Identifying and utilizing the ischemic penumbra | Neurology 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. Geng J.L., Zhang Y., Li S.J., Li S.N., Wang J.K., Wang H., Aa J.Y., Wang G.J. 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. 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. Hatten M.E. Mitochondrial Mechanisms of Neuronal Cell Death: Potential Therapeutics. NAMPT as a Therapeutic Target against Stroke. The complex underlying mechanisms responsible for the neuroprotection against IPC remain elusive. 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. Blood Vessel Reactivity - an overview | ScienceDirect Topics Bouzat P., Sala N., Suys T., Zerlauth J.B. Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain. 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. Yu Z., Li J., Ren Z., Sun R., Zhou Y., Zhang Q., Wang Q., Cui G., Li J., Li A., 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]. Lekoubou A., Ovbiagele B., Markovic D., Sanossian N., Towfighi A. Most ketones are generated in the liver, while the transport of ketone bodies across the blood-brain barrier (BBB) is the limiting step. 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. Licensee MDPI, Basel, Switzerland. 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]. Sato H., Nomura S., Maebara K., Sato K., Tamba M., Bannai S. Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. 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. To test whether acute changes in cardiac workload and metabolic demand impact the redox state of the myocardium and coronary arterial wall in vivo, we used high spatial resolution imaging mass . Busija D.W., Rutkai I., Dutta S., Katakam P.V. The ischemic penumbra: operationally . Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Yin J., Han P., Tang Z., Liu Q., Shi J. Sirtuin 3 mediates neuroprotection of ketones against ischemic stroke. Murry C.E., Jennings R.B., Reimer K.A. 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]. 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. Metabolic reprogramming for metabolic homeostasis maintenance. 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. Xi Q., Cheranov S.Y., Jaggar J.H. Intravenous thrombolysis and mechanical thrombectomy for selected . It was shown that free and protein-bound NADH differs regarding lifetime. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Li P., Quan W., Lu D., Wang Y., Zhang H.H., Liu S., Jiang R.C., Zhou Y.Y. 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]. Eventually, exogenous lactate administration can significantly increase cell survival in neuronal cultures against lethal oxygen glucose deprivation (OGD) [84]. Received 2021 Apr 13; Accepted 2021 May 6. Ischemic preconditioning treatment of astrocytes transfers ischemic tolerance to neurons. 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. Solved the ischemic penumbra can maintain metabolic demand | Chegg.com Identify the blocked artery that could potentially cause these symptoms. Furthermore, acute-on-chronic liver failure (ACLF) induces hyperammonemia and hypoxia in hepatocytes. 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. 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. Remote ischaemic conditioningA new paradigm of self-protection in the brain. It is usually located around an infarct core which represents the tissue which has already infarcted or is going to infarct regardless of reperfusion. Finally, the NAD+ pool declines by approximately 3550%. Immune cells also have distinct metabolic programs, in order to meet the energetic and biosynthetic requirements of their ever-changing micro-environments. Metabolic disorder and metabolic plasticity are salient features triggered by ischemia. The malateaspartate shuttle (MAS) is considered the most important NAD+/NADH shuttle in neurons, playing a prominent role in neuronal mitochondrial respiration. Both studies revealed that the metabolites have inhomogeneous distributions in the brain, with high levels of spatial specificity. These include: NADP+/NADPH. 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. Mitochondria are signaling, bioenergetic, and biosynthetic organelles. Thus, we propose that mitophagy could be developed as an effective and potential target for the treatment of 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]. When the CBF is below 10 mL/100 g per minute, irreversible cellular injury will occur, and the infarct core forms [10]. Ischemic Penumbra | Request PDF - ResearchGate Exploring the neuroprotective effects of ginkgolides injection in a rodent model of cerebral ischemia-reperfusion injury by GC-MS based metabolomic profiling. 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. FOIA The astrocytic glycolysis is also stimulated by neuronal activation, giving neurons the capacity of tight control over astrocyte metabolism. Likewise, as the most difficult challenge in ischemic stroke is energy failure, whether some other new energetic substrates are mobilized by IPC (e.g., fructose), in addition to the glucose and common alternative energy substrates, should be determined. . Heterogeneity in the penumbra - SAGE Journals These data are consistent with the original concepts of the penumbra and core, but recognize the dynamic complex heterogeneous processes involved. 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. 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. 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]. Advance in this active research field will stimulate a promising new direction in precision intervention and drug target discovery for ischemic stroke. McIntosh V.J., Lasley R.D. The primary aim of current acute stroke . This process is named the astrocyteneuron lactate shuttle (ANLS). 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. Increasing understanding of the related pathogenic mechanisms serves to highlight the importance of metabolic regulation. The ischemic penumbra can maintain metabolic demand with marginal blood flow from collateral circulation for a maximum of _____ before increasing in size. Waves of depolarizations, the peri-infarct spreading depres- . Lemasters J. . 