Geng J.L., Aa J.Y., Feng S.Q., Wang S.Y., Wang P., Zhang Y., Ouyang B.C. Thus, the pretreatment of cells with taurine could reduce oxidative stress [50]. 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. View. 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. NADP+ and its reduced counterpart, NADPH, are mainly required for anabolic reactions and cellular oxidative-stress defense. CEREBROVASC DIS. Tang X., Fang M., Cheng R., Zhang Z., Wang Y., Shen C., Han Y., Lu Q., Du Y., Liu Y., et al. 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. The translation of experimental . 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. In addition, age-related alterations in TCA cycle enzyme activities will likely contribute to the decline of mitochondrial bioenergetics [96]. Metabolic syndrome (MetS) is a common metabolic disorder, involving a constellation of insulin resistance, abdominal obesity, hypertension, and dyslipidemia. Trial of 2860 patients and followed them for 3.5 years. 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]. Chen W.L., Jin X., Wang M., Liu D., Luo Q., Tian H., Cai L., Meng L., Bi R., Wang L., et al. 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. In such tissue, blood flow is decreased below the metabolic demand, but energy metabolism is maintained at a level allowing morphologic preservation of tissue. 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]. 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]. ological, molecular, metabolic and perfusional disturbances. 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. 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. Yu Z., Li J., Ren Z., Sun R., Zhou Y., Zhang Q., Wang Q., Cui G., Li J., Li A., et al. 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. 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. 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. Nevertheless, metabolic reprogramming is a relatively new area for understanding the mechanisms of IPC, to the best of our knowledge, no relevant review has yet been published. Then, the accumulated free radicals damage cell membranes, mitochondria, and DNA, thus triggering caspase-mediated cell death. Lemasters J. 6-8 hours A patient presents to the emergency department with left leg weakness and numbness. The brain is an unusual organ, having the highest metabolic activity and energy requirement by mass. This pathway can produce precursors to synthesize nucleotides and aromatic amino acids, generating cytosolic NADPH simultaneously [30]. 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. Excessive glutamate release and impeded reuptake of excitatory amino acids result in the activation of NMDARs, AMPARs and KARs. 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 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. The malateaspartate shuttle (MAS) is considered the most important NAD+/NADH shuttle in neurons, playing a prominent role in neuronal mitochondrial respiration. Furthermore, IPC treatment also remarkably improves the metabolic disturbances in the TCA cycle during ischemia. It should be noted that metabolic reprogramming is a double-edged sword: the overactivation of metabolic reprogramming under ischemia may lead to secondary brain damage (Figure 2). Arrell D.K., Elliott S.T., Kane L.A., Guo Y., Ko Y.H., Pedersen P.L. Reduced Nicotinamide Adenine Dinucleotide Phosphate, a Pentose Phosphate Pathway Product, Might Be a Novel Drug Candidate for Ischemic Stroke. Concept of ischemic penumbra the extent of brain damage during a stroke depends on the severity and duration of the cerebral blood flow (CBF) disorder there are two major zones of injury within the ischemic area: core penumbra as blood flow decreases, there is an initial loss of function with structural integrity intact ( functional threshold) It was shown that free and protein-bound NADH differs regarding lifetime. Timely interventions are effective for avoiding the progression of the penumbra into infarction. 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. Metabolic reprogramming during ischemic stroke is also reflected in the large changes of genes and proteins related to carbon and lipid metabolism. 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. The Conditions Under Which Piracetam Is Used and the Factors That Can Improve National Institute of Health Stroke Scale Score in Ischemic Stroke Patients and the Importance of Previously Unnoticed Factors from a Hospital-Based Observational Study in Taiwan. Malpartida A.B., Williamson M., Narendra D.P., Wade M.R., Ryan B.J. 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. 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. 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. In the brain, astrocytes can also generate ketone bodies from fatty acid -oxidation. 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). 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. It has been found that metabolic disorder is a determinant of the incidence and progression of stroke. Up-regulation of the PPP is frequently observed in tumors, in order to increase the production of NADPH and ribulose-5-phosphate, promote glutathione production, and increase nucleic acid and fatty acid synthesis, helping cells to counteract oxidative stress and facilitate DNA damage repairs. Neuronal regulation of astroglial morphology and proliferation in vitro. 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. 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. It has been noted that a minimal CBF of 18 mL/100 g per minute is needed to maintain normal electroencephalographic (EEG) activity. Ischemic stroke is typically caused by blood vessel blockage, which accounts for approximately 87% of all stroke cases. Mitochondria are signaling, bioenergetic, and biosynthetic organelles. In: Murphy S., editor. Awooda H.A. The astrocytic glycolysis is also stimulated by neuronal activation, giving neurons the capacity of tight control over astrocyte metabolism. Erythrocytes are the only cell type responsible for delivering oxygen. It has been found that metabolic disorders are a determinant of the incidence and progression of stroke. Dirnagl U., Endres M. Found in translation preclinical stroke research predicts human pathophysiology clinical phenotypes, and therapeutic outcomes. Ischemic preconditioning triggers endogenous neuroprotection to defend against subsequent, more severe cerebral ischemia. The Ischemic Penumbra and the Ischemic Core Increasing understanding of the related pathogenic mechanisms serves to highlight the importance of metabolic regulation. quences as drastically increase d metabolic demand cannot be satisfied in regions with critically reduced blood supply. Hess D.C., Blauenfeldt R.A., Andersen G., Hougaard K.D., Hoda M.N., Ding Y., Ji X. 