Xi Q., Cheranov S.Y., Jaggar J.H. In the brain, astrocytes can also generate ketone bodies from fatty acid -oxidation. 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. These studies have indicated the time-specificity of IPC; however, the dynamic change of metabolic reprogramming induced by IPC is still unclear. Sarrafzadegan N., Gharipour M., Sadeghi M., Nezafati P., Talaie M., Oveisgharan S., Nouri F., Khosravi A. Metabolic Syndrome and the Risk of Ischemic Stroke. 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]. Yang Q., Guo M., Wang X., Zhao Y.X., Zhao Q., Ding H.Y., Dong Q., Cui M. Ischemic preconditioning with a ketogenic diet improves brain ischemic tolerance through increased extracellular adenosine levels and hypoxia-inducible factors. Excessive glutamate release and impeded reuptake of excitatory amino acids result in the activation of NMDARs, AMPARs and KARs. 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. To defend against this, the brain shifts the cellular machinery from aerobic to anaerobic metabolism. -ketoglutarate, produced by glutaminolysis, is vital for alternatively M2-activated macrophages [69]. View. Meanwhile, although restoring blood flow by thrombolysis and thrombectomy is essential in limiting ischemic neuronal damage, substantial neuronal, glial, and neurovascular damages may still occur, particularly due to reperfusion injury of the penumbra [5]. GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling. 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. There is also a beneficial role of erythrocyte S1P in hypertensive CKD, where S1P also induces 2,3-BPG production and oxygen delivery [72]. 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. 40.2% ischemic stroke individuals were diagnosed with MetS. 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. 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]. 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). Morris-Blanco K.C., Cohan C.H., Neumann J.T., Sick T.J., Perez-Pinzon M.A. 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. 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. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (, ischemic stroke, ischemic preconditioning (IPC), metabolic reprogramming. Protecting the ischaemic penumbra as an adjunct to - Nature Article. Dawson T.M., Dawson V.L. A previous study has revealed that, once IPC is conducted, autacoids stimulate a number of signaling pathways that convey a protective signal to the mitochondria, where signaling ROS are generated and activate protein kinases to provide the memory; this process can last up to 23 h. Meanwhile, evidence demonstrated the neuroprotection of IPC may depend on the activation of adenosine A1 receptors [90]. 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. 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. Collectively, these findings suggest IPC could specify metabolic reprogramming in neurons and astrocytes and contribute to functional homeostasis. Astrup J, Siesj BK . Moreover, the brain utilizes metabolic plasticity, a protective response to stroke injury. confirmed this: In a Huntington model, they discovered region-specific metabolic reprogramming of astrocytes, which directly induced neuronal susceptibility. Glutamate can be exchanged for cystine in a 1:1 ratio, such that the accumulation of extracellular glutamate could trigger ferroptosis in physiological contexts [44]. The latter form is informative in energy metabolism than free NADH. However, continuing ischemic stress, or additional energy demanding episodes, or both, will exhaust this limited capacity and transform penumbra into necrotic tissue. However, in response to changes in the micro-environment, metabolic reprogramming is notably crucial to maintaining metabolic homeostasis. Ischemic penumbra denotes the part of an acute ischemic stroke that is at risk of progressing to infarction but is still salvageable if reperfused. As the storage form of glucose, the polymer glycogen is entirely located in astrocytes, and the glycogen metabolism rarely occurs in neurons [99]. A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. As the main product of the oxidative PPP (oxPPP), NADPH provides the essential redox equivalent for GSH regeneration, enhancing the antioxidant defense capacity. Though glycolysis is advantageous for rapidly producing ATP to meet the high energy demands, hyperglycolysis can aggravate the brain damage caused by lactic acidosis and ROS overproduction [76]. Berthet C., Lei H.T., Thevenet J., Gruetter R. Neuroprotective role of lactate after cerebral ischemia. NAD+ levels and the NAD+/NADH redox couple provide a readout and regulator for cellular energy metabolism [30]. . 