Visualizing and Modulating Mitophagy for Therapeutic Studies of Neurodegeneration. Notably, neurons and astrocytes preferentially use quite different metabolic pathways in physiological conditions [98]. 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 malateaspartate shuttle (MAS) is considered the most important NAD+/NADH shuttle in neurons, playing a prominent role in neuronal mitochondrial respiration. Metabolic syndrome (MetS) is a common metabolic disorder, involving a constellation of insulin resistance, abdominal obesity, hypertension, and dyslipidemia. Ischaemic conditioning and reperfusion injury. energy metabolism might be intermittently compromised within the ischemic penumbra. 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]. Mechanisms underlying neuronal death in ischemic stroke (1) Mitochondrial response, including excessive ROS production, mitochondrial calcium overloading, and disrupted mitochondria quality control. Acute imaging of the penumbra is a critical step toward selection of patients that can best benefit from penumbral-salvaging reperfusion therapies. 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. Trial of 2860 patients and followed them for 3.5 years. Mitophagy is also essential in sustaining mitochondrial homeostasis, biogenesis, and the total number and quality of mitochondria. Upregulation of pentose phosphate pathway and preservation oftricarboxylic acid cycle flux after experimental brain injury. An increasing number of studies have shown the time-dependent metabolic changes during IPC or the acute-to-chronic post-stroke phase. Ham P.B., Raju R. Mitochondrial function in hypoxic ischemic injury and influence of aging. 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]. 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]. Furthermore, acute-on-chronic liver failure (ACLF) induces hyperammonemia and hypoxia in hepatocytes. 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. Geng J.L., Aa J.Y., Feng S.Q., Wang S.Y., Wang P., Zhang Y., Ouyang B.C. Morris-Blanco K.C., Cohan C.H., Neumann J.T., Sick T.J., Perez-Pinzon M.A. These include: NADP+/NADPH. As IPC is innocuous, cost-effective, and has fewer or no contraindications, and has exciting new prospects in the broader management of ischemic stroke (Figure 1). The https:// ensures that you are connecting to the These studies have indicated the time-specificity of IPC; however, the dynamic change of metabolic reprogramming induced by IPC is still unclear. Federal government websites often end in .gov or .mil. 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). Wender et al. Ischemic preconditioning treatment of astrocytes transfers ischemic tolerance to neurons. Murry C.E., Jennings R.B., Reimer K.A. 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. Ardito S., Oudin A., Ahmed S.U., Fack F., Keunen O., Zheng L., Miletic H., Sakariassen P.., Weinstock A., Wagner A., et al. Elucidation of these endogenous defense mechanisms against ischemic injury is considered crucial for the development of novel stroke therapies. found that ketone treatment in mice at 30 min after ischemia enhanced mitochondrial function, reduced oxidative stress and, therefore, reduced infarct volume [49]. Preserving pools of NAD+ confers neuroprotection after ischemic stress. Mouse genetic studies have shown that S1P protects against tissue hypoxia by inducing O2 release. Simmons E.C., Scholpa N.E., Schnellmann R.G. Furthermore, there exist some serious contraindications and complications; for example, thrombolytic agents have been associated with symptomatic intracerebral hemorrhage [6]. Hepatic NADH reductive stress underlies common variation in metabolic traits. Then, the accumulated free radicals damage cell membranes, mitochondria, and DNA, thus triggering caspase-mediated cell death. In the mammalian brain, neurons are outnumbered 10:1 by astrocytes in most regions. The biochemical control of ferroptosis includes amino acid metabolism, glutathione metabolism, lipid metabolism, iron metabolism, and other metabolic pathways [43]. Dixon S.J., Lemberg K.M., Lamprecht M.R., Skouta R., Zaitsev E.M. Gleason Ferroptosis: An iron-dependent form of nonapoptotic cell death. These preliminary results prompt the research on pathway-specifics alterations in metabolic reprogramming with aging during the stroke and IPC, which will be crucial for precision intervention for individuals of different ages, especially for patients with advanced age and a higher ischemic stroke incidence rate. Cellular metabolism is a flexible network to meet homeostasis demands in real-time. Aconitase is the main functional target of aging in the citric acid cycle of kidney mitochondria from mice. All brain cell types are able to uptake ketones; the ketones are then metabolized to acetyl-CoA to support the cell energy [29]. 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. 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]. 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]. Chen S.Y., Liu J.W., Wang Y.H., Huang J.Y., Chen S.C., Yang S.F., Wang P.H. In such tissue, blood flow is decreased below the metabolic demand, but energy metabolism is maintained at a level allowing morphologic preservation of tissue. Hirayama Y., Ikeda M.Y., Notomi S., Enaida H., Kinouchi H., Koizumi S. Astrocyte-mediated ischemic tolerance. Jaggar et al. Sphingosine 1-phosphate (S1P) is a bioactive signaling lipid highly enriched in mature erythrocytes. Protecting the ischaemic penumbra as an adjunct to - Nature Mounting evidence has shown that brain metabolic plasticity and IPC metabolic reprogramming are crucial for ischemic defense, typically through maintaining cellular energy and redox homeostasis. Careers, Unable to load your collection due to an error. 