For ischemic rats, 24 h after IPC treatment, the AMPK levels and glucose levels decreased and ATP increased in the penumbra, indicating that glucose catabolism is upregulated by IPC [18]. Does the Mismatch Match the Penumbra? | Stroke Geng J.L., Zhang Y., Li S.J., Li S.N., Wang J.K., Wang H., Aa J.Y., Wang G.J. Erythrocytes are the only cell type responsible for delivering oxygen. Efficacy of remote ischemic conditioning on improving WMHs and cognition in very elderly patients with intracranial atherosclerotic stenosis. 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]. official website and that any information you provide is encrypted Meanwhile, exogenous supplementation of lactate has shown remarkable effects in traumatic brain injury therapy [23]. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. L-glutamine protects mouse brain from ischemic injury via up-regulating heat shock protein 70. The ischemic penumbra: correlates in imaging and implications for Notably, neurons and astrocytes preferentially use quite different metabolic pathways in physiological conditions [98]. Sun K., Zhang Y., DAlessandro A., Nemkov T., Song A., Wu H., Liu H., Adebiyi M., Huang A., Wen Y.E., et al. In: Murphy S., editor. electrophysiological/ hemodynamic based definition to the wider metabolic-cellular-therapeutic concept that is managed today by neuroscientists. Parsons M.W., Barber P.A., Desmond P.M., Baird T.A., Darby D.G., Byrnes G., Tress B.M., Davis S.M. Glutamine importantly regulates this process by providing glutamate and promoting cystine uptake [82]. In 2020, Per E. Andrn et al. It is well-known that lysine, being an energy-providing amino acid, is necessary for the biosynthesis of L-carnitine. Mitochondria lie at the key location for neuronal survival [51]. Meanwhile, glucose-6-phosphate dehydrogenase (G6PD) activity was notably increased by IPC in both normal and ischemic brains, which is the key rate-limiting enzyme responsible for regulating the flux of glucose into the PPP. Adenosine receptor-mediated cardioprotection: Are all 4 subtypes required or redundant? Stroke Education Flashcards | Quizlet Reduced Nicotinamide Adenine Dinucleotide Phosphate, a Pentose Phosphate Pathway Product, Might Be a Novel Drug Candidate for Ischemic Stroke. Wang S., Xing Z., Vosler P.S., Yin H., Li W., Zhang F., Signore A.P., Stetler R.A., Gao Y., Chen J. Several studies also showed that transient ischemic attack (TIA) may produce IPC effect in people who have a subsequent stroke [101,102]. Bouzat P., Sala N., Suys T., Zerlauth J.B. Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain. 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. Ischemic preconditioning treatment of astrocytes transfers ischemic tolerance to neurons. Tang X., Fang M., Cheng R., Zhang Z., Wang Y., Shen C., Han Y., Lu Q., Du Y., Liu Y., et al. Raf kinase inhibitory protein (RKIP) is involved in the protective effect against stroke: Li et al. 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. 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 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 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. Sphingosine 1-phosphate is an important endogenous cardioprotectant released by ischemic pre- and postconditioning. The regulation of NAD+ by IPC is related to NAMPT (nicotinamide phosphoribosyl transferase). Effects of ischemic preconditioning on mitochondrial and metabolic neruoprotection: 5 adenosine monophosphate-activated protein kinase and sirtuins. Intravenous thrombolysis and mechanical thrombectomy for selected . The astrocytic glycolysis is also stimulated by neuronal activation, giving neurons the capacity of tight control over astrocyte metabolism. Received 2021 Apr 13; Accepted 2021 May 6. 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]. Mech. 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. Further study focus on ischemic preconditioning metabolic reprogramming is needed, and it will be valuable for exploring the mechanisms of ischemic preconditioning, and will be greatly beneficial for the understanding of ischemic stroke treatment and standardized application of ischemic preconditioning. 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. ischemic injury develops heterogeneously, and with time coalesces dynamically into a homogenous core. Meng R., Asmaro K., Meng L., Liu Y., Ma C., Xi C., Li G., Ren C., Luo Y., Ling F., et al. The ischemic penumbra: operationally . Introduction We aimed to assess metabolite profiles in peri-infarct tissue with magnetic resonance spectroscopy (MRS) and correlate these with early and late clinical recovery. Thus, there is an urgent need to develop new treatment strategies for ischemic stroke. Hausenloy D.J., Yellon D.M. Solved the ischemic penumbra can maintain metabolic demand | Chegg.com 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]. Consistent with this data, strategies aimed at increasing astrocyte glycogen have been successfully applied for mitigating neuronal loss [20]. 