The ischemic penumbra is defined as functionally impaired yet still viable tissue surrounding the ischemic core. Wang P., Miao C.Y. A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. Hou W., Xie Y., Song X., Sun X., Lotze M.T., Zeh H.J., Tang D. Autophagy promotes ferroptosis by degradation of ferritin. The Ischemic Penumbra: Correlates in Imaging and Implications for When ischemic stroke occurred, patients who had a target LDL cholesterol level of 90110 mg per deciliter had a higher risk of subsequent cardiovascular events than those who had a target range of less than 70 mg per deciliter. 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. 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. Blood Vessel Reactivity - an overview | ScienceDirect Topics In the absence of glutamine (or when glutaminolysis is inhibited), cystine starvation and ferroptosis occur. 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. Erythrocyte Metabolic Reprogramming by Sphingosine 1-Phosphate in Chronic Kidney Disease and Therapies. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. PDF Identifying and utilizing the ischemic penumbra 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]. When the CBF is below 10 mL/100 g per minute, irreversible cellular injury will occur, and the infarct core forms [10]. Sato H., Nomura S., Maebara K., Sato K., Tamba M., Bannai S. Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Regional cerebral blood flow thresholds during cerebral ischemia. Third, iron deficiency has been associated with an increased risk of ischemic stroke [46]. 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. The ischemic penumbra: From concept to reality utilized MALDI-MSI to observe the intracerebral distribution of neurotransmitters in Parkinsonian rats, primates, and human patients [88]. Wender et al. The role of ketone bodies in caloric homeostasis. Iron-Deficiency and Estrogen Are Associated with Ischemic Stroke by Up-Regulating Transferrin to Induce Hypercoagulability. Detailed metabolomics data verification with higher time and tissue-specific resolution will be needed in the future. CEREBROVASC DIS. PDF The Cerebral Ischemic Penumbra - Cambridge 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. Cerebral Blood Flow Threshold of Ischemic Penumbra and Infarct - Stroke ); nc.ude.aaub@9102gnorgnornah (R.H.), 2School of Engineering Medicine, Beihang University, Beijing 100191, China. Regulation of glycogen metabolism: Physiological, pharmacological and pathological aspects. Most ketones are generated in the liver, while the transport of ketone bodies across the blood-brain barrier (BBB) is the limiting step. 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. Mitochondria are major contributors to cellular ROS, and there are multiple antioxidant pathways to neutralize ROS, including superoxide dismutase (SOD2), glutathione, thioredoxin, and peroxiredoxins. Research has found that L-glutamine reduced brain infarct volume and promoted neurobehavioral recovery in cerebral ischemic mice [25]. Lekoubou A., Ovbiagele B., Markovic D., Sanossian N., Towfighi A. The complex underlying mechanisms responsible for the neuroprotection against IPC remain elusive. Several studies also showed that transient ischemic attack (TIA) may produce IPC effect in people who have a subsequent stroke [101,102]. Immune cells also have distinct metabolic programs, in order to meet the energetic and biosynthetic requirements of their ever-changing micro-environments. 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. In acute patients, PET documented areas of decreased 11 C-flumazenil uptake went on to show infarctions, while areas of relative . 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]. Efficient ketone metabolism generates relatively abundant energy, which may prevent activation of the hyperglycolytic pathway under oxygen and glucose deprivation [27]. At the onset of ischemia, NAD+ levels decrease within 30 min, a second depletion occurs at 6 h of reperfusion (when necrosis is prominent), and a third depletion of NAD+ happens at 24 h (when apoptosis is prominent). Hirayama Y., Ikeda M.Y., Notomi S., Enaida H., Kinouchi H., Koizumi S. Astrocyte-mediated ischemic tolerance. the ischemic penumbra can maintain metabolic demand with marginal blood flow from collateral circulation for a maximum of __ before increasing in size? Intriguing, the protective effect of IPC can be mimicked pharmacologically. 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. Chen S.Y., Liu J.W., Wang Y.H., Huang J.Y., Chen S.C., Yang S.F., Wang P.H. NADP+ is an essential cofactor for the rate-limiting step of the pentosephosphate pathway (PPP). 