ischemic penumbra metabolic demand

Wu Y., Zhang S., Gong X., Tam S., Xiao D., Liu S., Tao Y. 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]. One study showed that neurons made specific metabolic adaptations following IPC (transient OGD) with the regulation of oxygen utilization and lactate production [100]. Ischemic preconditioning triggers endogenous neuroprotection to defend against subsequent, more severe cerebral ischemia. Article. 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. 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. Studies also clearly demonstrate that IPC is quite effective in aged animals: in aged gerbils, IPC provided substantial neuroprotection (>80%) in CA1 neurons ten days after ischemia compared with 6% in ischemic gerbils [95]. At a practical level, however, this definition is unwieldy. Glycogen: The metabolism of glycogen is critical for the release of stored glucose. The Ischemic Penumbra and Cell Survival | SpringerLink 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. 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. 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. However, the underlying neuroprotection mechanisms of IPC remain elusive. Malpartida A.B., Williamson M., Narendra D.P., Wade M.R., Ryan B.J. Hatten M.E. Bang O.Y., Saver J.L., Kim S.J., Kim G.M., Chung C.S., Ovbiagele B. https://creativecommons.org/licenses/by/4.0/, Cohort study of 5398 adults aged 35 years or older followed for 10 years. Hence, the abundance and localization of polyunsaturated fatty acids are crucial for the degree of lipid peroxidation that occurs in cells. Chen S.Y., Liu J.W., Wang Y.H., Huang J.Y., Chen S.C., Yang S.F., Wang P.H. The vulnerable striatum is enriched in fatty acids, which the mitochondria reprogram to be metabolized as an energy source, but at the cost of ROS accumulation and induced damage. Stankovic S., Majkic-Singh N. Genetic aspects of ischemic stroke coagulation homocysteine, and lipoprotein metabolism as potential risk factors Critical Reviews in Clinical Laboratory. Once ischemic stroke occurs, the PPP is boosted and more glycolytic intermediates are diverted into the PPP to sustain NADPH production [18]. Simmons E.C., Scholpa N.E., Schnellmann R.G. The clearance of damaged mitochondria through mitophagy is critical for cellular fitness, as dysfunctional mitochondria can impair ETC function and increase oxidative stress. Furthermore, the accumulation of the TCA intermediate succinate is also responsible for mitochondrial ROS production during ischemic reperfusion [39]. 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. revealed that RKIP overexpression markedly reduced the necrotic area after ischemic stroke, mainly reflected in the metabolism of energy, amino acids, and lipids [38]. Previous research has revealed that S1P is an important endogenous protectant against ischemia, where the increased release of S1P from myocytes in response to IPC has been observed [86]. 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. Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases. Jackson C.W., Escobar I., Xu J., Perez-Pinzon M.A. Measurement of the Ischemic Penumbra With MRI: It's About Time Zong W.X., Rabinowitz J.D., White E. Mitochondria and Cancer. Yamamoto T., Byun J., Zhai P., Ikeda Y., Oka S., Sadoshima J. Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion. Elucidation of these endogenous defense mechanisms against ischemic injury is considered crucial for the development of novel stroke therapies. 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]. Therefore, given the critical role of these organelles in disease onset and progression, strategies . Early reperfusion aims to save the ischemic penumbra by preventing infarct core expansion and is the mainstay of acute ischemic stroke therapy. 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. government site. After hypoxic-ischemic insult, the perturbation of mitochondrial homeostasis can profoundly alter the ATP production and intracellular cellular energy status, leading to apoptotic cell death in the presence of increased ROS production, calcium accumulation, opening of mitochondrial permeability transition pores (mPTPs), and releasing cytochrome C [52,53]. For blood glucose and oxygen supply, IPC increases regional CBF and regulates the oxygen-delivery ability of erythrocytes through sphingosine 1-phosphate (S1P), in order to maintain glucose and oxygen metabolic consumption. Studies have revealed that inhibitors of ferroptosis, such as ferrostatins, carvacrol, and liproxstatins, could protect against cerebral ischemic injury in rodent models [43,48]. 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. TCA cycle reactions yield metabolite intermediates and energetic precursors for oxidative phosphorylation. The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression. 