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]. Yin J., Han P., Tang Z., Liu Q., Shi J. Sirtuin 3 mediates neuroprotection of ketones against ischemic stroke. One study showed that neurons made specific metabolic adaptations following IPC (transient OGD) with the regulation of oxygen utilization and lactate production [100]. The clearance of damaged mitochondria through mitophagy is critical for cellular fitness, as dysfunctional mitochondria can impair ETC function and increase oxidative stress. You'll get a detailed solution from a subject matter expert that helps you learn core concepts. To defend against this ischemic cascade, upon ischemia onset, brain tissues enhance their metabolic plasticity, in order to maintain the cerebral activity transiently, mainly through the regulation of CBF, extraction of oxygen and glucose, energy metabolic reprogramming, antioxidant defense, and mitophagy. General description of ischemic preconditioning (IPC), in which several cycles of brief non-lethal ischemia and reperfusion are applied either directly, regionally, or remotely. Ham P.B., Raju R. Mitochondrial function in hypoxic ischemic injury and influence of aging. Yarian C.S., Toroser D., Sohal R.S. However, continuing ischemic stress, or additional energy demanding episodes, or both, will exhaust this limited capacity and transform penumbra into necrotic tissue. Upregulation of pentose phosphate pathway and preservation oftricarboxylic acid cycle flux after experimental brain injury. To date, IPC has been replicated in humans and other species, and applied to other organs and tissues (e.g., the brain and kidney). 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. Hence, the abundance and localization of polyunsaturated fatty acids are crucial for the degree of lipid peroxidation that occurs in cells. HHS Vulnerability Disclosure, Help Sarrafzadegan N., Gharipour M., Sadeghi M., Nezafati P., Talaie M., Oveisgharan S., Nouri F., Khosravi A. Metabolic Syndrome and the Risk of Ischemic Stroke. 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]. McIntosh V.J., Lasley R.D. However, with persistent ischemia, irreversible damage may occur in the affected brain areas. To the best of our knowledge, no study has assessed whether IPC affects the oxygen delivery ability of erythrocytes. 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]. Direct NAD+ repletion, either in animal or in cultured neurons, markedly reduced ischemic cell death and DNA damage [32,33]. Ischemic preconditioning and glucose metabolism during low-flow ischemia: Role of the adenosine a receptor. Lactate in cerebrospinal fluid (CSF) has also been found to be higher in stroke patients [17]. Mitochondria are signaling, bioenergetic, and biosynthetic organelles. Ischemic heterogeneity is also demonstrated by recent PET studies. Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. NADP+ is an essential cofactor for the rate-limiting step of the pentosephosphate pathway (PPP). Furthermore, IPC treatment also remarkably improves the metabolic disturbances in the TCA cycle during ischemia. Collateral flow predicts response to endovascular therapy for acute ischemic stroke. de Jonge R., de Jong J.W. Excessive glutamate release and impeded reuptake of excitatory amino acids result in the activation of NMDARs, AMPARs and KARs. Busija D.W., Rutkai I., Dutta S., Katakam P.V. 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. Stroke is one of the leading causes of death and permanent disability worldwide. Increased pools of NAMPT and NAD+ are protective against oxygenglucose deprivation, as well as playing a crucial role in cell energy maintenance. 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. 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. However, continuing ischemic stress, or additional energy demanding episodes, or both, will exhaust this limited capacity and transform penumbra into necrotic tissue. the contents by NLM or the National Institutes of Health. Metabolomic Profiling Reveals That Reprogramming of Cerebral Glucose Metabolism is Involved in Ischemic Preconditioning Induced Neuroprotection in a Rodent Model of Ischemic Stroke. Li P., Quan W., Lu D., Wang Y., Zhang H.H., Liu S., Jiang R.C., Zhou Y.Y. Chen S.Y., Liu J.W., Wang Y.H., Huang J.Y., Chen S.C., Yang S.F., Wang P.H. In short, understanding the mechanism of metabolic reprogramming is expected to be greatly beneficial for our understanding of ischemic stroke treatment and for the standardized application of IPC. Careers, Unable to load your collection due to an error. Reduced nicotinamide adenine dinucleotide(NADH)/nicotinamide adenine dinucleotide (NAD+): The NAD+ and NADH redox couple is essential for a variety of electron exchange-dependent biochemical reactions, and serves as a cofactor for enzymes involved in glycolysis, the oxidative decarboxylation of pyruvate to acetyl-CoA, fatty acid -oxidation, and TCA cycle. All authors have read and agreed to the published version of the manuscript. 