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. 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. 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]. Consistent with IPC may effectively reprogram mitochondrial energy metabolism and benefit stroke. An increased understanding of the pathogenic mechanisms of stroke and IPC serves to highlight the importance of metabolic reprogramming. Increased pools of NAMPT and NAD+ are protective against oxygenglucose deprivation, as well as playing a crucial role in cell energy maintenance. Numerous in vitro, in vivo, and clinical studies have indicated that influenza infection induces hyperglycolysis in infected cells, activated immune cells, foci, and lymph nodes [68]. In addition, recent findings have indicated that mitochondria may represent a useful target to restore CBF after stroke, as it has been shown that ATP, adenosine monophosphate (AMP), and adenosine diphosphate (ADP) can alter cerebrovascular tone via plasmalemmal purinergic receptors [12]. Intriguing, the protective effect of IPC can be mimicked pharmacologically. During ischemia, the depletion of GSH and NADPH causes an iron-dependent accumulation of lipid hydroperoxides to lethal levels, thus inducing cell death, which is defined as ferroptosis [42]. Efficacy of remote ischemic conditioning on improving WMHs and cognition in very elderly patients with intracranial atherosclerotic stenosis. It has been found that metabolic disorder is a determinant of the incidence and progression of stroke. 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. 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. 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. Second, polyunsaturated fatty acids are susceptible to lipid peroxidation and are necessary for ferroptosis [45]. FOIA There are two major affected zones in an ischemic brain: The infarct core, surrounded by an ischemic penumbra. Metabolic disorder and metabolic plasticity are salient features triggered by ischemia. It is well-known that lysine, being an energy-providing amino acid, is necessary for the biosynthesis of L-carnitine. 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. Ischemic heterogeneity is also demonstrated by recent PET studies. Ketone. Stankovic S., Majkic-Singh N. Genetic aspects of ischemic stroke coagulation homocysteine, and lipoprotein metabolism as potential risk factors Critical Reviews in Clinical Laboratory. Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. In acute patients, PET documented areas of decreased 11 C-flumazenil uptake went on to show infarctions, while areas of relative . 8600 Rockville Pike Comprehensive mapping of neurotransmitter networks by MALDIMS imaging. 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). Interestingly, IPC has exhibited significant time-window effects in both basic and clinical research, where two phases have been observed. The ischemic penumbra is defined as functionally impaired yet still viable tissue surrounding the ischemic core. Ischemic stroke occurs most frequently in individuals aged 65 years. Ischemic preconditioning treatment of astrocytes transfers ischemic tolerance to neurons. Zhang T., Wang W., Huang J., Liu X., Zhang H., Zhang N. Metabolomic investigation of regional brain tissue dysfunctions induced by global cerebral ischemia. Neurons experience mitochondrial dysfunction, shifting the cellular machinery from aerobic to anaerobic metabolism, and a decrease of ATP production, directly resulting in energy failure. Consistently, a study showed that neurons benefited from the co-incubated astrocytes, enhancing lactate secretion induced by IPC in astrocytes. Wender R., Brown A.M., Fern R., Swanson R.A., Farrell K., Ransom B.R. Writingoriginal draft preparation, editing, J.L. 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. 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. 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. Mortality, morbidity, and risk factors in China and its provinces, 19902017: A systematic analysis for the Global Burden of Disease Study 2017. 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. Yin, J. et al. Therefore, a fastidious quality control system is important: as is well-known, mitochondrial dysfunction can initiate mitochondrial autophagy, which was first named mitophagy by Lemasters [54]. ischemic injury develops heterogeneously, and with time coalesces dynamically into a homogenous core. Another critical concern is the proper time window for IPC metabolic reprogramming in sustaining the neuroprotection effects for the forthcoming ischemia stroke. 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. 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 . Wender et al. https://creativecommons.org/licenses/by/4.0/, Cohort study of 5398 adults aged 35 years or older followed for 10 years. Wang H., He Z., Zhang Y., Zhang J. Both studies revealed that the metabolites have inhomogeneous distributions in the brain, with high levels of spatial specificity. Preservation of the IPC phenotype implicated a unifying endogenous mechanism, possibly involving energy and redox homeostasis maintenance. 