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 penumbra | Radiology Reference Article | Radiopaedia.org Age, sex, and race/ethnic temporal trends in metabolic syndrome prevalence among individuals with myocardial infarction or stroke in the United States. 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]. To maintain the cerebral activity transiently, upon ischemia onset, brain tissues enhance their metabolic plasticity, mainly through energy metabolic reprogramming and antioxidant defense. Hausenloy D.J., Yellon D.M. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. 6-8 hours A patient presents to the emergency department with left leg weakness and numbness. Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice. However, with persistent ischemia, irreversible damage may occur in the affected brain areas. PDF Identifying and utilizing the ischemic penumbra Brain, tumor, and proliferative tissues have high metabolic activity and energy requirements, necessitating that they have reliable mechanisms to adequately protect their metabolic homeostasis. 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. 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]. See Answer Exploring the neuroprotective effects of ginkgolides injection in a rodent model of cerebral ischemia-reperfusion injury by GC-MS based metabolomic profiling. The Ischemic Penumbra and Cell Survival | SpringerLink Metabolic syndrome (MetS) increases stroke incidence. 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. 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. The ischemic penumbra: correlates in imaging and implications for 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. 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. Meanwhile, exogenous supplementation of lactate has shown remarkable effects in traumatic brain injury therapy [23]. Metabolic disorder and metabolic plasticity are salient features triggered by ischemia. The ischemic penumbra can maintain metabolic demand with marginal blood flow from collateral circulation for a maximum of _____ before increasing in size. 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. Zhang T., Wang W., Huang J., Liu X., Zhang H., Zhang N. Metabolomic investigation of regional brain tissue dysfunctions induced by global cerebral ischemia. Irreversible injury to mitochondria is a cornerstone of pathogenesis of neurological diseases. NAMPT as a Therapeutic Target against Stroke. In the absence of glutamine (or when glutaminolysis is inhibited), cystine starvation and ferroptosis occur. The MAS has been implicated as potentially dysregulated during cerebral ischemia [31]. In-depth research considering these open questions will be valuable for exploring the mechanisms of IPC. 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. Polyzos A.A., Lee D.Y., Datta R., Hauser M., Budworth H., Holt A., Mihalik S., Goldschmidt P., Frankel K., Trego K., et al. Narayanan S.V., Perez-Pinzon M.A. Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia. Studies have revealed that inhibitors of ferroptosis, such as ferrostatins, carvacrol, and liproxstatins, could protect against cerebral ischemic injury in rodent models [43,48]. An increasing number of studies have shown that epidemiologic changes are likely responsible for the observed rise of stroke incidence (Table 1). Changes in the cerebral NAD+ pool under ischemia have been studied in detail. There are two major affected zones in an ischemic brain: The infarct core, surrounded by an ischemic penumbra. Mitochondria-derived reactive oxygen species dilate cerebral arteries by activating Ca. 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. 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. Identify the blocked artery that could potentially cause these symptoms. 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. Numerous in vitro, in vivo, and clinical studies have indicated that influenza infection induces hyperglycolysis in infected cells, activated immune cells, foci, and lymph nodes [68]. Ischemic penumbra denotes the part of an acute ischemic stroke that is at risk of progressing to infarction but is still salvageable if reperfused. 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. 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. To defend against oxidative stress, cells have developed complex systems that exploit and defend against this dilemma. 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]. 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. 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. FOIA The adult brain occupies less than 2% of the bodys weight, yet it consumes 25% of the cardiac output at rest and accounts for 20% of the total energy production of the body. It is usually located around an infarct core which represents the tissue which has already infarcted or is going to infarct regardless of reperfusion. 