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. PPFKFB3 controls glycolytic flux by synthesizing fructose-2,6-bisphosphate (F2,6BP), a potent allosteric activator of phosphofructokinase 1 (PFK-1), which is a master regulator of glycolysis [18]. 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. Furthermore, IPC treatment also remarkably improves the metabolic disturbances in the TCA cycle during ischemia. Visualizing and Modulating Mitophagy for Therapeutic Studies of Neurodegeneration. ological, molecular, metabolic and perfusional disturbances. ROS is not elevated and, so, this region sustains little damage [89]. The biochemical control of ferroptosis includes amino acid metabolism, glutathione metabolism, lipid metabolism, iron metabolism, and other metabolic pathways [43]. These studies have indicated the time-specificity of IPC; however, the dynamic change of metabolic reprogramming induced by IPC is still unclear. 2011;42 . 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]. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Direct IPC is conducted by brief, direct, repetitive clamping of the target artery, while regional IPC involves a repetitive occlusion of the circumflex artery, which is near to the target artery. Before Geng J.L., Zhang Y., Li S.J., Li S.N., Wang J.K., Wang H., Aa J.Y., Wang G.J. The Ischemic Penumbra and Cell Survival | SpringerLink 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]. However, the underlying neuroprotection mechanisms of IPC remain elusive. Glutamine is the most abundant free amino acid in human blood, which is converted to glutamate in mitochondria by glutaminase (GLS). Licensee MDPI, Basel, Switzerland. The normal CBF in healthy normal men is 54 mL/100 g per minute. Furthermore, as IPC not only can salvage the stroke patient at the acute period, but can also provide effective solutions for stroke rehabilitation during the chronic period, determination of the underlying metabolic regulation mechanism, which is still unclear, should be actively pursued. Energy failure leads to the depolarization of neurons and activation of specific glutamate receptors dramatically, which further induce the failure of the transmembrane electrochemical gradient established by the Na+, K+-ATPase pump. Malpartida A.B., Williamson M., Narendra D.P., Wade M.R., Ryan B.J. Metabolic Syndrome Is a Strong Risk Factor for Minor Ischemic Stroke and Subsequent Vascular Events. The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression. Faubert B., Solmonson A., DeBerardinis R.J. Metabolic reprogramming and cancer progression. Ischemic Penumbra | STROKE MANUAL The translation of experimental . Direct NAD+ repletion, either in animal or in cultured neurons, markedly reduced ischemic cell death and DNA damage [32,33]. 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. 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. If the ischemic penumbra is characterized by these approaches, then a reduction of CBF to levels between a lower threshold of 10-15 mL/100 g/min and an upper threshold of approximately 25 mL/100 g/min is likely to identify penumbral tissue. Oxygen is a crucial substrate in metabolism. . Yarian C.S., Toroser D., Sohal R.S. ; funding acquisition and editing, R.H.; funding acquisition, review and editing, B.Z. 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). In the meantime, free radicals trigger oxidative stress, which further induce damage to nucleic acid bases, lipids, and proteins, ultimately leading to cell death by necrosis or apoptosis. Heterogeneity in the penumbra - SAGE Journals de Jonge R., de Jong J.W. 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]. 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). Ischemic penumbra | Radiology Reference Article | Radiopaedia.org The ischemic penumbra has been in the center of ischemic stroke research for the last 40 years. 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. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Busija D.W., Rutkai I., Dutta S., Katakam P.V. 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. View. Bae J.E., Kang G.M., Min S.H., Jo D.S., Jung Y.K., Kim K., Kim M.S., Cho D.H. Primary cilia mediate mitochondrial stress responses to promote dopamine neuron survival in a Parkinsons disease model. Lactate in cerebrospinal fluid (CSF) has also been found to be higher in stroke patients [17]. 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]. U.S. National Health and Nutrition Examination Surveys of 12,502 adults during 19992010. 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]. Whereas in the delayed or the second protect phase of IPC, the brain is again ischemia-tolerant [93]. Eckel R.H., Grundy S.M., Zimmet P.Z. 