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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. Metabolic reprogramming by ischemic preconditioning (IPC). Protecting the ischaemic penumbra as an adjunct to - Nature alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Identifying and utilizing the ischemic penumbra | Neurology 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]. In the mammalian brain, neurons are outnumbered 10:1 by astrocytes in most regions. Writingoriginal draft preparation, editing, J.L. 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. Mitochondria lie at the key location for neuronal survival [51]. Clinical Imaging of the Penumbra in Ischemic Stroke: From the - PubMed 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. Article. Katayama H., Hama H., Nagasawa K., Kurokawa H., Sugiyama M., Ando R., Funata M., Yoshida N., Homma M., Nishimura T., et al. 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. All authors have read and agreed to the published version of the manuscript. 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. Consistent with this data, strategies aimed at increasing astrocyte glycogen have been successfully applied for mitigating neuronal loss [20]. 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]. https://creativecommons.org/licenses/by/4.0/, Cohort study of 5398 adults aged 35 years or older followed for 10 years. The complex underlying mechanisms responsible for the neuroprotection against IPC remain elusive. Hirayama Y., Ikeda M.Y., Notomi S., Enaida H., Kinouchi H., Koizumi S. Astrocyte-mediated ischemic tolerance. Mechanisms underlying neuronal death in ischemic stroke (1) Mitochondrial response, including excessive ROS production, mitochondrial calcium overloading, and disrupted mitochondria quality control. 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. Metabolic syndrome (MetS) increases stroke incidence. Patients underwent computer tomography . 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]. It has been demonstrated that mitochondria are a major target in ischemic injury. ROS is not elevated and, so, this region sustains little damage [89]. 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]. In subsequent hours after IPC, the brain regresses to its nave state. (1)H NMR metabolic signature of cerebrospinal fluid following repetitive lower-limb remote ischemia preconditioning. 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. Excessive glutamate release and impeded reuptake of excitatory amino acids result in the activation of NMDARs, AMPARs and KARs. Yamamoto T., Byun J., Zhai P., Ikeda Y., Oka S., Sadoshima J. Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion. 2011;42 . Mitochondria are major contributors to cellular ROS, and there are multiple antioxidant pathways to neutralize ROS, including superoxide dismutase (SOD2), glutathione, thioredoxin, and peroxiredoxins. Accessibility (2) Excitotoxicity. Meanwhile, the cerebellum is replete with amino acids, which are precursors for glucose regeneration through the pentosephosphate shunt or gluconeogenesis pathways. Increased pools of NAMPT and NAD+ are protective against oxygenglucose deprivation, as well as playing a crucial role in cell energy maintenance. 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. 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. Hou W., Xie Y., Song X., Sun X., Lotze M.T., Zeh H.J., Tang D. Autophagy promotes ferroptosis by degradation of ferritin. These studies have indicated the time-specificity of IPC; however, the dynamic change of metabolic reprogramming induced by IPC is still unclear. Mortality, morbidity, and risk factors in China and its provinces, 19902017: A systematic analysis for the Global Burden of Disease Study 2017. Then, the accumulated free radicals damage cell membranes, mitochondria, and DNA, thus triggering caspase-mediated cell death. Sarrafzadegan N., Gharipour M., Sadeghi M., Nezafati P., Talaie M., Oveisgharan S., Nouri F., Khosravi A. Metabolic Syndrome and the Risk of Ischemic Stroke. 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]. Stockwell B.R., Friedmann Angeli J.P., Bayir H., Bush A.I., Conrad M., Dixon S.J., Fulda S., Gascon S., Hatzios S.K., Kagan V.E., et al. Mitochondria are signaling, bioenergetic, and biosynthetic organelles. 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. Brain, tumor, and proliferative tissues have high metabolic activity and energy requirements, necessitating that they have reliable mechanisms to adequately protect their metabolic homeostasis. Notably, neurons and astrocytes preferentially use quite different metabolic pathways in physiological conditions [98]. revealed that RKIP overexpression markedly reduced the necrotic area after ischemic stroke, mainly reflected in the metabolism of energy, amino acids, and lipids [38]. 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. 