke is ischemic preconditioning (IPC). Trial of 2860 patients and followed them for 3.5 years. Before 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. Careers, Unable to load your collection due to an error. Meanwhile, IPC also boosts the PPP, providing an essential redox equivalent for GSH regeneration and enhancing the capacity of antioxidant defense. Zhang et al. Together, effective IPC metabolic reprogramming may happen and be assumed to sustain during the early and late phases of IPC. IPC is an endogenous metabolic protective strategy, whereby several cycles of brief, non-lethal ischemia, followed by reperfusion, confer protection against subsequent, more severe, and lethal ischemia. Acute hyperglycemia adversely affects stroke outcome: A magnetic resonance imaging and spectroscopy study. the ischemic penumbra can maintain metabolic demand with marginal blood flow from collateral circulation for a maximum of __ before increasing in size? In the mammalian brain, neurons are outnumbered 10:1 by astrocytes in most regions. Fructose can be readily catabolized to fuel fatty acid synthesis and palmitoleic acid generation by lung cancer cells, as a glucose alternative [65]. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Meanwhile, IPC-treated astrocytes significantly enhanced lactate secretion into the extracellular media. Metabolic syndrome (MetS) increases stroke incidence. This refinement has potential therapeutic implications. Targeting the Ischemic Penumbra 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). 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. 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. found that, after 60 min of glucose deprivation, astrocytes in the rat optic nerve (a CNS white matter tract) drove glycogen to be broken down to lactate, which was then transferred to fuel axons [19]. The primary definition of the ischemic penumbra is electrical. The ischemic penumbra: correlates in imaging and implications for 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. Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases. showed that the depolarization of mitochondria by diazoxide promoted the relaxation of vascular smooth muscle (VSM) cells in endothelium-denuded cerebral arteries or freshly dissociated VSM, through the generation and localized effects of reactive oxygen species (ROS) [13]. Intriguing, the protective effect of IPC can be mimicked pharmacologically. Mitochondria in Ischemic Stroke: New Insight and Implications Accessibility The primary aim of current acute 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. Oxygen is a crucial substrate in metabolism. 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. Regulation of glycogen metabolism: Physiological, pharmacological and pathological aspects. Direct intracerebroventricular or intravenous administration of lactate protected mouse brains against ischemic injury [22]. Creatine generally occurs as phosphocreatine (PCr), which is a storage form of high-energy phosphate and a shuttle for the transfer of high-energy phosphate from mitochondria to the cytosol. Under high altitude or chronic kidney disease, hypoxia-responsive sphingosine-1-phosphate (S1P) promotes erythrocyte glycolysis, channeling glucose metabolism toward RapoportLuebering Shunt and inducing 2,3-bisphosphoglycerate (2,3-BPG) production for O2 delivery [71,72]. alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Hepatic NADH reductive stress underlies common variation in metabolic traits. 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. . 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. More glycolytic intermediates divert into the pentosephosphate pathway (PPP), while the entrance of pyruvate for mitochondrial oxidation is downregulated [18].
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