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. Yarian C.S., Toroser D., Sohal R.S. revealed that RKIP overexpression markedly reduced the necrotic area after ischemic stroke, mainly reflected in the metabolism of energy, amino acids, and lipids [38]. Timely interventions are effective for avoiding the progression of the penumbra into infarction. Cellular NAD replenishment confers marked neuroprotection against ischemic cell death: Role of enhanced DNA repair. Under these circumstances, oxidative stress occurs, which further induces damage to nucleic acid bases, lipids, and proteins, ultimately leading to cell death by necrosis or apoptosis [40]. Ischemic Penumbra: Evidence From Functional Imaging in Man Immune cells also have distinct metabolic programs, in order to meet the energetic and biosynthetic requirements of their ever-changing micro-environments. Preserving pools of NAD+ confers neuroprotection after ischemic stress. Stroke Education Flashcards | Quizlet Eckel R.H., Grundy S.M., Zimmet P.Z. investigated genomic DNA from 501 ischemic stroke patients and 1211 comparable controls, and identified significant genetic associations between premature ischemic stroke in BHMT, CBS, FOLH1, MTR, PON2, TCN2, and TYMS genes, which are involved in methionine metabolism [35]. The ischemic penumbra: From concept to reality Growing evidence suggests that ischemic preconditioning takes advantage of brain plasticity for its neuroprotective purposes, among which, metabolic reprogramming is crucial to co-ordinate the metabolic imbalance, especially for energy and redox homeostasis. ischemic injury develops heterogeneously, and with time coalesces dynamically into a homogenous core. 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). 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. sharing sensitive information, make sure youre on a federal Vessey D.A., Li L., Honbo N., Karliner J.S. Meanwhile, the cerebellum is replete with amino acids, which are precursors for glucose regeneration through the pentosephosphate shunt or gluconeogenesis pathways. Yang W.S., Kim K.J., Gaschler M.M., Patel M., Shchepinov M.S., Stockwell B.R. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. 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. Previous studies reported that when MCAO is applied during the early IPC phase, the brain is ischemia-tolerant. To defend against this ischemic cascade, upon the onset of ischemia, brain tissues enhance their metabolic plasticity to maintain the cerebral activity transiently, mainly through the regulation of cerebral blood flow (CBF), mitochondrial adaption, and other defense systems; however, with persistent ischemia, irreversible damage can occur in the affected brain areas. 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. However, these conventional therapies have a narrow therapeutic window: the effective intravenous thrombolytic therapy is within 4.5 h of onset, and that of intra-arterial thrombectomy is within 6 h of onset [3], resulting in only a minority (35%) of stroke patients being able to receive these therapies [4]. Stroke is a leading cause of death and permanent disability, imposing heavy social and family burdens [1,2]. Polyzos A.A., Lee D.Y., Datta R., Hauser M., Budworth H., Holt A., Mihalik S., Goldschmidt P., Frankel K., Trego K., et al. The regulation of NAD+ by IPC is related to NAMPT (nicotinamide phosphoribosyl transferase). Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Federal government websites often end in .gov or .mil. 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]. Furthermore, the level of glycolytic products of lactate in CSF was found to be decreased following IPC [75]. 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. 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]. Zhang et al. Krebs H.A., Williamson D.H., Bates M.W., Page M.A., Hawkins R.A. Consistent with IPC may effectively reprogram mitochondrial energy metabolism and benefit stroke. Collaterals are demonstrated to be strong predictors of both response to endovascular therapy and functional outcomes [11]. Importantly, in adult neurons, to meet the higher energy requirements, neurons sustain a high rate of oxidative metabolism compared to astrocytes, by which aerobic glycolysis results in the generation of pyruvate, not lactate. 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. Regulation of glycogen metabolism: Physiological, pharmacological and pathological aspects. Stroke is one of the leading causes of death and permanent disability worldwide. NAMPT as a Therapeutic Target against Stroke. Preservation of the IPC phenotype implicated a unifying endogenous mechanism, possibly involving energy and redox homeostasis maintenance. Awooda H.A. 