Adenosine receptor-mediated cardioprotection: Are all 4 subtypes required or redundant? The ischemic penumbra: operationally . Mouse genetic studies have shown that S1P protects against tissue hypoxia by inducing O2 release. 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. 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. In the brain, astrocytes can also generate ketone bodies from fatty acid -oxidation. Ischemic penumbra is intercalated between normoxic (proximal) and anoxic (distal) fields. Hirayama Y., Ikeda M.Y., Notomi S., Enaida H., Kinouchi H., Koizumi S. Astrocyte-mediated ischemic tolerance. 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. 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]. 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]. Su L., Zhao H., Zhang X., Lou Z., Dong X. UHPLC-Q-TOF-MS based serum metabonomics revealed the metabolic perturbations of ischemic stroke and the protective effect of RKIP in rat models. 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. Ischemic preconditioning treatment of astrocytes transfers ischemic tolerance to neurons. Altogether, these results imply that subduing postischemic hyperglycolysis and the regulation of brain glucose metabolism play important roles in the neuroprotective aspect of IPC. Remarkably, specific neurotransmitters and neuromodulators could dictate astrocytes glycogenolysis. 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. 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]. It has been demonstrated that mitochondria are a major target in ischemic injury. However, the underlying neuroprotective mechanisms of IPC remain elusive. Direct NAD+ repletion, either in animal or in cultured neurons, markedly reduced ischemic cell death and DNA damage [32,33]. 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. Chen W.L., Jin X., Wang M., Liu D., Luo Q., Tian H., Cai L., Meng L., Bi R., Wang L., et al. -HB is a biomarker of the cytosolic NADH/NAD+ ratio [79], indicating that IPC can regulate the NADH/NAD+ ratio. The biochemical control of ferroptosis includes amino acid metabolism, glutathione metabolism, lipid metabolism, iron metabolism, and other metabolic pathways [43]. Irreversible injury to mitochondria is a cornerstone of pathogenesis of neurological diseases. 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. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. 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. McIntosh V.J., Lasley R.D. These data are consistent with the original concepts of the penumbra and core, but recognize the dynamic complex heterogeneous processes involved. . As the main product of the oxidative PPP (oxPPP), NADPH provides the essential redox equivalent for GSH regeneration, enhancing the antioxidant defense capacity. Mitochondria lie at the key location for neuronal survival [51]. The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression. 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. Furthermore, the level of glycolytic products of lactate in CSF was found to be decreased following IPC [75]. 2011;42 . alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Amarenco P., Kim J.S., Labreuche J., Charles H., Abtan J., Bejot Y., Cabrejo L., Cha J.K., Ducrocq G., Giroud M., et al. All authors have read and agreed to the published version of the manuscript. Zong W.X., Rabinowitz J.D., White E. Mitochondria and Cancer. Together, these findings reveal the biological activity of S1P in erythrocyte oxygen delivery, indicating that IPC may enhance erythrocyte oxygen delivery through S1P, thereby enhancing cerebral metabolism to defend against ischemic stress. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Eventually, exogenous lactate administration can significantly increase cell survival in neuronal cultures against lethal oxygen glucose deprivation (OGD) [84]. Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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]. 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. Hepatic NADH reductive stress underlies common variation in metabolic traits. Hirayama Y., Koizumi S. Astrocytes and ischemic tolerance. Iron is essential for the accumulation of lipid peroxides and execution of ferroptosis. 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]. This pathway can produce precursors to synthesize nucleotides and aromatic amino acids, generating cytosolic NADPH simultaneously [30]. IPC has been shown to enhance levels of NAD+ in the brain [77]. 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. In short, understanding the mechanism of metabolic reprogramming is expected to be greatly beneficial for our understanding of ischemic stroke treatment and for the standardized application of IPC. and increases energy demand and neurotransmitter effluxes, 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. A field of research that continues to show promise in developing therapies for ischemic stroke is ischemic preconditioning (IPC). 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. The accumulation of glucose and glycolytic intermediates is a prominent feature of brain ischemia-induced metabolic disturbance in rodents. 