40.2% ischemic stroke individuals were diagnosed with MetS. Tang X., Fang M., Cheng R., Zhang Z., Wang Y., Shen C., Han Y., Lu Q., Du Y., Liu Y., et al. Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases. Metabolic reprogramming during ischemic stroke is also reflected in the large changes of genes and proteins related to carbon and lipid metabolism. See Answer Ischemic penumbra in retina endures: vascular neuropathology is 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. 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. Jackson C.W., Escobar I., Xu J., Perez-Pinzon M.A. As the brain NADPH level decreases during ischemia, boosting the PPP activity may serve as a potential neuroprotective strategy for the regulation of the cellular redox environment [81]. Metabolic syndrome (MetS) is a common metabolic disorder, involving a constellation of insulin resistance, abdominal obesity, hypertension, and dyslipidemia. It has been found that direct administration of NADPH can significantly reduce infarct volume, improving post-stroke survival and neurological function recovery in mouse and rat stroke models, with a remarkable increase in the level of the reduced form of glutathione (GSH), while decreasing ROS levels [41]. As the main product of the oxidative PPP (oxPPP), NADPH provides the essential redox equivalent for GSH regeneration, enhancing the antioxidant defense capacity. It is well-known that lysine, being an energy-providing amino acid, is necessary for the biosynthesis of L-carnitine. Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immune metabolism. Marchiq I., Pouyssgur J. Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H+ symporters. However, due to the structural complexity and their specific physiological functions and metabolic patterns, the conclusive details on whether the dynamic metabolic reprogramming behavior accompanied with astrocyte-neuron interaction is induced by ischemia or IPC are still lacking. GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling. and transmitted securely. 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. TCA cycle reactions yield metabolite intermediates and energetic precursors for oxidative phosphorylation. We can see that antioxidant defense plays an important role in the redox control, which may promote new therapeutic strategies for ischemic stroke in the future. 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. 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. 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]. 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]. Bahadoran A., Bezavada L., Smallwood H.S. The metaphor of the ischemic penumbra was coined to describe this intermediate zone of ischemia between functionally normal and dead brain tissue. Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia. 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. de Jonge R., de Jong J.W. Solved the ischemic penumbra can maintain metabolic demand | Chegg.com 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). 1 and represented an important milestone for understanding the temporal and spatial evolution of focal ischemic brain injury. 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) The brain is an unusual organ, having the highest metabolic activity and energy requirement by mass. 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]. 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. Remarkably, specific neurotransmitters and neuromodulators could dictate astrocytes glycogenolysis. Meanwhile, IPC also boosts the PPP, providing an essential redox equivalent for GSH regeneration and enhancing the capacity of antioxidant defense. Such emerging evidence of the metabolic reprogramming involved in metabolic homeostasis on the progression of different diseases has revealed that metabolic reprogramming is an important stress-protective mechanism, which plays a key role in many biological activities. 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. The ischemic penumbra can maintain metabolic demand with marginal blood flow from collateral circulation for a maximum of _____ before increasing in size. official website and that any information you provide is encrypted Preserving pools of NAD+ confers neuroprotection after ischemic stress. Mitochondrial Dysfunction and Mitophagy in Parkinsons Disease: From Mechanism to Therapy. Upon ischemic stroke, cerebral glycolysis exhibits an increasing trend. However, continuing ischemic stress, or additional energy demanding episodes, or both, will exhaust this limited capacity and transform penumbra into necrotic tissue. Lactate: Previous research has suggested that astrocytes play a pivotal role in the induction of ischemic tolerance [83], during which lactate is extremely crucial. Malpartida A.B., Williamson M., Narendra D.P., Wade M.R., Ryan B.J. Meanwhile, exogenous supplementation of lactate has shown remarkable effects in traumatic brain injury therapy [23]. Cellular metabolism is a flexible network to meet homeostasis demands in real-time. Visualizing and Modulating Mitophagy for Therapeutic Studies of Neurodegeneration. However, research on metabolic reprogramming in the neuroscience field is still in its infancy. 