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. Solved the ischemic penumbra can maintain metabolic demand | Chegg.com Through neuronal, humoral, and immunological pathways, IPC confers protection against subsequent, more severe, and lethal ischemia. https://creativecommons.org/licenses/by/4.0/, Cohort study of 5398 adults aged 35 years or older followed for 10 years. To maintain the cerebral activity transiently, upon ischemia onset, brain tissues enhance their metabolic plasticity, mainly through energy metabolic reprogramming and antioxidant defense. Bang O.Y., Saver J.L., Kim S.J., Kim G.M., Chung C.S., Ovbiagele B. Another critical concern is the proper time window for IPC metabolic reprogramming in sustaining the neuroprotection effects for the forthcoming ischemia stroke. In this work, we review how the concept of ischemic penumbra has been evolving from its purely electrophysiological/ hemodynamic based definition to the wider metabolic-cellular-therapeutic concept that is managed today by neuroscientists. Lactate: Brain fuel in human traumatic brain injury: A comparison with normal healthy control subjects. 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. An increasing number of studies have shown that epidemiologic changes are likely responsible for the observed rise of stroke incidence (Table 1). 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 . 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 primary definition of the ischemic penumbra is electrical. Effects of ischemic preconditioning on mitochondrial and metabolic neruoprotection: 5 adenosine monophosphate-activated protein kinase and sirtuins. Metabolic reprogramming during ischemic stroke is also reflected in the large changes of genes and proteins related to carbon and lipid metabolism. Organic Acids. ROS is not elevated and, so, this region sustains little damage [89]. Glycogen: The metabolism of glycogen is critical for the release of stored glucose. Glutamine importantly regulates this process by providing glutamate and promoting cystine uptake [82]. As a library, NLM provides access to scientific literature. Bahadoran A., Bezavada L., Smallwood H.S. In: Murphy S., editor. found that ketone treatment in mice at 30 min after ischemia enhanced mitochondrial function, reduced oxidative stress and, therefore, reduced infarct volume [49]. Excitingly, emerging evidence from recent research has indicated that metabolic reprogramming may be the crucial neuroprotective mechanism of IPC for ischemia treatment. 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. 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. To defend against oxidative stress, cells have developed complex systems that exploit and defend against this dilemma. Ischemic penumbra is intercalated between normoxic (proximal) and anoxic (distal) fields. Lactate: Previous research has suggested that astrocytes play a pivotal role in the induction of ischemic tolerance [83], during which lactate is extremely crucial. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Aconitase is the main functional target of aging in the citric acid cycle of kidney mitochondria from mice. 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]. 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. At a practical level, however, this definition is unwieldy. The research by Polyzos et al. It was first discovered by Murry et al., in the canine heart, in 1986 [7]. Malpartida A.B., Williamson M., Narendra D.P., Wade M.R., Ryan B.J. The primary aim of current acute stroke . 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. 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. One study showed that neurons made specific metabolic adaptations following IPC (transient OGD) with the regulation of oxygen utilization and lactate production [100]. It has been found that metabolic disorders are a determinant of the incidence and progression of stroke. In such tissue, blood flow is decreased below the metabolic demand, but energy metabolism is maintained at a level allowing morphologic preservation of tissue. Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. Current evidence-based . Collateral flow predicts response to endovascular therapy for acute ischemic stroke. MetS prevalence was 61.2% in stroke survivors. 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. Ischemic Neuroprotectant PKCepsilon Restores Mitochondrial Glutamate Oxaloacetate Transaminase in the Neuronal NADH Shuttle after Ischemic Injury. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. 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. Hatten M.E. 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]. 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 . A diagram showing metabolism in the ischemic, penumbra and distant This problem has been solved! 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. Writingoriginal draft preparation, editing, J.L. Ischemic penumbra in retina endures: vascular neuropathology is 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]. This refinement has potential therapeutic implications. Studies have revealed that inhibitors of ferroptosis, such as ferrostatins, carvacrol, and liproxstatins, could protect against cerebral ischemic injury in rodent models [43,48]. 