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. Finally, the NAD+ pool declines by approximately 3550%. Wang G.S., Tong D.M., Chen X.D., Yang T.H., Zhou Y.T., Ma X.B. 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. Visualizing and Modulating Mitophagy for Therapeutic Studies of Neurodegeneration. Show abstract. Li P., Quan W., Lu D., Wang Y., Zhang H.H., Liu S., Jiang R.C., Zhou Y.Y. Eventually, exogenous lactate administration can significantly increase cell survival in neuronal cultures against lethal oxygen glucose deprivation (OGD) [84]. 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. Dixon S.J., Lemberg K.M., Lamprecht M.R., Skouta R., Zaitsev E.M. Gleason Ferroptosis: An iron-dependent form of nonapoptotic cell death. Thus, the pretreatment of cells with taurine could reduce oxidative stress [50]. 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. 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. Xie T., Chen C., Peng Z., Brown B.C., Reisz J.A., Xu P., Zhou Z., Song A., Zhang Y., Bogdanov M.V., et al. 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]. 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. The research by Polyzos 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. Tang X., Fang M., Cheng R., Zhang Z., Wang Y., Shen C., Han Y., Lu Q., Du Y., Liu Y., et al. These multifaceted functions make them important cellular stress sensors, and they drive metabolic reprogramming for cellular adaptation to harsh environments, such as nutrient depletion or hypoxia [15]. Within cells, the selective autophagy of ferritin (abbreviated as ferritinophagy), by modulating iron metabolism and controlling iron availability, occurs to enhance ferroptosis sensitivity [47]. All authors have read and agreed to the published version of the manuscript. L-glutamine protects mouse brain from ischemic injury via up-regulating heat shock protein 70. Upregulation of pentose phosphate pathway and preservation oftricarboxylic acid cycle flux after experimental brain injury. Morris-Blanco K.C., Cohan C.H., Neumann J.T., Sick T.J., Perez-Pinzon M.A. 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. The relaxation of VSM can also be indirectly regulated by the action of NO and other vasoactive agents. 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 regulation of NAD+ by IPC is related to NAMPT (nicotinamide phosphoribosyl transferase). To the best of our knowledge, no study has assessed whether IPC affects the oxygen delivery ability of erythrocytes. Efficient ketone metabolism generates relatively abundant energy, which may prevent activation of the hyperglycolytic pathway under oxygen and glucose deprivation [27]. TCA cycle reactions yield metabolite intermediates and energetic precursors for oxidative phosphorylation. Transient ischemic attack before nonlacunar ischemic stroke in the elderly. Metabolic Syndrome Is a Strong Risk Factor for Minor Ischemic Stroke and Subsequent Vascular Events. Restoration of normal CBF to the penumbral zone may reverse the functional disturbance. Ischemic preconditioning (IPC) is an endogenous protective strategy, which has been reported to exhibit a significant neuroprotective effect in reducing the incidence of ischemic stroke. 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. 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]. 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. Metabolic reprogramming for metabolic homeostasis maintenance. 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. Rothman D.L., Behar K.L., Hyder F. In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: Implications for brain function. Xu J., Khoury N., Jackson C.W., Escobar I., Stegelmann S.D., Dave K.R., Perez-Pinzon M.A. This refinement has potential therapeutic implications. The site is secure. Accessibility It will be a further explanation that the pathophysiological mechanisms in ischemic stroke are closely related to metabolic disorder. Ischemic penumbra is intercalated between normoxic (proximal) and anoxic (distal) fields. Whereas in the delayed or the second protect phase of IPC, the brain is again ischemia-tolerant [93]. Geng J.L., Zhang Y., Li S.J., Li S.N., Wang J.K., Wang H., Aa J.Y., Wang G.J. Busija D.W., Rutkai I., Dutta S., Katakam P.V. However, continuing ischemic stress, or additional energy demanding episodes, or both, will exhaust this limited capacity and transform penumbra into necrotic tissue. ; funding acquisition and editing, R.H.; funding acquisition, review and editing, B.Z. Waves of depolarizations, the peri-infarct spreading depres- . NADP+ is an essential cofactor for the rate-limiting step of the pentosephosphate pathway (PPP). Current evidence-based . 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. 