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]. 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]. Geng J.L., Zhang Y., Li S.J., Li S.N., Wang J.K., Wang H., Aa J.Y., Wang G.J. Article. 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]. Remote ischaemic conditioningA new paradigm of self-protection in the brain. The accumulation of glucose and glycolytic intermediates is a prominent feature of brain ischemia-induced metabolic disturbance in rodents. The biochemical control of ferroptosis includes amino acid metabolism, glutathione metabolism, lipid metabolism, iron metabolism, and other metabolic pathways [43]. 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]. Meanwhile, exogenous supplementation of lactate has shown remarkable effects in traumatic brain injury therapy [23]. Simultaneously, the anaplerotic pathway is promoted to refill the macromolecular biosynthesis for rapid proliferation in some cells. Consistent with IPC may effectively reprogram mitochondrial energy metabolism and benefit stroke. de Jonge R., de Jong J.W. 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. In the absence of glutamine (or when glutaminolysis is inhibited), cystine starvation and ferroptosis occur. Bang O.Y., Saver J.L., Kim S.J., Kim G.M., Chung C.S., Ovbiagele B. Ischemic preconditioning treatment of astrocytes transfers ischemic tolerance to neurons. Wang S., Xing Z., Vosler P.S., Yin H., Li W., Zhang F., Signore A.P., Stetler R.A., Gao Y., Chen J. Mechanisms underlying neuronal death in ischemic stroke (1) Mitochondrial response, including excessive ROS production, mitochondrial calcium overloading, and disrupted mitochondria quality control. the ischemic penumbra can maintain metabolic demand with marginal blood flow from collateral circulation for a maximum of __ before increasing in size? Stroke is a leading cause of death and permanent disability, imposing heavy social and family burdens [1,2]. 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. 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. Murry C.E., Jennings R.B., Reimer K.A. Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone. 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. 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. 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. There is also a beneficial role of erythrocyte S1P in hypertensive CKD, where S1P also induces 2,3-BPG production and oxygen delivery [72]. Most ketones are generated in the liver, while the transport of ketone bodies across the blood-brain barrier (BBB) is the limiting step. 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. Direct intracerebroventricular or intravenous administration of lactate protected mouse brains against ischemic injury [22]. Exploring the neuroprotective effects of ginkgolides injection in a rodent model of cerebral ischemia-reperfusion injury by GC-MS based metabolomic profiling. This research was funded by National Natural Science Foundation of China [No.81971198]; Beijing Municipal Natural Science Foundation [No.7192103]; Chinese Ministry of science and Technology [No.2019YFA0508603]; and the China Postdoctoral Science Foundation (2020M670103). An increasing number of studies have shown that epidemiologic changes are likely responsible for the observed rise of stroke incidence (Table 1). It is common that tumor cells reside in nutrient- and oxygen-poor environments, such that they adapt, through multiple metabolic reprogramming, to meet the energy, macromolecular biosynthesis, and redox needs required for rapid proliferation [63]. Metabolic reprogramming is notably crucial in this regard, especially for energy and redox homeostasis maintenance. ROS is not elevated and, so, this region sustains little damage [89]. Cells adapt to environmental changes through metabolic remodeling, in order to maintain cellular homeostasis, which is an important stress-protective mechanism that plays a key role in many biological activities (see Figure 3). 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). 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]. However, the underlying neuroprotection mechanisms of IPC remain elusive. 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. Bethesda, MD 20894, Web Policies Ham P.B., Raju R. Mitochondrial function in hypoxic ischemic injury and influence of aging. Finally, the NAD+ pool declines by approximately 3550%. Busija D.W., Rutkai I., Dutta S., Katakam P.V. 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]. 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. 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]. Betti et al. 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. Together, effective IPC metabolic reprogramming may happen and be assumed to sustain during the early and late phases of IPC. Ischemic penumbra is intercalated between normoxic (proximal) and anoxic (distal) fields. Mitophagy is also essential in sustaining mitochondrial homeostasis, biogenesis, and the total number and quality of mitochondria. Mitochondria-derived reactive oxygen species dilate cerebral arteries by activating Ca. Lactate: Previous research has suggested that astrocytes play a pivotal role in the induction of ischemic tolerance [83], during which lactate is extremely crucial. General description of ischemic preconditioning (IPC), in which several cycles of brief non-lethal ischemia and reperfusion are applied either directly, regionally, or remotely. Rothman D.L., Behar K.L., Hyder F. In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: Implications for brain function. As the main product of the oxidative PPP (oxPPP), NADPH provides the essential redox equivalent for GSH regeneration, enhancing the antioxidant defense capacity. Furthermore, there exist some serious contraindications and complications; for example, thrombolytic agents have been associated with symptomatic intracerebral hemorrhage [6]. Metabolic reprogramming for metabolic homeostasis maintenance. Bahadoran A., Bezavada L., Smallwood H.S. Zong W.X., Rabinowitz J.D., White E. Mitochondria and Cancer.
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