ischemic penumbra metabolic demand ischemic penumbra metabolic demand

Li P., Quan W., Lu D., Wang Y., Zhang H.H., Liu S., Jiang R.C., Zhou Y.Y. However, continuing ischemic stress, or additional energy demanding episodes, or both, will exhaust this limited capacity and transform penumbra into necrotic tissue. Furthermore, IPC treatment also remarkably improves the metabolic disturbances in the TCA cycle during ischemia. Neuronal regulation of astroglial morphology and proliferation in vitro. 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. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Wang P., Miao C.Y. This necessitates that the brain has reliable mechanisms to adequately protect its metabolic homeostasis. 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. One study showed that neurons made specific metabolic adaptations following IPC (transient OGD) with the regulation of oxygen utilization and lactate production [100]. Amarenco P., Kim J.S., Labreuche J., Charles H., Abtan J., Bejot Y., Cabrejo L., Cha J.K., Ducrocq G., Giroud M., et al. Within cells, the selective autophagy of ferritin (abbreviated as ferritinophagy), by modulating iron metabolism and controlling iron availability, occurs to enhance ferroptosis sensitivity [47]. 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). To defend against this, the brain shifts the cellular machinery from aerobic to anaerobic metabolism. 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. The brain is an unusual organ, having the highest metabolic activity and energy requirement by mass. Chouchani E.T., Pell V.R., Gaude E., Aksentijevic D., Sundier S.Y., Robb E.L., Logan A., Nadtochiy S.M., Ord E.N.J., Smith A.C., et al. FOIA -ketoglutarate, produced by glutaminolysis, is vital for alternatively M2-activated macrophages [69]. 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). Mitochondria lie at the key location for neuronal survival [51]. ); nc.ude.aaub@9102gnorgnornah (R.H.), 2School of Engineering Medicine, Beihang University, Beijing 100191, China. The ischemic core . To date, IPC has been replicated in humans and other species, and applied to other organs and tissues (e.g., the brain and kidney). There are two major affected zones in an ischemic brain: The infarct core, surrounded by an ischemic penumbra. Lekoubou A., Ovbiagele B., Markovic D., Sanossian N., Towfighi A. Ferroptosis. 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. Wang H., He Z., Zhang Y., Zhang J. 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. https://creativecommons.org/licenses/by/4.0/, Cohort study of 5398 adults aged 35 years or older followed for 10 years. Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immune metabolism. In-depth research considering these open questions will be valuable for exploring the mechanisms of IPC. 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. In acute patients, PET documented areas of decreased 11 C-flumazenil uptake went on to show infarctions, while areas of relative . -HB is a biomarker of the cytosolic NADH/NAD+ ratio [79], indicating that IPC can regulate the NADH/NAD+ ratio. It has been noted that a minimal CBF of 18 mL/100 g per minute is needed to maintain normal electroencephalographic (EEG) activity. 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. de Jonge R., de Jong J.W. 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. It has been found that metabolic disorder is a determinant of the incidence and progression of stroke. MetS patients had a 3.542-fold increased odds ratio (OR) for cognitive impairment. sharing sensitive information, make sure youre on a federal Background and Purpose In ischemic stroke, diffusion-weighted (DW) and perfusion-weighted (PW) magnet resonance imaging (MRI) is used to define the mismatch as the therapeutic target. 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. Guan X., Li X., Yang X., Yan J., Shi P., Ba L., Cao Y., Wang P. The neuroprotective effects of carvacrol on ischemia/reperfusion-induced hippocampal neuronal impairment by ferroptosis mitigation. First, the availability of cysteine is the limiting link in GSH biosynthesis. Eventually, exogenous lactate administration can significantly increase cell survival in neuronal cultures against lethal oxygen glucose deprivation (OGD) [84]. (2014) Multi-parametric imaging of cerebral hemodynamic and metabolic response followed by ischemic injury . 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. Age, sex, and race/ethnic temporal trends in metabolic syndrome prevalence among individuals with myocardial infarction or stroke in the United States. Patients underwent computer tomography . 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. If the ischemic penumbra is characterized by these approaches, then a reduction of CBF to levels between a lower threshold of 10-15 mL/100 g/min and an upper threshold of approximately 25 mL/100 g/min is likely to identify penumbral tissue. However, in response to changes in the micro-environment, metabolic reprogramming is notably crucial to maintaining metabolic homeostasis. Metabolic syndrome (MetS) is a common metabolic disorder, involving a constellation of insulin resistance, abdominal obesity, hypertension, and dyslipidemia. Both studies revealed that the metabolites have inhomogeneous distributions in the brain, with high levels of spatial specificity. Hausenloy D.J., Yellon D.M. However, the complex connection between the neuroprotective function of IPC and cerebral metabolic reprogramming is still an exciting area of investigation, especially with respect to their spatiotemporal variation in consideration of the brain metabolic compartmentalization and time dependence. Glutamine importantly regulates this process by providing glutamate and promoting cystine uptake [82]. The research by Polyzos et al. Katsyuba E., Romani M., Hofer D., Auwerx J. NAD. The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression. Ischemic preconditioning triggers endogenous neuroprotection to defend against subsequent, more severe cerebral ischemia. Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia. 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. In addition, age-related alterations in TCA cycle enzyme activities will likely contribute to the decline of mitochondrial bioenergetics [96]. Mitochondria-derived reactive oxygen species dilate cerebral arteries by activating Ca. Fructose can be readily catabolized to fuel fatty acid synthesis and palmitoleic acid generation by lung cancer cells, as a glucose alternative [65]. Moreover, the brain utilizes metabolic plasticity, a protective response to stroke injury. Hou W., Xie Y., Song X., Sun X., Lotze M.T., Zeh H.J., Tang D. Autophagy promotes ferroptosis by degradation of ferritin. 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. Finally, the NAD+ pool declines by approximately 3550%. 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. At a practical level, however, this definition is unwieldy. 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]. 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). 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. Acute hyperglycemia adversely affects stroke outcome: A magnetic resonance imaging and spectroscopy study. Simultaneously, the anaplerotic pathway is promoted to refill the macromolecular biosynthesis for rapid proliferation in some cells. the contents by NLM or the National Institutes of Health. The primary definition of the ischemic penumbra is electrical. Ischemic penumbra is intercalated between normoxic (proximal) and anoxic (distal) fields. 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]. Bartnik B.L., Sutton R.L., Fukushima M., Harris N.G., Hovda D.A., Lee S.M. Narayanan S.V., Perez-Pinzon M.A. Intravenous thrombolysis and mechanical thrombectomy for selected . Zhang T., Wang W., Huang J., Liu X., Zhang H., Zhang N. Metabolomic investigation of regional brain tissue dysfunctions induced by global cerebral ischemia. Upon the onset of ischemia, the level of AMP dramatically decreases in the cortex and hippocampus tissues, indicating energy failure in these tissues [16]. Banks M.A., Porter D.W., Martin W.G., Castranova V. Ozone-induced lipid-peroxidation and membrane leakage in isolated rat alveolar macrophages- protective effects of taurine. Increasing understanding of the related pathogenic mechanisms serves to highlight the importance of metabolic regulation. 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. Upregulation of pentose phosphate pathway and preservation oftricarboxylic acid cycle flux after experimental brain injury. 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. revealed that RKIP overexpression markedly reduced the necrotic area after ischemic stroke, mainly reflected in the metabolism of energy, amino acids, and lipids [38]. Cellular NAD replenishment confers marked neuroprotection against ischemic cell death: Role of enhanced DNA repair. In 2020, Per E. Andrn et al. official website and that any information you provide is encrypted 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. Zong W.X., Rabinowitz J.D., White E. Mitochondria and Cancer. 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. 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. 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. CEREBROVASC DIS. Paez D.T., Garces M., Calabro V., Bin E.P., DAnnunzio V., Del Mauro J. Adenosine a1 receptors and mitochondria: Targets of remote ischemic preconditioning. confirmed this: In a Huntington model, they discovered region-specific metabolic reprogramming of astrocytes, which directly induced neuronal susceptibility. Betti et al. The metabolic syndrome. However, the underlying biological mechanisms of ischemic preconditioning are still confusing. Remarkably, specific neurotransmitters and neuromodulators could dictate astrocytes glycogenolysis. More glycolytic intermediates divert into the pentosephosphate pathway (PPP), while the entrance of pyruvate for mitochondrial oxidation is downregulated [18]. Mitochondrial Dysfunction and Mitophagy in Parkinsons Disease: From Mechanism to Therapy. Wang G.S., Tong D.M., Chen X.D., Yang T.H., Zhou Y.T., Ma X.B. If ischemic stress is applied during this phase, the neuroprotection effects of IPC vanish. 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. Meng R., Asmaro K., Meng L., Liu Y., Ma C., Xi C., Li G., Ren C., Luo Y., Ling F., et al. Shariatgorji M., Nilsson A., Fridjonsdottir E., Vallianatou T., Kllback P., Katan L., Svmarker J., Mantas I., Zhang X., Bezard E., et al. 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. These include: NADP+/NADPH. In biosynthetic pathways, cancer cells require that intermediate pools are maintained. Together, effective IPC metabolic reprogramming may happen and be assumed to sustain during the early and late phases of IPC. 1 and represented an important milestone for understanding the temporal and spatial evolution of focal ischemic brain injury. Noteworthy, at the early ischemia-reperfusion (I/R) phase, the impaired mitochondrial function was attenuated by IPC and mediated by adenosine A1 receptors [91,92]. However, the underlying neuroprotective mechanisms of IPC remain elusive. Whereas in the delayed or the second protect phase of IPC, the brain is again ischemia-tolerant [93]. Notably, neurons and astrocytes preferentially use quite different metabolic pathways in physiological conditions [98]. Preserving pools of NAD+ confers neuroprotection after ischemic stress. Metabolic syndrome (MetS) increases stroke incidence. Oxygen is a crucial substrate in metabolism. Acute imaging of the penumbra is a critical step toward selection of patients that can best benefit from penumbral-salvaging reperfusion therapies. 