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. Wang G.S., Tong D.M., Chen X.D., Yang T.H., Zhou Y.T., Ma X.B. Wang H., He Z., Zhang Y., Zhang J. Fructose can be readily catabolized to fuel fatty acid synthesis and palmitoleic acid generation by lung cancer cells, as a glucose alternative [65]. 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. -ketoglutarate, produced by glutaminolysis, is vital for alternatively M2-activated macrophages [69]. Meng R., Asmaro K., Meng L., Liu Y., Ma C., Xi C., Li G., Ren C., Luo Y., Ling F., et al. 6-8 hours A patient presents to the emergency department with left leg weakness and numbness. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Zhou M., Wang H., Zeng X., Yin P., Zhu J., Chen W., Li X., Wang L., Wang L., Liu Y., et al. Bang O.Y., Saver J.L., Kim S.J., Kim G.M., Chung C.S., Ovbiagele B. The clearance of damaged mitochondria through mitophagy is critical for cellular fitness, as dysfunctional mitochondria can impair ETC function and increase oxidative stress. However, the underlying biological mechanisms of ischemic preconditioning are still confusing. 8600 Rockville Pike Hatten M.E. Several studies also showed that transient ischemic attack (TIA) may produce IPC effect in people who have a subsequent stroke [101,102]. 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. Metabolic reprogramming by ischemic preconditioning (IPC). In subsequent hours after IPC, the brain regresses to its nave state. Accessibility 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. 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). Efficient ketone metabolism generates relatively abundant energy, which may prevent activation of the hyperglycolytic pathway under oxygen and glucose deprivation [27]. Then, the accumulated free radicals damage cell membranes, mitochondria, and DNA, thus triggering caspase-mediated cell death. 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. 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. It has been found that metabolic disorder is a determinant of the incidence and progression of stroke. It has recently been demonstrated that mitophagy is highly involved in ischemic stroke and could be neuroprotective; furthermore, insufficient or altered mitophagy can lead to cell death and may promote the development and propagation of neurodegeneration [55,56]. HHS Vulnerability Disclosure, Help The concept of the ischemic penumbra was formulated 30 years ago based on experiments in animal models showing functional impairment and electrophysiological disturbances with decreasing flow to the brain below defined values (the threshold for function) and irreversible tissue damage with the blood TCA cycle reactions yield metabolite intermediates and energetic precursors for oxidative phosphorylation. Federal government websites often end in .gov or .mil. Yu Z., Li J., Ren Z., Sun R., Zhou Y., Zhang Q., Wang Q., Cui G., Li J., Li A., et al. It has been noted that a minimal CBF of 18 mL/100 g per minute is needed to maintain normal electroencephalographic (EEG) activity. Efficacy of remote ischemic conditioning on improving WMHs and cognition in very elderly patients with intracranial atherosclerotic stenosis. Metabolic syndrome (MetS) is a common metabolic disorder, involving a constellation of insulin resistance, abdominal obesity, hypertension, and dyslipidemia. (1)H NMR metabolic signature of cerebrospinal fluid following repetitive lower-limb remote ischemia preconditioning. Zhang et al. The primary aim of current acute stroke . At a practical level, however, this definition is unwieldy. Apart from complete reperfusion, IPC is a powerful intervention known for reducing ischemic infarct size. Vessey D.A., Li L., Honbo N., Karliner J.S. The Conditions Under Which Piracetam Is Used and the Factors That Can Improve National Institute of Health Stroke Scale Score in Ischemic Stroke Patients and the Importance of Previously Unnoticed Factors from a Hospital-Based Observational Study in Taiwan. 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. Jaggar 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. Ischemic Neuroprotectant PKCepsilon Restores Mitochondrial Glutamate Oxaloacetate Transaminase in the Neuronal NADH Shuttle after Ischemic Injury. It will be a further explanation that the pathophysiological mechanisms in ischemic stroke are closely related to metabolic disorder. Mitochondria are major contributors to cellular ROS, and there are multiple antioxidant pathways to neutralize ROS, including superoxide dismutase (SOD2), glutathione, thioredoxin, and peroxiredoxins. IPC has also demonstrated neuroprotective activity through the activation of Nrf2 both in vivo and in vitro, which is a transcription factor that helps to maintain mitochondrial coupling and antioxidant protein expression [75]. The Ischemic Penumbra and the Ischemic Core GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling. It is well-known that lysine, being an energy-providing amino acid, is necessary for the biosynthesis of L-carnitine. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Upon ischemic stroke, cerebral glycolysis exhibits an increasing trend. 