ischemic penumbra metabolic demand
The cerebral collateral circulationknown as the subsidiary network of vascular channelscan stabilize the CBF when principal conduits fail. The relaxation of VSM can also be indirectly regulated by the action of NO and other vasoactive agents. Elevated PPP flux enhances the reducing power, in the form of NADPH and GSH. ological, molecular, metabolic and perfusional disturbances. Yu Z., Li J., Ren Z., Sun R., Zhou Y., Zhang Q., Wang Q., Cui G., Li J., Li A., et al. There is also a beneficial role of erythrocyte S1P in hypertensive CKD, where S1P also induces 2,3-BPG production and oxygen delivery [72]. Direct intracerebroventricular or intravenous administration of lactate protected mouse brains against ischemic injury [22]. 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 Altogether, these results imply that subduing postischemic hyperglycolysis and the regulation of brain glucose metabolism play important roles in the neuroprotective aspect of IPC. Bang O.Y., Saver J.L., Kim S.J., Kim G.M., Chung C.S., Ovbiagele B. Xi Q., Cheranov S.Y., Jaggar J.H. -ketoglutarate, produced by glutaminolysis, is vital for alternatively M2-activated macrophages [69]. Second, polyunsaturated fatty acids are susceptible to lipid peroxidation and are necessary for ferroptosis [45]. Bethesda, MD 20894, Web Policies 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. TCA cycle reactions yield metabolite intermediates and energetic precursors for oxidative phosphorylation. After ischaemic stroke, brain damage can be curtailed by rescuing the 'ischaemic penumbra' that is, the severely hypoperfused, at-risk but not yet infarcted tissue. However, in response to changes in the micro-environment, metabolic reprogramming is notably crucial to maintaining metabolic homeostasis. Wang S., Xing Z., Vosler P.S., Yin H., Li W., Zhang F., Signore A.P., Stetler R.A., Gao Y., Chen J. Sphingosine 1-phosphate (S1P) is a bioactive signaling lipid highly enriched in mature erythrocytes. Both studies revealed that the metabolites have inhomogeneous distributions in the brain, with high levels of spatial specificity. 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. 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. 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. Metabolic Syndrome Is a Strong Risk Factor for Minor Ischemic Stroke and Subsequent Vascular Events. 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]. Collaterals are demonstrated to be strong predictors of both response to endovascular therapy and functional outcomes [11]. Cellular NAD replenishment confers marked neuroprotection against ischemic cell death: Role of enhanced DNA repair. Tang X., Fang M., Cheng R., Zhang Z., Wang Y., Shen C., Han Y., Lu Q., Du Y., Liu Y., et al. Acute imaging of the penumbra is a critical step toward selection of patients that can best benefit from penumbral-salvaging reperfusion therapies. Accessibility At a practical level, however, this definition is unwieldy. The biochemical control of ferroptosis includes amino acid metabolism, glutathione metabolism, lipid metabolism, iron metabolism, and other metabolic pathways [43]. NAD+ levels and the NAD+/NADH redox couple provide a readout and regulator for cellular energy metabolism [30]. Research has found that brain ischemia-refusion (I/R) injury can activate AMPK, which is an adaptive response to stress that plays an essential role in maintaining energy homeostasis, while the overactivation of AMPK accentuates hyperglycolysis, which can lead to serious metabolic distress. Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone. Ferroptosis. Then, the accumulated free radicals damage cell membranes, mitochondria, and DNA, thus triggering caspase-mediated cell death. Bartnik B.L., Sutton R.L., Fukushima M., Harris N.G., Hovda D.A., Lee S.M. 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]. Paez D.T., Garces M., Calabro V., Bin E.P., DAnnunzio V., Del Mauro J. Adenosine a1 receptors and mitochondria: Targets of remote ischemic preconditioning. Studies also clearly demonstrate that IPC is quite effective in aged animals: in aged gerbils, IPC provided substantial neuroprotection (>80%) in CA1 neurons ten days after ischemia compared with 6% in ischemic gerbils [95]. 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). Sarrafzadegan N., Gharipour M., Sadeghi M., Nezafati P., Talaie M., Oveisgharan S., Nouri F., Khosravi A. Metabolic Syndrome and the Risk of Ischemic Stroke. McIntosh V.J., Lasley R.D. Metabolic syndrome (MetS) is a common metabolic disorder, involving a constellation of insulin resistance, abdominal obesity, hypertension, and dyslipidemia. Magistretti P.J., Martin J.L. MetS prevalence was 61.2% in stroke survivors. Direct NAD+ repletion, either in animal or in cultured neurons, markedly reduced ischemic cell death and DNA damage [32,33]. Zhou M., Wang H., Zeng X., Yin P., Zhu J., Chen W., Li X., Wang L., Wang L., Liu Y., et al. 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: Correlates in Imaging and Implications . In the mammalian brain, neurons are outnumbered 10:1 by astrocytes in most regions. During glycolysis, NAD+ is reduced to NADH, which is then oxidized by complex I of the mitochondrial electron transport chain (ETC) to supply the necessary proton gradient for ATP production. Yang W.S., Kim K.J., Gaschler M.M., Patel M., Shchepinov M.S., Stockwell B.R. The translation of experimental . 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]. Before 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. 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. Marchiq I., Pouyssgur J. Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H+ symporters. 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. This problem has been solved! This process is named the astrocyteneuron lactate shuttle (ANLS). 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. In response to ischemia, there exists a cerebral vessel autoregulatory mechanism, inducing the enhancement of cerebral collateral circulation and vasodilation, in order to stabilize or increase the CBF and oxygen/glucose extraction for viable neurons. 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 . Hirayama Y., Koizumi S. Astrocytes and ischemic tolerance. 