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. Inclusion in an NLM database does not imply endorsement of, or agreement with, 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). . Sep 2011. 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. (2014) Multi-parametric imaging of cerebral hemodynamic and metabolic response followed by ischemic injury . Dirnagl U., Endres M. Found in translation preclinical stroke research predicts human pathophysiology clinical phenotypes, and therapeutic outcomes. Here we provide a summary of metabolic mechanism of ischemic preconditioning when it is applied to ischemic stroke. In response to the NAD+ decline, NAMPT was upregulated in brain, plasma, and cultured neurons, which is the rate-limiting enzyme in mammalian NAD+ salvage biosynthesis [34]. Wang S., Xing Z., Vosler P.S., Yin H., Li W., Zhang F., Signore A.P., Stetler R.A., Gao Y., Chen J. Amarenco P., Kim J.S., Labreuche J., Charles H., Abtan J., Bejot Y., Cabrejo L., Cha J.K., Ducrocq G., Giroud M., et al. 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]. 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. Glenn T.C., Martin N.A., Horning M.A. 8600 Rockville Pike 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]. Erythrocyte Metabolic Reprogramming by Sphingosine 1-Phosphate in Chronic Kidney Disease and Therapies. Collaterals are demonstrated to be strong predictors of both response to endovascular therapy and functional outcomes [11]. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Direct intracerebroventricular or intravenous administration of lactate protected mouse brains against ischemic injury [22]. Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Most ketones are generated in the liver, while the transport of ketone bodies across the blood-brain barrier (BBB) is the limiting step. 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). 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]. Collateral flow predicts response to endovascular therapy for acute ischemic stroke. Erythrocytes are the only cell type responsible for delivering oxygen. 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. A comprehensive analysis of metabolic changes in the salvaged penumbra Metabolic Syndrome Is a Strong Risk Factor for Minor Ischemic Stroke and Subsequent Vascular Events. Durukan A., Tatlisumak T. Preconditioning-induced ischemic tolerance: A window into endogenous gearing for cerebroprotection. The regulation of NAD+ by IPC is related to NAMPT (nicotinamide phosphoribosyl transferase). ischemic penumbra as a biochemical target (intermittent bioenergetic compromise); (3) the ischemic penumbra as a . Mitochondria are major contributors to cellular ROS, and there are multiple antioxidant pathways to neutralize ROS, including superoxide dismutase (SOD2), glutathione, thioredoxin, and peroxiredoxins. Therefore, it can be seen that mitochondrial mechanism is an important, but underutilized, target for improving CBF and decreasing brain injury in stroke patients [14]. The Ischemic Penumbra: Correlates in Imaging and Implications for Treatment of Ischemic Stroke. In the brain, astrocytes can also generate ketone bodies from fatty acid -oxidation. 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. Metabolic reprogramming to maintain metabolic homeostasis, by correcting the metabolic disorder and enhancing metabolic plasticity, serves as an attractive potential therapeutic strategy for ischemic stroke. Transient ischemic attack before nonlacunar ischemic stroke in the elderly. Eckel R.H., Grundy S.M., Zimmet P.Z. 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. The Ischemic Penumbra and the Ischemic Core In steady-state, cells sustain themselves catabolically by using glycolytic carbons to fuel the TCA cycle. The ischemic protection of IPC has been applied in various organs, such as the heart, brain, kidney, liver, lungs, and intestine. Protein kinase C epsilon regulates mitochondrial pools of Nampt and NAD following resveratrol and ischemic preconditioning in the rat cortex. Writingoriginal draft preparation, editing, J.L. Comprehensive mapping of neurotransmitter networks by MALDIMS imaging. 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. Hirayama Y., Koizumi S. Astrocytes and ischemic tolerance. Stankovic S., Majkic-Singh N. Genetic aspects of ischemic stroke coagulation homocysteine, and lipoprotein metabolism as potential risk factors Critical Reviews in Clinical Laboratory. 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. 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. An official website of the United States government. confirmed this: In a Huntington model, they discovered region-specific metabolic reprogramming of astrocytes, which directly induced neuronal susceptibility. Frontiers | Clinical Imaging of the Penumbra in Ischemic Stroke: From and increases energy demand and neurotransmitter effluxes, 1 and represented an important milestone for understanding the temporal and spatial evolution of focal ischemic brain injury. 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]. Previous studies reported that when MCAO is applied during the early IPC phase, the brain is ischemia-tolerant. 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]. Third, iron deficiency has been associated with an increased risk of ischemic stroke [46]. 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.

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