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]. Ivanisevic J., Epstein A.A., Kurczy M.E., Benton P.H., Uritboonthai W., Fox H.S., Boska M.D., Gendelman H.E., Siuzdak G. Brain region mapping using global metabolomics. Mitochondrial Mechanisms of Neuronal Cell Death: Potential Therapeutics. Before Ketone. General description of ischemic preconditioning (IPC), in which several cycles of brief non-lethal ischemia and reperfusion are applied either directly, regionally, or remotely. Further study focus on ischemic preconditioning metabolic reprogramming is needed, and it will be valuable for exploring the mechanisms of ischemic preconditioning, and will be greatly beneficial for the understanding of ischemic stroke treatment and standardized application of ischemic preconditioning. (Stroke. Yarian C.S., Toroser D., Sohal R.S. Trial of 2860 patients and followed them for 3.5 years. Bethesda, MD 20894, Web Policies revealed that S1P promoted erythrocyte glycolysis and oxygen release for adaptation to hypoxia. 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. Received 2021 Apr 13; Accepted 2021 May 6. https://creativecommons.org/licenses/by/4.0/, Cohort study of 5398 adults aged 35 years or older followed for 10 years. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. 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). 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]. 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. A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. 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. 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. 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. Elevated PPP flux enhances the reducing power, in the form of NADPH and GSH. There are two major affected zones in an ischemic brain: The infarct core, surrounded by an ischemic penumbra. Bartnik B.L., Sutton R.L., Fukushima M., Harris N.G., Hovda D.A., Lee S.M. The relaxation of VSM can also be indirectly regulated by the action of NO and other vasoactive agents. Once ischemic stroke occurs, the PPP is boosted and more glycolytic intermediates are diverted into the PPP to sustain NADPH production [18]. To the best of our knowledge, no study has assessed whether IPC affects the oxygen delivery ability of erythrocytes. Therefore, given the critical role of these organelles in disease onset and progression, strategies . Glutamine importantly regulates this process by providing glutamate and promoting cystine uptake [82]. You'll get a detailed solution from a subject matter expert that helps you learn core concepts. Metabolic syndrome (MetS) increases stroke incidence. Stroke incidence rates for those with and without MetS were 2.6% and 1.1%, respectively. 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. Most ketones are generated in the liver, while the transport of ketone bodies across the blood-brain barrier (BBB) is the limiting step. To maintain the cerebral activity transiently, upon ischemia onset, brain tissues enhance their metabolic plasticity, mainly through energy metabolic reprogramming and antioxidant defense. NADP+ and its reduced counterpart, NADPH, are mainly required for anabolic reactions and cellular oxidative-stress defense. The authors declare no conflict of interest. Metabolic reprogramming for metabolic homeostasis maintenance. 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 . The latter form is informative in energy metabolism than free NADH. The role of ketone bodies in caloric homeostasis. 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. Neuronal regulation of astroglial morphology and proliferation in vitro. 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 pathophysiology of MetS seems to be largely attributable to the metabolic disorder caused by insulin resistance, with glucose intolerance and excessive flux of fatty acids also being implicated [57]. Increased pools of NAMPT and NAD+ are protective against oxygenglucose deprivation, as well as playing a crucial role in cell energy maintenance. Though the information about IPC-mediated metabolic reprogramming in older adults is scant, these promising findings drive the hypothesis that IPC-mediated metabolomic reprogramming may have a subtle susceptibility to aging. 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. The research by Polyzos et al. MetS prevalence was 61.2% in stroke survivors. Sep 2011. Sato H., Nomura S., Maebara K., Sato K., Tamba M., Bannai S. Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. Ischemic preconditioning and glucose metabolism during low-flow ischemia: Role of the adenosine a receptor. Rapid NAD+ depletion inevitably disrupts intracellular energy homeostasis. Servick K. Reprogrammed cells could tackle brain damage. revealed that RKIP overexpression markedly reduced the necrotic area after ischemic stroke, mainly reflected in the metabolism of energy, amino acids, and lipids [38]. Ischemic stroke is the consequence of a sharp reduction of regional cerebral blood flow (CBF), resulting in oxygen and glucose deprivation (OGD). Furthermore, there exist some serious contraindications and complications; for example, thrombolytic agents have been associated with symptomatic intracerebral hemorrhage [6]. For ischemic stroke, IPC can reduce the infarct size and improve prognosis, which is supported by increasing the cerebral blood flow (CBF), protecting mitochondrial function, and maintaining neuronal activity.