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]. Vessey D.A., Li L., Honbo N., Karliner J.S. Within cells, the selective autophagy of ferritin (abbreviated as ferritinophagy), by modulating iron metabolism and controlling iron availability, occurs to enhance ferroptosis sensitivity [47]. Collectively, these findings suggest IPC could specify metabolic reprogramming in neurons and astrocytes and contribute to functional homeostasis. alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. 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. IPC is neuroprotective for ischemic stroke, but the precise mechanisms through which it exerts protection against ischemic insults remain unclear at present. 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]. The https:// ensures that you are connecting to the Della Morte D., Abete P., Gallucci F., Scaglione A., DAmbrosio D., Gargiulo G., De Rosa G., Dave K.R., Lin H.W., Cacciatore F., et al. 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. View. . ); nc.ude.aaub@9102gnorgnornah (R.H.), 2School of Engineering Medicine, Beihang University, Beijing 100191, China. Neurons experience mitochondrial dysfunction, shifting the cellular machinery from aerobic to anaerobic metabolism, and a decrease of ATP production, directly resulting in energy failure. Wang G.S., Tong D.M., Chen X.D., Yang T.H., Zhou Y.T., Ma X.B. Furthermore, the accumulation of the TCA intermediate succinate is also responsible for mitochondrial ROS production during ischemic reperfusion [39]. 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. 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. Erythrocyte Metabolic Reprogramming by Sphingosine 1-Phosphate in Chronic Kidney Disease and Therapies. Upregulation of pentose phosphate pathway and preservation oftricarboxylic acid cycle flux after experimental brain injury. Lactate: Brain fuel in human traumatic brain injury: A comparison with normal healthy control subjects. National Library of Medicine Meanwhile, exogenous supplementation of lactate has shown remarkable effects in traumatic brain injury therapy [23]. In addition, age-related alterations in TCA cycle enzyme activities will likely contribute to the decline of mitochondrial bioenergetics [96]. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Regulation of glycogen metabolism: Physiological, pharmacological and pathological aspects. 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. It has been found that metabolic disorder is a determinant of the incidence and progression of stroke. Eventually, exogenous lactate administration can significantly increase cell survival in neuronal cultures against lethal oxygen glucose deprivation (OGD) [84]. 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. 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. However, continuing ischemic stress, or additional energy demanding episodes, or both, will exhaust this limited capacity and transform penumbra into necrotic tissue. Meanwhile, IPC-treated astrocytes significantly enhanced lactate secretion into the extracellular media. 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). To maintain the cerebral activity transiently, upon ischemia onset, brain tissues enhance their metabolic plasticity, mainly through energy metabolic reprogramming and antioxidant defense. Mortality, morbidity, and risk factors in China and its provinces, 19902017: A systematic analysis for the Global Burden of Disease Study 2017. Betti et al. The authors declare no conflict of interest. Protein kinase C epsilon regulates mitochondrial pools of Nampt and NAD following resveratrol and ischemic preconditioning in the rat cortex. 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) Stankovic S., Majkic-Singh N. Genetic aspects of ischemic stroke coagulation homocysteine, and lipoprotein metabolism as potential risk factors Critical Reviews in Clinical Laboratory. 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. (2014) Multi-parametric imaging of cerebral hemodynamic and metabolic response followed by ischemic injury . 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. 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]. Ischemic stroke occurs most frequently in individuals aged 65 years. Identify the blocked artery that could potentially cause these symptoms. 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. Mitochondrial Dysfunction and Mitophagy in Parkinsons Disease: From Mechanism to Therapy. Ham P.B., Raju R. Mitochondrial function in hypoxic ischemic injury and influence of aging. Glenn T.C., Martin N.A., Horning M.A. An increasing number of studies have shown the time-dependent metabolic changes during IPC or the acute-to-chronic post-stroke phase. However, the underlying neuroprotection mechanisms of IPC remain elusive. 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. Sun K., Zhang Y., DAlessandro A., Nemkov T., Song A., Wu H., Liu H., Adebiyi M., Huang A., Wen Y.E., et al. The most famous metabolic reprogramming process is the Warburg effect: Switching the energy metabolism largely to glycolysis, even in the presence of oxygen, implicating an increased rate of glucose uptake by cancer cells. The most immediate biochemical alterations in neurons affected by ischemia are mitochondrial dysfunction, shifting the cellular machinery from aerobic to anaerobic metabolism, and energy production decreasing from 32 adenosine triphosphate (ATP) molecules to 2 ATP molecules. 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. Narayanan S.V., Perez-Pinzon M.A. Adenosine receptor-mediated cardioprotection: Are all 4 subtypes required or redundant? 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. 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. 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. Ischemic penumbra denotes the part of an acute ischemic stroke that is at risk of progressing to infarction but is still salvageable if reperfused. Polyzos A.A., Lee D.Y., Datta R., Hauser M., Budworth H., Holt A., Mihalik S., Goldschmidt P., Frankel K., Trego K., et al. Mitochondria lie at the key location for neuronal survival [51]. Chen S.Y., Liu J.W., Wang Y.H., Huang J.Y., Chen S.C., Yang S.F., Wang P.H. Thus, we propose that mitophagy could be developed as an effective and potential target for the treatment 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. Preservation of the IPC phenotype implicated a unifying endogenous mechanism, possibly involving energy and redox homeostasis maintenance.
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