The ischemic penumbra is defined as functionally impaired yet still viable tissue surrounding the ischemic core. Iron is essential for the accumulation of lipid peroxides and execution of ferroptosis. 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. 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). The metabolic syndrome. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Ischaemic conditioning and reperfusion injury. Licensee MDPI, Basel, Switzerland. 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. The ischemic protection of IPC has been applied in various organs, such as the heart, brain, kidney, liver, lungs, and intestine. 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. The site is secure. 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. This pathway can produce precursors to synthesize nucleotides and aromatic amino acids, generating cytosolic NADPH simultaneously [30]. 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. National Library of Medicine energy metabolism might be intermittently compromised within the ischemic penumbra. Second, polyunsaturated fatty acids are susceptible to lipid peroxidation and are necessary for ferroptosis [45]. Cellular metabolism is a flexible network to meet homeostasis demands in real-time. 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. To date, IPC has been replicated in humans and other species, and applied to other organs and tissues (e.g., the brain and kidney). These studies have indicated the time-specificity of IPC; however, the dynamic change of metabolic reprogramming induced by IPC is still unclear. 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. Ischemic preconditioning treatment of astrocytes transfers ischemic tolerance to neurons. Hatten M.E. Metabolic reprogramming during ischemic stroke is also reflected in the large changes of genes and proteins related to carbon and lipid metabolism. As a library, NLM provides access to scientific literature. To the best of our knowledge, no study has assessed whether IPC affects the oxygen delivery ability of erythrocytes. Mech. The astrocytic glycolysis is also stimulated by neuronal activation, giving neurons the capacity of tight control over astrocyte metabolism. 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 . Glutamate can be converted back to -ketoglutarate by oxidative deamination in astrocytes, to undergo further oxidation in the TCA cycle for the purpose of energy generation [24]. 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. Acute hyperglycemia adversely affects stroke outcome: A magnetic resonance imaging and spectroscopy study. 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. (1)H NMR metabolic signature of cerebrospinal fluid following repetitive lower-limb remote ischemia preconditioning. Thus, there is an urgent need to develop new treatment strategies for ischemic stroke. Altogether, these results imply that subduing postischemic hyperglycolysis and the regulation of brain glucose metabolism play important roles in the neuroprotective aspect of IPC. Changes in the cerebral NAD+ pool under ischemia have been studied in detail. 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. Direct intracerebroventricular or intravenous administration of lactate protected mouse brains against ischemic injury [22]. Wu Y., Zhang S., Gong X., Tam S., Xiao D., Liu S., Tao Y. Other metabolic-related genes in the pathogenesis of ischemic stroke include MTHFR, CBS, and MTR, which are involved in homocysteine metabolism, and apo E, LPL, CETP, ABCA1, apo AI, apo CIII, apo AIV, apo AV, apo B, apo H, apo(a), PON1/2/3, and LDLR/LOX-1, which are involved in lipid metabolism [36]. Ketone: Notably, the brain and plasma -hydroxybutyrate (-HB) levels both increase under IPC stimulation, indicating that the brain can increase ketone body oxidation to replenish its energy supply. Furthermore, acute-on-chronic liver failure (ACLF) induces hyperammonemia and hypoxia in hepatocytes. Studies have shown that IPC upregulates NAMPT protein, and the protective effect of IPC against ischemia (30 min) and reperfusion (24 h) was attenuated in NAMPT knockdown mice, suggesting that NAMPT is essential in mediating the protective effect of IPC [80]. In the mammalian brain, neurons are outnumbered 10:1 by astrocytes in most regions. Upregulation of pentose phosphate pathway and preservation oftricarboxylic acid cycle flux after experimental brain injury. The concept of the ischemic penumbra was initially proposed by Astrup et al. and increases energy demand and neurotransmitter effluxes, 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. Zhang T., Wang W., Huang J., Liu X., Zhang H., Zhang N. Metabolomic investigation of regional brain tissue dysfunctions induced by global cerebral ischemia. However, the underlying neuroprotective mechanisms of IPC remain elusive. Zong W.X., Rabinowitz J.D., White E. Mitochondria and Cancer. Intravenous thrombolysis and mechanical thrombectomy for selected . Timely interventions are effective for avoiding the progression of the penumbra into infarction. Iron-Deficiency and Estrogen Are Associated with Ischemic Stroke by Up-Regulating Transferrin to Induce Hypercoagulability. Dixon S.J., Lemberg K.M., Lamprecht M.R., Skouta R., Zaitsev E.M. Gleason Ferroptosis: An iron-dependent form of nonapoptotic cell death. IPC is neuroprotective for ischemic stroke, but the precise mechanisms through which it exerts protection against ischemic insults remain unclear at present. Furthermore, the level of glycolytic products of lactate in CSF was found to be decreased following IPC [75]. Hirayama Y., Koizumi S. Astrocytes and ischemic tolerance. At a practical level, however, this definition is unwieldy. McIntosh V.J., Lasley R.D. 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]. Durukan A., Tatlisumak T. Preconditioning-induced ischemic tolerance: A window into endogenous gearing for cerebroprotection. Studies have revealed that inhibitors of ferroptosis, such as ferrostatins, carvacrol, and liproxstatins, could protect against cerebral ischemic injury in rodent models [43,48]. To defend against this, the brain shifts the cellular machinery from aerobic to anaerobic metabolism. