Simultaneously, IPC increases regional CBF, in order to enhance the supply of blood glucose and oxygen to maintain metabolic consumption. 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. For ischemic rats, 24 h after IPC treatment, the AMPK levels and glucose levels decreased and ATP increased in the penumbra, indicating that glucose catabolism is upregulated by IPC [18]. In remote IPC, inflation of a blood-pressure cuff on the arm or leg is used [8]. Heterogeneity in the penumbra - SAGE Journals In steady-state, cells sustain themselves catabolically by using glycolytic carbons to fuel the TCA cycle. 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. Hepatic NADH reductive stress underlies common variation in metabolic traits. Lactate: Previous research has suggested that astrocytes play a pivotal role in the induction of ischemic tolerance [83], during which lactate is extremely crucial. Ferroptosis. Immune cells also have distinct metabolic programs, in order to meet the energetic and biosynthetic requirements of their ever-changing micro-environments. The metaphor of the ischemic penumbra was coined to describe this intermediate zone of ischemia between functionally normal and dead brain tissue. confirmed this: In a Huntington model, they discovered region-specific metabolic reprogramming of astrocytes, which directly induced neuronal susceptibility. 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. Wang S., Xing Z., Vosler P.S., Yin H., Li W., Zhang F., Signore A.P., Stetler R.A., Gao Y., Chen J. It will be a further explanation that the pathophysiological mechanisms in ischemic stroke are closely related to metabolic disorder. 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. 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. Studies have revealed that inhibitors of ferroptosis, such as ferrostatins, carvacrol, and liproxstatins, could protect against cerebral ischemic injury in rodent models [43,48]. 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. Ischemic penumbra in retina endures: vascular neuropathology is This process is named the astrocyteneuron lactate shuttle (ANLS). The Ischemic Penumbra: Correlates in Imaging and Implications for Treatment of Ischemic Stroke. 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. 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. In this review, we summarize the metabolic disorder and metabolic plasticity in the incidence and progression of ischemic stroke. Amarenco P., Kim J.S., Labreuche J., Charles H., Abtan J., Bejot Y., Cabrejo L., Cha J.K., Ducrocq G., Giroud M., et al. Glutamine is the most abundant free amino acid in human blood, which is converted to glutamate in mitochondria by glutaminase (GLS). 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. In biosynthetic pathways, cancer cells require that intermediate pools are maintained. Moreover, the brain utilizes metabolic plasticity, a protective response to stroke injury. 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. 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]. One study showed that neurons made specific metabolic adaptations following IPC (transient OGD) with the regulation of oxygen utilization and lactate production [100]. 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). 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. Remarkably, specific neurotransmitters and neuromodulators could dictate astrocytes glycogenolysis. 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. Wender R., Brown A.M., Fern R., Swanson R.A., Farrell K., Ransom B.R. 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. 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]. 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. The relaxation of VSM can also be indirectly regulated by the action of NO and other vasoactive agents. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Recently, Yang X. et al. Likewise, as the most difficult challenge in ischemic stroke is energy failure, whether some other new energetic substrates are mobilized by IPC (e.g., fructose), in addition to the glucose and common alternative energy substrates, should be determined. Second, polyunsaturated fatty acids are susceptible to lipid peroxidation and are necessary for ferroptosis [45]. The ischemic penumbra can maintain metabolic demand with marginal blood flow from collateral circulation for a maximum of _____ before increasing in size. 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]. 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. TCA cycle reactions yield metabolite intermediates and energetic precursors for oxidative phosphorylation. Katayama H., Hama H., Nagasawa K., Kurokawa H., Sugiyama M., Ando R., Funata M., Yoshida N., Homma M., Nishimura T., et al. Zong W.X., Rabinowitz J.D., White E. Mitochondria and Cancer. The normal CBF in healthy normal men is 54 mL/100 g per minute. Mitochondria are major contributors to cellular ROS, and there are multiple antioxidant pathways to neutralize ROS, including superoxide dismutase (SOD2), glutathione, thioredoxin, and peroxiredoxins. However, with persistent ischemia, irreversible damage may occur in the affected brain areas. It has been found that metabolic disorder is a determinant of the incidence and progression of stroke. Consistent with this data, strategies aimed at increasing astrocyte glycogen have been successfully applied for mitigating neuronal loss [20]. Rothman D.L., Behar K.L., Hyder F. In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: Implications for brain function. Mitochondrial dysfunction in neurological disorders: Exploring HHS Vulnerability Disclosure, Help 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]. Oxygen is a crucial substrate in metabolism. Bahadoran A., Bezavada L., Smallwood H.S. 