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. Protein kinase C epsilon regulates mitochondrial pools of Nampt and NAD following resveratrol and ischemic preconditioning in the rat cortex. MetS patients had a 3.542-fold increased odds ratio (OR) for cognitive impairment. 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. Laursen M.R., Hansen J., Elkjaer C., Stavnager N., Nielsen C.B., Pryds K., Johnsen J., Nielsen J.M., Botker H.E., Johannsen M. Untargeted metabolomics reveals a mild impact of remote ischemic conditioning on the plasma metabolome and alpha-hydroxybutyrate as a possible cardioprotective factor and biomarker of tissue ischemia. Glenn T.C., Martin N.A., Horning M.A. 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). Sato H., Nomura S., Maebara K., Sato K., Tamba M., Bannai S. Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. Sun K., Zhang Y., DAlessandro A., Nemkov T., Song A., Wu H., Liu H., Adebiyi M., Huang A., Wen Y.E., et al. It has been found that metabolic disorder is a determinant of the incidence and progression of stroke. The .gov means its official. 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). In subsequent hours after IPC, the brain regresses to its nave state. Stroke is a leading cause of death and permanent disability, imposing heavy social and family burdens [1,2]. Exploring the neuroprotective effects of ginkgolides injection in a rodent model of cerebral ischemia-reperfusion injury by GC-MS based metabolomic profiling. Arrell D.K., Elliott S.T., Kane L.A., Guo Y., Ko Y.H., Pedersen P.L. Hirayama Y., Ikeda M.Y., Notomi S., Enaida H., Kinouchi H., Koizumi S. Astrocyte-mediated ischemic tolerance. National Library of Medicine In 2020, Per E. Andrn et al. Magistretti P.J., Martin J.L. As the main product of the oxidative PPP (oxPPP), NADPH provides the essential redox equivalent for GSH regeneration, enhancing the antioxidant defense capacity. 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. Awooda H.A. 6-8 hours A patient presents to the emergency department with left leg weakness and numbness. Lekoubou A., Ovbiagele B., Markovic D., Sanossian N., Towfighi A. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. The ischemic penumbra is defined as the severely hypoperfused, functionally impaired, at-risk but not yet infarcted tissue that will be progressively recruited into the infarct core. 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. Bethesda, MD 20894, Web Policies Lactate in cerebrospinal fluid (CSF) has also been found to be higher in stroke patients [17]. The ischemic protection of IPC has been applied in various organs, such as the heart, brain, kidney, liver, lungs, and intestine. Metabolic disorder and metabolic plasticity are salient features triggered by ischemia. Simultaneously, the anaplerotic pathway is promoted to refill the macromolecular biosynthesis for rapid proliferation in some cells. Metabolic syndrome (MetS) is a common metabolic disorder, involving a constellation of insulin resistance, abdominal obesity, hypertension, and dyslipidemia. The accumulation of glucose and glycolytic intermediates is a prominent feature of brain ischemia-induced metabolic disturbance in rodents. Wang G.S., Tong D.M., Chen X.D., Yang T.H., Zhou Y.T., Ma X.B. 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. 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]. Collaterals are demonstrated to be strong predictors of both response to endovascular therapy and functional outcomes [11]. The regulation of NAD+ by IPC is related to NAMPT (nicotinamide phosphoribosyl transferase). In delayed IPC, those protein kinases activate transcription factors, which facilitate the synthesis of distal mediators, such as cyclooxygenase-2 (COX-2) and heat shock protein (Hsp72), to induce the protective effect 1224 h after IPC. Remarkably, specific neurotransmitters and neuromodulators could dictate astrocytes glycogenolysis. 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). Second, polyunsaturated fatty acids are susceptible to lipid peroxidation and are necessary for ferroptosis [45]. IPC has been shown to enhance levels of NAD+ in the brain [77]. Increased pools of NAMPT and NAD+ are protective against oxygenglucose deprivation, as well as playing a crucial role in cell energy maintenance. de Jonge R., de Jong J.W. Moreover, the brain utilizes metabolic plasticity, a protective response to stroke injury. Mech. 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. If ischemic stress is applied during this phase, the neuroprotection effects of IPC vanish. 