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. Adenosine receptor-mediated cardioprotection: Are all 4 subtypes required or redundant? 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. 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. Wang S., Xing Z., Vosler P.S., Yin H., Li W., Zhang F., Signore A.P., Stetler R.A., Gao Y., Chen J. In 2020, Per E. Andrn et al. However, continuing ischemic stress, or additional energy demanding episodes, or both, will exhaust this limited capacity and transform penumbra into necrotic tissue. Brainin M., Feigin V.L., Norrving B., Martins S.C.O., Hankey G.J., Hachinski V. Global prevention of stroke and dementia: The WSO Declaration. 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]. Yu Z., Li J., Ren Z., Sun R., Zhou Y., Zhang Q., Wang Q., Cui G., Li J., Li A., et al. 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. Mitochondrial Dysfunction and Mitophagy in Parkinsons Disease: From Mechanism to Therapy. The https:// ensures that you are connecting to the These include: NADP+/NADPH. Current evidence-based . Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. In addition, age-related alterations in TCA cycle enzyme activities will likely contribute to the decline of mitochondrial bioenergetics [96]. Murry C.E., Jennings R.B., Reimer K.A. 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. 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. First, the availability of cysteine is the limiting link in GSH biosynthesis. 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. Metabolomic Profiling Reveals That Reprogramming of Cerebral Glucose Metabolism is Involved in Ischemic Preconditioning Induced Neuroprotection in a Rodent Model of Ischemic Stroke. 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. Ischemic preconditioning triggers endogenous neuroprotection to defend against subsequent, more severe cerebral ischemia. Lactate: Studies in the past two decades have indicated that lactate is also an efficient energy substrate for maintaining neuronal integrity and functioning during cerebral ischemia [21]. 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. Neurons experience mitochondrial dysfunction, shifting the cellular machinery from aerobic to anaerobic metabolism, and a decrease of ATP production, directly resulting in energy failure. Jaggar et al. L-glutamine protects mouse brain from ischemic injury via up-regulating heat shock protein 70. 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. Guan X., Li X., Yang X., Yan J., Shi P., Ba L., Cao Y., Wang P. The neuroprotective effects of carvacrol on ischemia/reperfusion-induced hippocampal neuronal impairment by ferroptosis mitigation. Direct intracerebroventricular or intravenous administration of lactate protected mouse brains against ischemic injury [22]. Age, sex, and race/ethnic temporal trends in metabolic syndrome prevalence among individuals with myocardial infarction or stroke in the United States. Coincidentally, a clinical study has implicated the effectiveness of IPC in preventing the progression of white matter hyperintensities (WMHs) and in ameliorating cognitive impairment of very elderly patients (83.5 2.3 year) with ICAS [94]. Comprehensive mapping of neurotransmitter networks by MALDIMS imaging. This refinement has potential therapeutic implications. To date, IPC has been replicated in humans and other species, and applied to other organs and tissues (e.g., the brain and kidney). Here we provide a summary of metabolic mechanism of ischemic preconditioning when it is applied to 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. Identify the blocked artery that could potentially cause these symptoms. Vessey D.A., Li L., Honbo N., Karliner J.S. 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. The research by Polyzos et al. 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 mammalian brain, neurons are outnumbered 10:1 by astrocytes in most regions. Then, the accumulated free radicals damage cell membranes, mitochondria, and DNA, thus triggering caspase-mediated cell death. Previous studies reported that when MCAO is applied during the early IPC phase, the brain is ischemia-tolerant. A previous study has shown ketone bodies to reduce ROS by using NADH as an electron donor. Metabolic disorder and metabolic plasticity are salient features triggered by ischemia. The metabolic syndrome. There is also a beneficial role of erythrocyte S1P in hypertensive CKD, where S1P also induces 2,3-BPG production and oxygen delivery [72]. 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. Yin, J. et al. In this review, we summarize the metabolic disorder and metabolic plasticity in the incidence and progression of ischemic stroke. Irreversible injury to mitochondria is a cornerstone of pathogenesis of neurological diseases. 