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. Hausenloy D.J., Yellon D.M. Wender R., Brown A.M., Fern R., Swanson R.A., Farrell K., Ransom B.R. Ischemic stroke is the consequence of a sharp reduction of regional cerebral blood flow (CBF), resulting in oxygen and glucose deprivation (OGD). 1 and represented an important milestone for understanding the temporal and spatial evolution of focal ischemic brain injury. 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. Simmons E.C., Scholpa N.E., Schnellmann R.G. To date, IPC has been replicated in humans and other species, and applied to other organs and tissues (e.g., the brain and kidney). Iron is essential for the accumulation of lipid peroxides and execution of ferroptosis. IPC is neuroprotective for ischemic stroke, but the precise mechanisms through which it exerts protection against ischemic insults remain unclear at present. Frontiers | Clinical Imaging of the Penumbra in Ischemic Stroke: From 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. Elucidation of these endogenous defense mechanisms against ischemic injury is considered crucial for the development of novel stroke therapies. 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. In the absence of glutamine (or when glutaminolysis is inhibited), cystine starvation and ferroptosis occur. Rapid NAD+ depletion inevitably disrupts intracellular energy homeostasis. energy metabolism might be intermittently compromised within the ischemic penumbra. Licensee MDPI, Basel, Switzerland. Furthermore, there exist some serious contraindications and complications; for example, thrombolytic agents have been associated with symptomatic intracerebral hemorrhage [6]. Lekoubou A., Ovbiagele B., Markovic D., Sanossian N., Towfighi A. Show abstract. Most ketones are generated in the liver, while the transport of ketone bodies across the blood-brain barrier (BBB) is the limiting step. L-glutamine protects mouse brain from ischemic injury via up-regulating heat shock protein 70. 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. 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]. As mentioned before, astrocytes play an essential role in the re-flux of glucose into neurons for energy production and utilization. Wu Y., Zhang S., Gong X., Tam S., Xiao D., Liu S., Tao Y. Chapter 4 Cerebral blood flow and the ischemic penumbra - ResearchGate 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). Ischemic preconditioning triggers endogenous neuroprotection to defend against subsequent, more severe cerebral ischemia. 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]. Over the past few decades, considerable progress has been made in ischemic stroke treatment, typically in intravenous thrombolysis and mechanical thrombectomy. Consistently, a study showed that neurons benefited from the co-incubated astrocytes, enhancing lactate secretion induced by IPC in astrocytes. Thus, there is an urgent need to develop new treatment strategies for ischemic stroke. Jackson C.W., Escobar I., Xu J., Perez-Pinzon M.A. Acute hyperglycemia adversely affects stroke outcome: A magnetic resonance imaging and spectroscopy study. (2) Excitotoxicity. The ischemic core . 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. 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. Amarenco P., Kim J.S., Labreuche J., Charles H., Abtan J., Bejot Y., Cabrejo L., Cha J.K., Ducrocq G., Giroud M., et al. 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 Metabolomic Profiling Reveals That Reprogramming of Cerebral Glucose Metabolism is Involved in Ischemic Preconditioning Induced Neuroprotection in a Rodent Model of Ischemic Stroke. Simultaneously, the anaplerotic pathway is promoted to refill the macromolecular biosynthesis for rapid proliferation in some cells. Furthermore, metabolic reprogramming is a double-edged sword; for example, the enhancement of glucose uptake and glycolysis can provide ATP faster, but the ongoing delivery of large amounts of glucose to the ischemic tissue along with an anaerobic glycolysis shift can adversely promote lactic acidosis, thus leading to tissue necrosis. 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]. The cerebral collateral circulationknown as the subsidiary network of vascular channelscan stabilize the CBF when principal conduits fail. When the CBF is below 10 mL/100 g per minute, irreversible cellular injury will occur, and the infarct core forms [10]. Ferroptosis. The .gov means its official. It has been demonstrated that mitochondria are a major target in ischemic injury. 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].
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