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. Zhang T., Wang W., Huang J., Liu X., Zhang H., Zhang N. Metabolomic investigation of regional brain tissue dysfunctions induced by global cerebral ischemia. Trial of 2860 patients and followed them for 3.5 years. In response to ischemia, there exists a cerebral vessel autoregulatory mechanism, inducing the enhancement of cerebral collateral circulation and vasodilation, in order to stabilize or increase the CBF and oxygen/glucose extraction for viable neurons. Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute-On-Chronic Liver Failure. This described evidence highlights the capability of IPC in improving mitochondrial efficiency and regulating the reprogramming processes related to mitochondrial function and cellular metabolism. Fluorodeoxyglucosepositron emission tomography (FDG-PET) has demonstrated the preferential utilization of lactate over glucose to fuel neurons, when both were available [85]. 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. Identify the blocked artery that could potentially cause these symptoms. 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. Third, iron deficiency has been associated with an increased risk of ischemic stroke [46]. Then, the accumulated free radicals damage cell membranes, mitochondria, and DNA, thus triggering caspase-mediated cell death. Iron-Deficiency and Estrogen Are Associated with Ischemic Stroke by Up-Regulating Transferrin to Induce Hypercoagulability. Therefore, it can be seen that mitochondrial mechanism is an important, but underutilized, target for improving CBF and decreasing brain injury in stroke patients [14]. Visualizing and Modulating Mitophagy for Therapeutic Studies of Neurodegeneration. 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. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. You'll get a detailed solution from a subject matter expert that helps you learn core concepts. When ischemic stroke occurs, a rapid increase in the production of ROS rapidly overwhelms the antioxidant defenses, which are inadequate to completely clear the ROS. The more we understand the underlying metabolic reprogramming mechanisms manipulated by IPC affecting its efficiency and function against ischemic stroke, the more we will be able to experimentally (and, eventually, clinically) utilize the metabolic homeostasis to confer protection against the ischemic insult. The ischemic core . 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. Yin J., Han P., Tang Z., Liu Q., Shi J. Sirtuin 3 mediates neuroprotection of ketones against ischemic stroke. Elevated PPP flux enhances the reducing power, in the form of NADPH and GSH. Two activities that provide compensatory fluxes to refill the TCA cycle, respectively, are glutaminolysis (which produces -ketoglutarate from glutamine) and oxidation of the branched-chain amino acids and fatty acids [66,67]. Hess D.C., Blauenfeldt R.A., Andersen G., Hougaard K.D., Hoda M.N., Ding Y., Ji X. The ischemic penumbra: From concept to reality 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. Metabolic Syndrome Is a Strong Risk Factor for Minor Ischemic Stroke and Subsequent Vascular Events. Thus, we propose that mitophagy could be developed as an effective and potential target for the treatment of ischemic stroke. View. Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia. Ischemic preconditioning treatment of astrocytes transfers ischemic tolerance to neurons. Remote ischaemic conditioningA new paradigm of self-protection in the brain. All brain cell types are able to uptake ketones; the ketones are then metabolized to acetyl-CoA to support the cell energy [29]. In steady-state, cells sustain themselves catabolically by using glycolytic carbons to fuel the TCA cycle. 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]. An increasing number of studies have shown the time-dependent metabolic changes during IPC or the acute-to-chronic post-stroke phase. This process is named the astrocyteneuron lactate shuttle (ANLS). 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. Association between Metabolic Syndrome and Cognitive Impairment after Acute Ischemic Stroke: A Cross-Sectional Study in a Chinese Population. Finally, the NAD+ pool declines by approximately 3550%. A diagram showing metabolism in the ischemic, penumbra and distant Mitochondria are major contributors to cellular ROS, and there are multiple antioxidant pathways to neutralize ROS, including superoxide dismutase (SOD2), glutathione, thioredoxin, and peroxiredoxins. Intriguing, the protective effect of IPC can be mimicked pharmacologically. Mitophagy is also essential in sustaining mitochondrial homeostasis, biogenesis, and the total number and quality of mitochondria. To the best of our knowledge, no study has assessed whether IPC affects the oxygen delivery ability of erythrocytes. and transmitted securely. Stroke incidence rates for those with and without MetS were 2.6% and 1.1%, respectively. 