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. Vessey D.A., Li L., Honbo N., Karliner J.S. Awooda H.A. 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]. Ischemic Neuroprotectant PKCepsilon Restores Mitochondrial Glutamate Oxaloacetate Transaminase in the Neuronal NADH Shuttle after Ischemic Injury. Meng R., Asmaro K., Meng L., Liu Y., Ma C., Xi C., Li G., Ren C., Luo Y., Ling F., et al. Astrocytes state in a particular position to both sense neuronal signaling and capture glucose directly from the capillary and permit them to govern astrocyte-neurons cooperation. Sun K., Zhang Y., DAlessandro A., Nemkov T., Song A., Wu H., Liu H., Adebiyi M., Huang A., Wen Y.E., et al. Changes in the cerebral NAD+ pool under ischemia have been studied in detail. Detailed metabolomics data verification with higher time and tissue-specific resolution will be needed in the future. The Ischemic Penumbra: Correlates in Imaging and Implications for Treatment of Ischemic Stroke. Berthet C., Lei H.T., Thevenet J., Gruetter R. Neuroprotective role of lactate after cerebral ischemia. The cerebral collateral circulationknown as the subsidiary network of vascular channelscan stabilize the CBF when principal conduits fail. The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression. Hirayama Y., Ikeda M.Y., Notomi S., Enaida H., Kinouchi H., Koizumi S. Astrocyte-mediated ischemic tolerance. The role of ketone bodies in caloric homeostasis. Licensee MDPI, Basel, Switzerland. Narayanan S.V., Perez-Pinzon M.A. 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. Yu Z., Li J., Ren Z., Sun R., Zhou Y., Zhang Q., Wang Q., Cui G., Li J., Li A., et al. Lekoubou A., Ovbiagele B., Markovic D., Sanossian N., Towfighi A. 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]. 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]. Glenn T.C., Martin N.A., Horning M.A. Direct NAD+ repletion, either in animal or in cultured neurons, markedly reduced ischemic cell death and DNA damage [32,33]. Recent research has shown that metabolic disorders have significant effects, both before and after the onset of ischemic stroke. 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. These studies have indicated the time-specificity of IPC; however, the dynamic change of metabolic reprogramming induced by IPC is still unclear. de Jonge R., de Jong J.W. This described evidence highlights the capability of IPC in improving mitochondrial efficiency and regulating the reprogramming processes related to mitochondrial function and cellular metabolism. Upon the onset of ischemia, the level of AMP dramatically decreases in the cortex and hippocampus tissues, indicating energy failure in these tissues [16]. Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia. Meanwhile, IPC-treated astrocytes significantly enhanced lactate secretion into the extracellular media. Collateral flow predicts response to endovascular therapy for acute ischemic stroke. Neuronal regulation of astroglial morphology and proliferation in vitro. Meanwhile, IPC also boosts the PPP, providing an essential redox equivalent for GSH regeneration and enhancing the capacity of antioxidant defense. ROS is not elevated and, so, this region sustains little damage [89]. 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. 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. 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. Sphingosine 1-phosphate is an important endogenous cardioprotectant released by ischemic pre- and postconditioning. All brain cell types are able to uptake ketones; the ketones are then metabolized to acetyl-CoA to support the cell energy [29]. U.S. National Health and Nutrition Examination Surveys of 12,502 adults during 19992010. In steady-state, cells sustain themselves catabolically by using glycolytic carbons to fuel the TCA cycle. and transmitted securely. If ischemic stress is applied during this phase, the neuroprotection effects of IPC vanish. revealed that RKIP overexpression markedly reduced the necrotic area after ischemic stroke, mainly reflected in the metabolism of energy, amino acids, and lipids [38]. Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice. The malateaspartate shuttle (MAS) is considered the most important NAD+/NADH shuttle in neurons, playing a prominent role in neuronal mitochondrial respiration. Mitochondria are signaling, bioenergetic, and biosynthetic organelles. 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. In the brain, astrocytes can also generate ketone bodies from fatty acid -oxidation. Recently, Yang X. et al. Therefore, given the critical role of these organelles in disease onset and progression, strategies . More glycolytic intermediates divert into the pentosephosphate pathway (PPP), while the entrance of pyruvate for mitochondrial oxidation is downregulated [18]. Wolf-Dieter Heiss. 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.
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