ischemic penumbra metabolic demand

The ischemic protection of IPC has been applied in various organs, such as the heart, brain, kidney, liver, lungs, and intestine. General description of ischemic preconditioning (IPC), in which several cycles of brief non-lethal ischemia and reperfusion are applied either directly, regionally, or remotely. All authors have read and agreed to the published version of the manuscript. 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]. 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. Zong W.X., Rabinowitz J.D., White E. Mitochondria and Cancer. 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. Accumulating evidence has suggested that IPC regulates the cerebral metabolism by providing alternative energy substrates, which partly reduce the dependence of the brain on a continuous supply of glucose, therefore improving the brains resistance to ischemia. Acute hyperglycemia adversely affects stroke outcome: A magnetic resonance imaging and spectroscopy study. 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]. Furthermore, IPC treatment also remarkably improves the metabolic disturbances in the TCA cycle during ischemia. 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. The https:// ensures that you are connecting to the 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. Protein kinase C epsilon regulates mitochondrial pools of Nampt and NAD following resveratrol and ischemic preconditioning in the rat cortex. This pathway can produce precursors to synthesize nucleotides and aromatic amino acids, generating cytosolic NADPH simultaneously [30]. We designed a prospective study to investigate the metabolic changes in the ischemic penumbra for patients with ICA flow lesions and cerebral infarct (or ischemia) before and after CEA using localized in vivo proton magnetic resonance spectroscopy ( (1)H-MRS). 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. An official website of the United States government. 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). TCA cycle reactions yield metabolite intermediates and energetic precursors for oxidative phosphorylation. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Patients underwent computer tomography . Licensee MDPI, Basel, Switzerland. The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression. Lactate: Previous research has suggested that astrocytes play a pivotal role in the induction of ischemic tolerance [83], during which lactate is extremely crucial. However, the underlying neuroprotective mechanisms of IPC remain elusive. However, research on metabolic reprogramming in the neuroscience field is still in its infancy. Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Lekoubou A., Ovbiagele B., Markovic D., Sanossian N., Towfighi A. The metabolic syndrome. This described evidence highlights the capability of IPC in improving mitochondrial efficiency and regulating the reprogramming processes related to mitochondrial function and cellular metabolism. 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]. 40.2% ischemic stroke individuals were diagnosed with MetS. 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. Glutamine is the most abundant free amino acid in human blood, which is converted to glutamate in mitochondria by glutaminase (GLS). 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. . revealed that S1P promoted erythrocyte glycolysis and oxygen release for adaptation to hypoxia. Chen W.L., Jin X., Wang M., Liu D., Luo Q., Tian H., Cai L., Meng L., Bi R., Wang L., et al. The more we understand the underlying metabolic reprogramming mechanisms manipulated by IPC affecting its efficiency and function against ischemic stroke, the more we will be able to experimentally (and, eventually, clinically) utilize the metabolic homeostasis to confer protection against the ischemic insult. Lactate in cerebrospinal fluid (CSF) has also been found to be higher in stroke patients [17]. Hou W., Xie Y., Song X., Sun X., Lotze M.T., Zeh H.J., Tang D. Autophagy promotes ferroptosis by degradation of ferritin. U.S. National Health and Nutrition Examination Surveys of 12,502 adults during 19992010. Hirayama Y., Koizumi S. Astrocytes and ischemic tolerance. Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice. Reactive oxygen species (ROS), in the form of superoxide and hydroxyl free radicals, as well as hydrogen peroxide, are produced from multiple physiological reactions, including electron transport by the ETC and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, which are often exacerbated under hypoxic micro-environments. To defend against this, the brain shifts the cellular machinery from aerobic to anaerobic metabolism. Ischemic preconditioning treatment of astrocytes transfers ischemic tolerance to neurons. NADP+ and its reduced counterpart, NADPH, are mainly required for anabolic reactions and cellular oxidative-stress defense. 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. Intriguing, the protective effect of IPC can be mimicked pharmacologically. Shariatgorji M., Nilsson A., Fridjonsdottir E., Vallianatou T., Kllback P., Katan L., Svmarker J., Mantas I., Zhang X., Bezard E., et al. Excitingly, emerging evidence from recent research has indicated that metabolic reprogramming may be the crucial neuroprotective mechanism of IPC for ischemia treatment. 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]. ischemic penumbra as a biochemical target (intermittent bioenergetic compromise); (3) the ischemic penumbra as a . Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Bartnik B.L., Sutton R.L., Fukushima M., Harris N.G., Hovda D.A., Lee S.M. Previous studies reported that when MCAO is applied during the early IPC phase, the brain is ischemia-tolerant. Preserving pools of NAD+ confers neuroprotection after ischemic stress. Astrocytes state in a particular position to both sense neuronal signaling and capture glucose directly from the capillary and permit them to govern astrocyte-neurons cooperation. (Stroke. ); nc.ude.aaub@9102gnorgnornah (R.H.), 2School of Engineering Medicine, Beihang University, Beijing 100191, China. 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]. Advance in this active research field will stimulate a promising new direction in precision intervention and drug target discovery for ischemic stroke. A previous study has shown ketone bodies to reduce ROS by using NADH as an electron donor. Then, the accumulated free radicals damage cell membranes, mitochondria, and DNA, thus triggering caspase-mediated cell death. Stroke incidence rates for those with and without MetS were 2.6% and 1.1%, respectively. 