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. ischemic injury develops heterogeneously, and with time coalesces dynamically into a homogenous core. Upon ischemic stroke, cerebral glycolysis exhibits an increasing trend. revealed that S1P promoted erythrocyte glycolysis and oxygen release for adaptation to hypoxia. 1 and represented an important milestone for understanding the temporal and spatial evolution of focal ischemic brain injury. Excessive glutamate release and impeded reuptake of excitatory amino acids result in the activation of NMDARs, AMPARs and KARs. It is usually located around an infarct core which represents the tissue which has already infarcted or is going to infarct regardless of reperfusion. Previous studies reported that when MCAO is applied during the early IPC phase, the brain is ischemia-tolerant. official website and that any information you provide is encrypted Meanwhile, IPC also boosts the PPP, providing an essential redox equivalent for GSH regeneration and enhancing the capacity of antioxidant defense. 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. Additionally, GSH is synthesized from glutamate, cysteine, and glycine. ; funding acquisition and editing, R.H.; funding acquisition, review and editing, B.Z. Mitochondrial Mechanisms of Neuronal Cell Death: Potential Therapeutics. These include: NADP+/NADPH. Durukan A., Tatlisumak T. Preconditioning-induced ischemic tolerance: A window into endogenous gearing for cerebroprotection. To defend against this, the brain shifts the cellular machinery from aerobic to anaerobic metabolism. 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]. Both studies revealed that the metabolites have inhomogeneous distributions in the brain, with high levels of spatial specificity. The malateaspartate shuttle (MAS) is considered the most important NAD+/NADH shuttle in neurons, playing a prominent role in neuronal mitochondrial respiration. Chen W.L., Jin X., Wang M., Liu D., Luo Q., Tian H., Cai L., Meng L., Bi R., Wang L., et al. Xi Q., Cheranov S.Y., Jaggar J.H. All authors have read and agreed to the published version of the manuscript. Before Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Baron, Donnan, Heiss, and others have re-explored the penumbra concept using PET markers [].The benzodiazepine 11 C-flumazenil binds to the intact GABA-A receptors of presumably intact neural tissue. 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. Metabolic syndrome (MetS) increases stroke incidence. 2,3-BPG is an erythrocyte-specific glycolytic intermediate that facilitates O2 release [71]; concurrently, hypoxia promotes renal damage and progression of chronic kidney disease (CKD). Ketone: Notably, the brain and plasma -hydroxybutyrate (-HB) levels both increase under IPC stimulation, indicating that the brain can increase ketone body oxidation to replenish its energy supply. 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]. 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. A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. Waves of depolarizations, the peri-infarct spreading depres- . alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. 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]. However, in response to changes in the micro-environment, metabolic reprogramming is notably crucial to maintaining metabolic homeostasis. Licensee MDPI, Basel, Switzerland. Collateral flow predicts response to endovascular therapy for acute ischemic stroke. An official website of the United States government. Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice. Bartnik B.L., Sutton R.L., Fukushima M., Harris N.G., Hovda D.A., Lee S.M. 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. As the storage form of glucose, the polymer glycogen is entirely located in astrocytes, and the glycogen metabolism rarely occurs in neurons [99]. ological, molecular, metabolic and perfusional disturbances. Current evidence-based . Other significant changes in amino acid metabolic pathways have also been confirmed upon ischemia: the levels of some well-known energy-providing amino acids, such as leucine, isoleucine, valine, tyrosine, and lysine, increased significantly in brain tissues of mice treated by IPC, indicating that proteolysis was up-regulated [16]. Sarrafzadegan N., Gharipour M., Sadeghi M., Nezafati P., Talaie M., Oveisgharan S., Nouri F., Khosravi A. Metabolic Syndrome and the Risk of Ischemic Stroke. NADP+ and its reduced counterpart, NADPH, are mainly required for anabolic reactions and cellular oxidative-stress defense. The ischemic penumbra: correlates in imaging and implications for
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