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]. Hepatic NADH reductive stress underlies common variation in metabolic traits. Blood Vessel Reactivity - an overview | ScienceDirect Topics 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. Within cells, the selective autophagy of ferritin (abbreviated as ferritinophagy), by modulating iron metabolism and controlling iron availability, occurs to enhance ferroptosis sensitivity [47]. 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]. 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. Jennifer D. Ischemic preconditioning in 18- to 20-month-old gerbils long-term survival with functional outcome measures. To defend against this, the brain shifts the cellular machinery from aerobic to anaerobic metabolism. Article. 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]. Interestingly, IPC has exhibited significant time-window effects in both basic and clinical research, where two phases have been observed. Chen W.L., Jin X., Wang M., Liu D., Luo Q., Tian H., Cai L., Meng L., Bi R., Wang L., et al. Association between Metabolic Syndrome and Cognitive Impairment after Acute Ischemic Stroke: A Cross-Sectional Study in a Chinese Population. In biosynthetic pathways, cancer cells require that intermediate pools are maintained. 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. A previous study has shown ketone bodies to reduce ROS by using NADH as an electron donor. Narayanan S.V., Perez-Pinzon M.A. Both studies revealed that the metabolites have inhomogeneous distributions in the brain, with high levels of spatial specificity. Laursen M.R., Hansen J., Elkjaer C., Stavnager N., Nielsen C.B., Pryds K., Johnsen J., Nielsen J.M., Botker H.E., Johannsen M. Untargeted metabolomics reveals a mild impact of remote ischemic conditioning on the plasma metabolome and alpha-hydroxybutyrate as a possible cardioprotective factor and biomarker of tissue ischemia. 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. However, the underlying neuroprotective mechanisms of IPC remain elusive. View. 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. The ischemic penumbra has been in the center of ischemic stroke research for the last 40 years. 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. 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. Bahadoran A., Bezavada L., Smallwood H.S. 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. Morawetz R.B., Crowell R.H., De Girolami U. GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling. Yu Z., Li J., Ren Z., Sun R., Zhou Y., Zhang Q., Wang Q., Cui G., Li J., Li A., et al. The authors declare no conflict of interest. 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. As the main product of the oxidative PPP (oxPPP), NADPH provides the essential redox equivalent for GSH regeneration, enhancing the antioxidant defense capacity. Faubert B., Solmonson A., DeBerardinis R.J. Metabolic reprogramming and cancer progression. Stroke incidence rates for those with and without MetS were 2.6% and 1.1%, respectively. Ardito S., Oudin A., Ahmed S.U., Fack F., Keunen O., Zheng L., Miletic H., Sakariassen P.., Weinstock A., Wagner A., et al. Altogether, these results imply that subduing postischemic hyperglycolysis and the regulation of brain glucose metabolism play important roles in the neuroprotective aspect of IPC. This described evidence highlights the capability of IPC in improving mitochondrial efficiency and regulating the reprogramming processes related to mitochondrial function and cellular metabolism. Visualizing and Modulating Mitophagy for Therapeutic Studies of Neurodegeneration. 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]. Immune cells also have distinct metabolic programs, in order to meet the energetic and biosynthetic requirements of their ever-changing micro-environments. The MAS has been implicated as potentially dysregulated during cerebral ischemia [31]. 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]. 2011;42 . Wu Y., Zhang S., Gong X., Tam S., Xiao D., Liu S., Tao Y. As the storage form of glucose, the polymer glycogen is entirely located in astrocytes, and the glycogen metabolism rarely occurs in neurons [99]. 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. 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. 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. Pathophysiology of Cerebral Ischemia: Role of Oxidative/Nitrosative Stress.
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