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]. ; funding acquisition and editing, R.H.; funding acquisition, review and editing, B.Z. The MAS has been implicated as potentially dysregulated during cerebral ischemia [31]. ); nc.ude.aaub@9102gnorgnornah (R.H.), 2School of Engineering Medicine, Beihang University, Beijing 100191, China. ischemic penumbra as a biochemical target (intermittent bioenergetic compromise); (3) the ischemic penumbra as a . To test whether acute changes in cardiac workload and metabolic demand impact the redox state of the myocardium and coronary arterial wall in vivo, we used high spatial resolution imaging mass . 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. 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. The ischemic penumbra: correlates in imaging and implications for Arrell D.K., Elliott S.T., Kane L.A., Guo Y., Ko Y.H., Pedersen P.L. Since astrocytes play an integral role in inducing ischemic tolerance [97], the traditional view of astrocytes as passive supporters of neurons is revised, and the survival of neurons tightly associated with astrocytes is recognized. 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. It has been noted that a minimal CBF of 18 mL/100 g per minute is needed to maintain normal electroencephalographic (EEG) activity. Therefore, given the critical role of these organelles in disease onset and progression, strategies . Intravenous thrombolysis and mechanical thrombectomy for selected . Association between Metabolic Syndrome and Cognitive Impairment after Acute Ischemic Stroke: A Cross-Sectional Study in a Chinese Population. Metabolic Syndrome Is a Strong Risk Factor for Minor Ischemic Stroke and Subsequent Vascular Events. 40.2% ischemic stroke individuals were diagnosed with MetS. 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). See Answer 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. Ham P.B., Raju R. Mitochondrial function in hypoxic ischemic injury and influence of aging. 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. 1 and represented an important milestone for understanding the temporal and spatial evolution of focal ischemic brain injury. Ischemic penumbra is intercalated between normoxic (proximal) and anoxic (distal) fields. Collectively, these findings suggest IPC could specify metabolic reprogramming in neurons and astrocytes and contribute to functional homeostasis. 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). With positron emission tomography (PET), we characterized the metabolic patterns of tissue compartments identified by MRI and compared the volumes of mismatch to those of PET-defined penumbra. The Ischemic Penumbra and the Ischemic Core Stankovic S., Majkic-Singh N. Genetic aspects of ischemic stroke coagulation homocysteine, and lipoprotein metabolism as potential risk factors Critical Reviews in Clinical Laboratory. Sato H., Nomura S., Maebara K., Sato K., Tamba M., Bannai S. Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. 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. Whereas in the delayed or the second protect phase of IPC, the brain is again ischemia-tolerant [93]. Preserving pools of NAD+ confers neuroprotection after ischemic stress. 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. L-carnitine is the only transporter of fatty acids across the mitochondrial membrane, to be metabolized with the generation of energy, indicating an energetic compensatory mechanism by IPC for neuronal survival. The biochemical control of ferroptosis includes amino acid metabolism, glutathione metabolism, lipid metabolism, iron metabolism, and other metabolic pathways [43]. Chen W.L., Jin X., Wang M., Liu D., Luo Q., Tian H., Cai L., Meng L., Bi R., Wang L., et al. 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. official website and that any information you provide is encrypted There are two major affected zones in an ischemic brain: The infarct core, surrounded by an ischemic penumbra. 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. To date, IPC has been replicated in humans and other species, and applied to other organs and tissues (e.g., the brain and kidney). Hess D.C., Blauenfeldt R.A., Andersen G., Hougaard K.D., Hoda M.N., Ding Y., Ji X. 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. Betti et al. Acute hyperglycemia adversely affects stroke outcome: A magnetic resonance imaging and spectroscopy study. NADP+ and its reduced counterpart, NADPH, are mainly required for anabolic reactions and cellular oxidative-stress defense. You'll get a detailed solution from a subject matter expert that helps you learn core concepts. Collateral flow predicts response to endovascular therapy for acute ischemic stroke. Waves of depolarizations, the peri-infarct spreading depres- . https://creativecommons.org/licenses/by/4.0/, Cohort study of 5398 adults aged 35 years or older followed for 10 years. First, the availability of cysteine is the limiting link in GSH biosynthesis. An increasing number of studies have shown the time-dependent metabolic changes during IPC or the acute-to-chronic post-stroke phase. 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. Mitochondrial Mechanisms of Neuronal Cell Death: Potential Therapeutics. Protein kinase C epsilon regulates mitochondrial pools of Nampt and NAD following resveratrol and ischemic preconditioning in the rat cortex. Third, iron deficiency has been associated with an increased risk of ischemic stroke [46]. Clinical Imaging of the Penumbra in Ischemic Stroke: From the - PubMed The Ischemic Penumbra: Correlates in Imaging and Implications for Hence, the abundance and localization of polyunsaturated fatty acids are crucial for the degree of lipid peroxidation that occurs in cells. 