8600 Rockville Pike It is usually located around an infarct core which represents the tissue which has already infarcted or is going to infarct regardless of reperfusion. 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. Previous research has revealed that S1P is an important endogenous protectant against ischemia, where the increased release of S1P from myocytes in response to IPC has been observed [86]. 2,3-BPG is an erythrocyte-specific glycolytic intermediate that facilitates O2 release [71]; concurrently, hypoxia promotes renal damage and progression of chronic kidney disease (CKD). NADP+ and its reduced counterpart, NADPH, are mainly required for anabolic reactions and cellular oxidative-stress defense. 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]. Targeting the Ischemic Penumbra | Stroke Note incursions of preferentially-oxygenated peri-arterial cells across planar hypoxic (ht) and anoxic (at) pO 2 thresholds. Regulation of glycogen metabolism: Physiological, pharmacological and pathological aspects. Exogenous application of nicotinamide mononucleotide (NMN), an intermediate of NAD+ synthesis, mimics the protective effect of IPC under ischemia and reperfusion injury. The malateaspartate shuttle (MAS) is considered the most important NAD+/NADH shuttle in neurons, playing a prominent role in neuronal mitochondrial respiration. 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. 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. 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]. In-depth research considering these open questions will be valuable for exploring the mechanisms of IPC. Since astrocytes play an integral role in inducing ischemic tolerance [97], the traditional view of astrocytes as passive supporters of neurons is revised, and the survival of neurons tightly associated with astrocytes is recognized. Recent research has shown that metabolic disorders have significant effects, both before and after the onset of ischemic stroke. First, the availability of cysteine is the limiting link in GSH biosynthesis. 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. ; funding acquisition and editing, R.H.; funding acquisition, review and editing, B.Z. Efficacy of remote ischemic conditioning on improving WMHs and cognition in very elderly patients with intracranial atherosclerotic stenosis. Bartnik B.L., Sutton R.L., Fukushima M., Harris N.G., Hovda D.A., Lee S.M. Mitochondria-derived reactive oxygen species dilate cerebral arteries by activating Ca. Eventually, exogenous lactate administration can significantly increase cell survival in neuronal cultures against lethal oxygen glucose deprivation (OGD) [84]. Several studies also showed that transient ischemic attack (TIA) may produce IPC effect in people who have a subsequent stroke [101,102]. Lemasters J. 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. Careers, Unable to load your collection due to an error. Intriguing, the protective effect of IPC can be mimicked pharmacologically. An increased understanding of the pathogenic mechanisms of stroke and IPC serves to highlight the importance of metabolic reprogramming. 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]. Chen W.L., Jin X., Wang M., Liu D., Luo Q., Tian H., Cai L., Meng L., Bi R., Wang L., et al. found that ketone treatment in mice at 30 min after ischemia enhanced mitochondrial function, reduced oxidative stress and, therefore, reduced infarct volume [49]. 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. IPC is an endogenous metabolic protective strategy, whereby several cycles of brief, non-lethal ischemia, followed by reperfusion, confer protection against subsequent, more severe, and lethal ischemia. CEREBROVASC DIS. Detailed metabolomics data verification with higher time and tissue-specific resolution will be needed in the future. The metabolic syndrome. 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. 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). 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. Excitingly, emerging evidence from recent research has indicated that metabolic reprogramming may be the crucial neuroprotective mechanism of IPC for ischemia treatment. Busija D.W., Rutkai I., Dutta S., Katakam P.V. Glycogen: The metabolism of glycogen is critical for the release of stored glucose. 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). It was first discovered by Murry et al., in the canine heart, in 1986 [7]. In the brain, astrocytes can also generate ketone bodies from fatty acid -oxidation.