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Wender R., Brown A.M., Fern R., Swanson R.A., Farrell K., Ransom B.R. Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Early reperfusion aims to save the ischemic penumbra by preventing infarct core expansion and is the mainstay of acute ischemic stroke therapy. Note incursions of preferentially-oxygenated peri-arterial cells across planar hypoxic (ht) and anoxic (at) pO 2 thresholds. Ischemic stroke is typically caused by blood vessel blockage, which accounts for approximately 87% of all stroke cases. However, the underlying neuroprotective mechanisms of IPC remain elusive. NADP+ is an essential cofactor for the rate-limiting step of the pentosephosphate pathway (PPP). Mitophagy is also essential in sustaining mitochondrial homeostasis, biogenesis, and the total number and quality of mitochondria. Stroke is a leading cause of death and permanent disability, imposing heavy social and family burdens [1,2]. 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. Noteworthy, at the early ischemia-reperfusion (I/R) phase, the impaired mitochondrial function was attenuated by IPC and mediated by adenosine A1 receptors [91,92]. NAMPT levels were enhanced by protein kinase C (PKC) in an AMPK-dependent manner, which was required for increased mitochondrial NAMPT after IPC [77]. Consistent with this data, strategies aimed at increasing astrocyte glycogen have been successfully applied for mitigating neuronal loss [20]. 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). Several studies also showed that transient ischemic attack (TIA) may produce IPC effect in people who have a subsequent stroke [101,102]. Transient ischemic attack before nonlacunar ischemic stroke in the elderly. Mitochondria-derived reactive oxygen species dilate cerebral arteries by activating Ca. 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. Once ischemic stroke occurs, the PPP is boosted and more glycolytic intermediates are diverted into the PPP to sustain NADPH production [18]. Simmons E.C., Scholpa N.E., Schnellmann R.G. 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]. Yang W.S., Kim K.J., Gaschler M.M., Patel M., Shchepinov M.S., Stockwell B.R. Metabolic reprogramming for metabolic homeostasis maintenance. Simultaneously, the anaplerotic pathway is promoted to refill the macromolecular biosynthesis for rapid proliferation in some cells. This problem has been solved! the contents by NLM or the National Institutes of Health. Liu P.S., Wang H., Li X., Chao T., Teav T., Christen S., Di Conza G., Cheng W.C., Chou C.H., Vavakova M., et al. Hence, the abundance and localization of polyunsaturated fatty acids are crucial for the degree of lipid peroxidation that occurs in cells. Elucidation of these endogenous defense mechanisms against ischemic injury is considered crucial for the development of novel stroke therapies. General description of ischemic preconditioning (IPC), in which several cycles of brief non-lethal ischemia and reperfusion are applied either directly, regionally, or remotely. The brain is an unusual organ, having the highest metabolic activity and energy requirement by mass. 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. 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. 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. 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. The role of ketone bodies in caloric homeostasis. These data are consistent with the original concepts of the penumbra and core, but recognize the dynamic complex heterogeneous processes involved. Therefore, how to accurately and effectively utilize the metabolic reprogramming strategy is crucial, with which we anticipate its broad application in the prevention and treatment of ischemic stroke. Research has found that L-glutamine reduced brain infarct volume and promoted neurobehavioral recovery in cerebral ischemic mice [25]. Upon the onset of ischemia, the level of AMP dramatically decreases in the cortex and hippocampus tissues, indicating energy failure in these tissues [16]. Banks M.A., Porter D.W., Martin W.G., Castranova V. Ozone-induced lipid-peroxidation and membrane leakage in isolated rat alveolar macrophages- protective effects of taurine. 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]. Before It will be a further explanation that the pathophysiological mechanisms in ischemic stroke are closely related to metabolic disorder. Mitochondrial Dysfunction and Mitophagy in Parkinsons Disease: From Mechanism to Therapy. 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]. 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. In acute patients, PET documented areas of decreased 11 C-flumazenil uptake went on to show infarctions, while areas of relative . The ischemic core . Sphingosine 1-phosphate is an important endogenous cardioprotectant released by ischemic pre- and postconditioning. 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. Ischemic preconditioning triggers endogenous neuroprotection to defend against subsequent, more severe cerebral ischemia. Then, the accumulated free radicals damage cell membranes, mitochondria, and DNA, thus triggering caspase-mediated cell death. An untargeted metabolomics study has revealed that -hydroxybutyrate (-HB) stands out as highly significantly upregulated after IPC [78], while previous studies have shown that an elevation in the cytosolic NADH/NAD+ ratio would promote -HB formation. Another critical concern is the proper time window for IPC metabolic reprogramming in sustaining the neuroprotection effects for the forthcoming ischemia stroke. Received 2021 Apr 13; Accepted 2021 May 6. 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. Katsyuba E., Romani M., Hofer D., Auwerx J. NAD. 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. The ischemic penumbra (defined as local cerebral blood flow (LCBF) of 20-40% of control) forms an irregular rim around the ischemic core and tends to be greatest in frontal and occipital cortex . Detailed metabolomics data verification with higher time and tissue-specific resolution will be needed in the future.
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