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. Above all, metabolism is essential for life activities. 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. The most immediate biochemical alterations in neurons affected by ischemia are mitochondrial dysfunction, shifting the cellular machinery from aerobic to anaerobic metabolism, and energy production decreasing from 32 adenosine triphosphate (ATP) molecules to 2 ATP molecules. 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). In such tissue, blood flow is decreased below the metabolic demand, but energy metabolism is maintained at a level allowing morphologic preservation of tissue. 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. It is well-known that lysine, being an energy-providing amino acid, is necessary for the biosynthesis of L-carnitine. Neurons experience mitochondrial dysfunction, shifting the cellular machinery from aerobic to anaerobic metabolism, and a decrease of ATP production, directly resulting in energy failure. 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. Ischemic heterogeneity is also demonstrated by recent PET studies. Efficacy of remote ischemic conditioning on improving WMHs and cognition in very elderly patients with intracranial atherosclerotic stenosis. 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]. Waves of depolarizations, the peri-infarct spreading depres- . 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]. utilized MALDI-MSI to observe the intracerebral distribution of neurotransmitters in Parkinsonian rats, primates, and human patients [88]. Stroke is a leading cause of death and permanent disability, imposing heavy social and family burdens [1,2]. Early reperfusion aims to save the ischemic penumbra by preventing infarct core expansion and is the mainstay of acute ischemic stroke therapy. quences as drastically increase d metabolic demand cannot be satisfied in regions with critically reduced blood supply. . General description of ischemic preconditioning (IPC), in which several cycles of brief non-lethal ischemia and reperfusion are applied either directly, regionally, or remotely. Sphingosine 1-phosphate is an important endogenous cardioprotectant released by ischemic pre- and postconditioning. Efficient ketone metabolism generates relatively abundant energy, which may prevent activation of the hyperglycolytic pathway under oxygen and glucose deprivation [27]. Xi Q., Cheranov S.Y., Jaggar J.H. The Ischemic Penumbra: Correlates in Imaging and Implications for Treatment of Ischemic Stroke. Note incursions of preferentially-oxygenated peri-arterial cells across planar hypoxic (ht) and anoxic (at) pO 2 thresholds. 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. Thus, the pretreatment of cells with taurine could reduce oxidative stress [50]. Servick K. Reprogrammed cells could tackle brain damage. Furthermore, the accumulation of the TCA intermediate succinate is also responsible for mitochondrial ROS production during ischemic reperfusion [39]. 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. 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. Direct intracerebroventricular or intravenous administration of lactate protected mouse brains against ischemic injury [22]. Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Ischaemic conditioning and reperfusion injury. Simultaneously, IPC increases regional CBF, in order to enhance the supply of blood glucose and oxygen to maintain metabolic consumption. In the absence of glutamine (or when glutaminolysis is inhibited), cystine starvation and ferroptosis occur. It has been implied that the neuroprotective ability of IPC may be related with the promotion of ANLS, where lactate serves as a potential agent to protect neurons against lethal ischemic injury. Zhang et al. NADP+ is an essential cofactor for the rate-limiting step of the pentosephosphate pathway (PPP). 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]. Faubert B., Solmonson A., DeBerardinis R.J. Metabolic reprogramming and cancer progression. Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice. 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]. 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. Lemasters J. 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. revealed that, upon ischemia, the levels of three oxidative stress-related metabolitessuccinate, taurine, and malonatewere dramatically disturbed in the cortex tissues of ischemic mice: taurine decreased, while malonate and succinate increased [16]. 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. The primary aim of current acute stroke . Berthet C., Lei H.T., Thevenet J., Gruetter R. Neuroprotective role of lactate after cerebral ischemia. 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. 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]. MetS prevalence was 61.2% in stroke survivors. 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. An increased understanding of the pathogenic mechanisms of stroke and IPC serves to highlight the importance of metabolic reprogramming. Metabolic disorder and metabolic plasticity are salient features triggered by ischemia. Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases. The site is secure. Morris-Blanco K.C., Cohan C.H., Neumann J.T., Sick T.J., Perez-Pinzon M.A. found that ketone treatment in mice at 30 min after ischemia enhanced mitochondrial function, reduced oxidative stress and, therefore, reduced infarct volume [49]. 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). Metabolic reprogramming is notably crucial in this regard, especially for energy and redox homeostasis maintenance.