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. Hess D.C., Blauenfeldt R.A., Andersen G., Hougaard K.D., Hoda M.N., Ding Y., Ji X. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Effects of ischemic preconditioning on mitochondrial and metabolic neruoprotection: 5 adenosine monophosphate-activated protein kinase and sirtuins. The metabolic characteristics of HBV-related ACLF patients revealed the inhibition of glycolysis, TCA and urea cycle, and the enhancement of fatty acid oxidation and glutamine anaplerosis [70]. Ischemic stroke occurs most frequently in individuals aged 65 years. Wu Y., Zhang S., Gong X., Tam S., Xiao D., Liu S., Tao Y. The ischemic penumbra can maintain metabolic demand with marginal blood flow from collateral circulation for a maximum of _____ before increasing in size. In biosynthetic pathways, cancer cells require that intermediate pools are maintained. Ischemic Penumbra: Evidence From Functional Imaging in Man 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). 40.2% ischemic stroke individuals were diagnosed with MetS. and transmitted securely. Reduced Nicotinamide Adenine Dinucleotide Phosphate, a Pentose Phosphate Pathway Product, Might Be a Novel Drug Candidate for Ischemic Stroke. Hirayama Y., Koizumi S. Astrocytes and ischemic tolerance. It has been noted that a minimal CBF of 18 mL/100 g per minute is needed to maintain normal electroencephalographic (EEG) activity. Amino acids: To sustain fuel oxidation by the tricarboxylic acid (TCA) cycle, nerve cells upregulate glutaminolysis and use of fatty acids and branched chain amino acids. Once ischemic stroke occurs, the PPP is boosted and more glycolytic intermediates are diverted into the PPP to sustain NADPH production [18]. There are two major affected zones in an ischemic brain: The infarct core, surrounded by an ischemic penumbra. 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. In steady-state, cells sustain themselves catabolically by using glycolytic carbons to fuel the TCA cycle. Metabolic reprogramming for metabolic homeostasis maintenance. 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. 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. Organic Acids. Li P., Quan W., Lu D., Wang Y., Zhang H.H., Liu S., Jiang R.C., Zhou Y.Y. The penumbral concept suggests that different areas within the ischemic region evolve into irreversible brain injury over time and that this evolution is most critically linked to the severity . McIntosh V.J., Lasley R.D. 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. Sarrafzadegan N., Gharipour M., Sadeghi M., Nezafati P., Talaie M., Oveisgharan S., Nouri F., Khosravi A. Metabolic Syndrome and the Risk of Ischemic Stroke. 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. The brain is an unusual organ, having the highest metabolic activity and energy requirement by mass. You'll get a detailed solution from a subject matter expert that helps you learn core concepts. Elevated PPP flux enhances the reducing power, in the form of NADPH and GSH. Advance in this active research field will stimulate a promising new direction in precision intervention and drug target discovery for ischemic stroke. Significantly lower levels of glutamine and glycine in CSF following IPC have been observed [75], indicating that the replenishment of GSH is accelerated, eventually imposing reductive stress in the ischemic brain tissue. 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). 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]. Goodman R.P., Markhard A.L., Shah H., Sharma R., Skinner O.S., Clish C.B., Deik A., Patgiri A., Hsu Y.H., Masia R., et al. Polyzos A.A., Lee D.Y., Datta R., Hauser M., Budworth H., Holt A., Mihalik S., Goldschmidt P., Frankel K., Trego K., et al. Stroke is one of the leading causes of death and permanent disability worldwide. Exploring the neuroprotective effects of ginkgolides injection in a rodent model of cerebral ischemia-reperfusion injury by GC-MS based metabolomic profiling. Magistretti P.J., Martin J.L. 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. 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). The Ischemic Penumbra and the Ischemic Core Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Mitochondrial Mechanisms of Neuronal Cell Death: Potential Therapeutics. Previous evidence has revealed that IPC diverts excess glucose to oxPPP. 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. 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. Upon the onset of ischemia, the level of AMP dramatically decreases in the cortex and hippocampus tissues, indicating energy failure in these tissues [16].