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 . The penumbral concept suggests that different areas within the ischemic region evolve into irreversible brain injury over time and that this evolution is most critically linked to the severity . Mortality, morbidity, and risk factors in China and its provinces, 19902017: A systematic analysis for the Global Burden of Disease Study 2017. Consistent with IPC may effectively reprogram mitochondrial energy metabolism and benefit stroke. 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. Hess D.C., Blauenfeldt R.A., Andersen G., Hougaard K.D., Hoda M.N., Ding Y., Ji X. Meng R., Asmaro K., Meng L., Liu Y., Ma C., Xi C., Li G., Ren C., Luo Y., Ling F., et al. Meanwhile, exogenous supplementation of lactate has shown remarkable effects in traumatic brain injury therapy [23]. Simultaneously, the anaplerotic pathway is promoted to refill the macromolecular biosynthesis for rapid proliferation in some cells. Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute-On-Chronic Liver Failure. An increased understanding of the pathogenic mechanisms of stroke and IPC serves to highlight the importance of metabolic reprogramming. The normal CBF in healthy normal men is 54 mL/100 g per minute. Berthet C., Lei H.T., Thevenet J., Gruetter R. Neuroprotective role of lactate after cerebral ischemia. To defend against oxidative stress, cells have developed complex systems that exploit and defend against this dilemma. Note incursions of preferentially-oxygenated peri-arterial cells across planar hypoxic (ht) and anoxic (at) pO 2 thresholds. 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. IPC has also demonstrated neuroprotective activity through the activation of Nrf2 both in vivo and in vitro, which is a transcription factor that helps to maintain mitochondrial coupling and antioxidant protein expression [75]. L-glutamine protects mouse brain from ischemic injury via up-regulating heat shock protein 70. the contents by NLM or the National Institutes of Health. The ischemic core . Sphingosine 1-phosphate (S1P) is a bioactive signaling lipid highly enriched in mature erythrocytes. Coincidentally, a clinical study has implicated the effectiveness of IPC in preventing the progression of white matter hyperintensities (WMHs) and in ameliorating cognitive impairment of very elderly patients (83.5 2.3 year) with ICAS [94]. Hence, the abundance and localization of polyunsaturated fatty acids are crucial for the degree of lipid peroxidation that occurs in cells. Regional cerebral blood flow thresholds during cerebral ischemia. 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 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. Ischemic preconditioning and glucose metabolism during low-flow ischemia: Role of the adenosine a receptor. This feature determines that the metabolic homeostasis of neurons is related to their brain micro-environment, which may provide different substrates to fuel the neurons. Transient ischemic attack before nonlacunar ischemic stroke in the elderly. There is also a beneficial role of erythrocyte S1P in hypertensive CKD, where S1P also induces 2,3-BPG production and oxygen delivery [72]. 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]. Yarian C.S., Toroser D., Sohal R.S. Katayama H., Hama H., Nagasawa K., Kurokawa H., Sugiyama M., Ando R., Funata M., Yoshida N., Homma M., Nishimura T., et al. Ischemic stroke is the consequence of a sharp reduction of regional cerebral blood flow (CBF), resulting in oxygen and glucose deprivation (OGD). Hu S., Dong H., Zhang H., Wang S., Hou L., Chen S. Noninvasive limb remote ischemic preconditioning contributes neuroprotective effects via activation of adenosine a1 receptor and redox status after transient focal cerebral ischemia in rats. utilized MALDI-MSI to observe the intracerebral distribution of neurotransmitters in Parkinsonian rats, primates, and human patients [88]. It has been noted that a minimal CBF of 18 mL/100 g per minute is needed to maintain normal electroencephalographic (EEG) activity. 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]. Moreover, the brain utilizes metabolic plasticity, a protective response to stroke injury. Apart from complete reperfusion, IPC is a powerful intervention known for reducing ischemic infarct size. Above all, metabolism is essential for life activities. 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. Astrup J, Siesj BK . The latter form is informative in energy metabolism than free NADH. Changes in the cerebral NAD+ pool under ischemia have been studied in detail. Zhou D., Ding J.Y., Ya J.Y., Pan L.Q., Bai C.B., Guan J.W., Wang Z.G., Jin K.X., Yang Q., Ji X.M., et al. In subsequent hours after IPC, the brain regresses to its nave state. quences as drastically increase d metabolic demand cannot be satisfied in regions with critically reduced blood supply. 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. Zhang et al. Association between Metabolic Syndrome and Cognitive Impairment after Acute Ischemic Stroke: A Cross-Sectional Study in a Chinese Population. Related studies have mainly focused on the processes of humoral and neuronal factors interacting to initiate and transmit signals, in order to increase the cerebral blood flow and protect mitochondria to reduce oxidative stress [73], as well as several key enzymes and regulatory factors, such as AMP-activated protein kinase (AMPK), SIRT1, and SIRT574. The brain is an unusual organ, having the highest metabolic activity and energy requirement by mass. At a practical level, however, this definition is unwieldy. 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. Zhang T., Wang W., Huang J., Liu X., Zhang H., Zhang N. Metabolomic investigation of regional brain tissue dysfunctions induced by global cerebral ischemia. 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. Glenn T.C., Martin N.A., Horning M.A. Ischemic stroke is typically caused by blood vessel blockage, which accounts for approximately 87% of all stroke cases. PPFKFB3 controls glycolytic flux by synthesizing fructose-2,6-bisphosphate (F2,6BP), a potent allosteric activator of phosphofructokinase 1 (PFK-1), which is a master regulator of glycolysis [18]. Mitochondria-derived reactive oxygen species dilate cerebral arteries by activating Ca.

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