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. 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. Wolf-Dieter Heiss. This enhanced glycolysis drives the generation of energy-rich molecules (e.g., ATP, NADH, and NADPH) and the supply of carbon pool for the synthesis of amino acids, nucleotides, and lipids [64]. Current evidence-based . NAMPT levels were enhanced by protein kinase C (PKC) in an AMPK-dependent manner, which was required for increased mitochondrial NAMPT after IPC [77]. This pathway can produce precursors to synthesize nucleotides and aromatic amino acids, generating cytosolic NADPH simultaneously [30]. Bartnik B.L., Sutton R.L., Fukushima M., Harris N.G., Hovda D.A., Lee S.M. 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]. Apart from complete reperfusion, IPC is a powerful intervention known for reducing ischemic infarct size. L-glutamine protects mouse brain from ischemic injury via up-regulating heat shock protein 70. (2014) Multi-parametric imaging of cerebral hemodynamic and metabolic response followed by ischemic injury . 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. Busija D.W., Rutkai I., Dutta S., Katakam P.V. 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). Simultaneously, the anaplerotic pathway is promoted to refill the macromolecular biosynthesis for rapid proliferation in some cells. 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. Protecting the ischaemic penumbra as an adjunct to - Nature However, continuing ischemic stress, or additional energy demanding episodes, or both, will exhaust this limited capacity and transform penumbra into necrotic tissue. 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. Stroke is one of the leading causes of death and permanent disability worldwide. Once ischemic stroke occurs, the PPP is boosted and more glycolytic intermediates are diverted into the PPP to sustain NADPH production [18]. Dixon S.J., Lemberg K.M., Lamprecht M.R., Skouta R., Zaitsev E.M. Gleason Ferroptosis: An iron-dependent form of nonapoptotic cell death. The concept of the ischemic penumbra was initially proposed by Astrup et al. 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. 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]. Remote ischaemic conditioningA new paradigm of self-protection in the brain. 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]. Zhang et al. The authors declare no conflict of interest. In addition, age-related alterations in TCA cycle enzyme activities will likely contribute to the decline of mitochondrial bioenergetics [96]. Metabolic reprogramming during ischemic stroke is also reflected in the large changes of genes and proteins related to carbon and lipid metabolism. Ischemic preconditioning triggers endogenous neuroprotection to defend against subsequent, more severe cerebral ischemia. Cellular NAD replenishment confers marked neuroprotection against ischemic cell death: Role of enhanced DNA repair. Sep 2011. Regional cerebral blood flow thresholds during cerebral ischemia. All brain cell types are able to uptake ketones; the ketones are then metabolized to acetyl-CoA to support the cell energy [29]. Excitingly, emerging evidence from recent research has indicated that metabolic reprogramming may be the crucial neuroprotective mechanism of IPC for ischemia treatment. 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. MetS patients had a 3.542-fold increased odds ratio (OR) for cognitive impairment. 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. The https:// ensures that you are connecting to the Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Geng J.L., Zhang Y., Li S.J., Li S.N., Wang J.K., Wang H., Aa J.Y., Wang G.J. The glucose taken up by astrocytes may have one of two primary fates: it may be converted to lactate through astrocytic glycolysis or converted via glycogenesis to glycogen storage. (2) Excitotoxicity. 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. It was first discovered by Murry et al., in the canine heart, in 1986 [7]. 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]. 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. Stroke Education Flashcards | Quizlet Brain, tumor, and proliferative tissues have high metabolic activity and energy requirements, necessitating that they have reliable mechanisms to adequately protect their metabolic homeostasis. In this work, we review how the concept of ischemic penumbra has been evolving from its purely electrophysiological/ hemodynamic based definition to the wider metabolic-cellular-therapeutic concept that is managed today by neuroscientists. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (, ischemic stroke, ischemic preconditioning (IPC), metabolic reprogramming. The astrocytic glycolysis is also stimulated by neuronal activation, giving neurons the capacity of tight control over astrocyte metabolism. the contents by NLM or the National Institutes of Health. -HB is a biomarker of the cytosolic NADH/NAD+ ratio [79], indicating that IPC can regulate the NADH/NAD+ ratio. PDF The Cerebral Ischemic Penumbra - Cambridge These studies have indicated the time-specificity of IPC; however, the dynamic change of metabolic reprogramming induced by IPC is still unclear. 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]. Raf kinase inhibitory protein (RKIP) is involved in the protective effect against stroke: Li et al. Sphingosine 1-phosphate (S1P) is a bioactive signaling lipid highly enriched in mature erythrocytes. alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Before Stroke incidence rates for those with and without MetS were 2.6% and 1.1%, respectively.
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