2 The penumbra includes ischemic areas that recover spontaneously (benign oligemia; Figure 1, area a) and areas that progress to irreversible changes, unless effective treatment is used (referred to as penumbra; Figure 1, area b). Preservation of the IPC phenotype implicated a unifying endogenous mechanism, possibly involving energy and redox homeostasis maintenance. PDF The Cerebral Ischemic Penumbra - Cambridge Oxygen is a crucial substrate in metabolism. 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. 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. Collaterals are demonstrated to be strong predictors of both response to endovascular therapy and functional outcomes [11]. Giusti B., Saracini C., Bolli P., Magi A., Martinelli I. Early-onset Ischaemic Stroke: Analysis of 58 Polymorphisms in 17 Genes Involved in Methionine Metabolism. This necessitates that the brain has reliable mechanisms to adequately protect its metabolic homeostasis. 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. Regulation of glycogen metabolism: Physiological, pharmacological and pathological aspects. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Zong W.X., Rabinowitz J.D., White E. Mitochondria and Cancer. 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]. 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. Once ischemic stroke occurs, the PPP is boosted and more glycolytic intermediates are diverted into the PPP to sustain NADPH production [18]. Ischemic stroke occurs most frequently in individuals aged 65 years. Together, effective IPC metabolic reprogramming may happen and be assumed to sustain during the early and late phases of IPC. found that ketone treatment in mice at 30 min after ischemia enhanced mitochondrial function, reduced oxidative stress and, therefore, reduced infarct volume [49]. Irreversible injury to mitochondria is a cornerstone of pathogenesis of neurological diseases. The accumulation of glucose and glycolytic intermediates is a prominent feature of brain ischemia-induced metabolic disturbance in rodents. 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. Furthermore, IPC treatment also remarkably improves the metabolic disturbances in the TCA cycle during ischemia. Ischemic stroke is the consequence of a sharp reduction of regional cerebral blood flow (CBF), resulting in oxygen and glucose deprivation (OGD). Studies have shown that IPC upregulates NAMPT protein, and the protective effect of IPC against ischemia (30 min) and reperfusion (24 h) was attenuated in NAMPT knockdown mice, suggesting that NAMPT is essential in mediating the protective effect of IPC [80]. 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. Cerebral Blood Flow Threshold of Ischemic Penumbra and Infarct - Stroke 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. Stankovic S., Majkic-Singh N. Genetic aspects of ischemic stroke coagulation homocysteine, and lipoprotein metabolism as potential risk factors Critical Reviews in Clinical Laboratory. An increasing number of studies have shown that epidemiologic changes are likely responsible for the observed rise of stroke incidence (Table 1). Notably, neurons and astrocytes preferentially use quite different metabolic pathways in physiological conditions [98]. 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. Whereas in the delayed or the second protect phase of IPC, the brain is again ischemia-tolerant [93]. Sarrafzadegan N., Gharipour M., Sadeghi M., Nezafati P., Talaie M., Oveisgharan S., Nouri F., Khosravi A. Metabolic Syndrome and the Risk of Ischemic Stroke. Article. Iron-Deficiency and Estrogen Are Associated with Ischemic Stroke by Up-Regulating Transferrin to Induce Hypercoagulability. electrophysiological/ hemodynamic based definition to the wider metabolic-cellular-therapeutic concept that is managed today by neuroscientists. Furthermore, there exist some serious contraindications and complications; for example, thrombolytic agents have been associated with symptomatic intracerebral hemorrhage [6]. de Jonge R., de Jong J.W. These studies have indicated the time-specificity of IPC; however, the dynamic change of metabolic reprogramming induced by IPC is still unclear. 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. Here we provide a summary of metabolic mechanism of ischemic preconditioning when it is applied to ischemic stroke. The Ischemic Penumbra and the Ischemic Core 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]. Inclusion in an NLM database does not imply endorsement of, or agreement with, 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]. In: Murphy S., editor. ischemic injury develops heterogeneously, and with time coalesces dynamically into a homogenous core. 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. A diagram showing metabolism in the ischemic, penumbra and distant 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. A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. 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]. Malpartida A.B., Williamson M., Narendra D.P., Wade M.R., Ryan B.J. Mitochondria are major contributors to cellular ROS, and there are multiple antioxidant pathways to neutralize ROS, including superoxide dismutase (SOD2), glutathione, thioredoxin, and peroxiredoxins. In biosynthetic pathways, cancer cells require that intermediate pools are maintained. Metabolic reprogramming is notably crucial in this regard, especially for energy and redox homeostasis maintenance. 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. Lactate levels have been shown to decrease 24 h after IPC treatment in MCAO rats, indicating that the glycolytic pathway is downregulated by IPC; meanwhile, the activity of fructose-2,6-biphosphatase 3 (PFKFB3) was inhibited by IPC. The Ischemic Penumbra: Correlates in Imaging and Implications . 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]. Meanwhile, IPC-treated astrocytes significantly enhanced lactate secretion into the extracellular media. 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]. Ischemic Penumbra | STROKE MANUAL Ischemic penumbra | Radiology Reference Article | Radiopaedia.org An untargeted metabolomics study has revealed that -hydroxybutyrate (-HB) stands out as highly significantly upregulated after IPC [78], while previous studies have shown that an elevation in the cytosolic NADH/NAD+ ratio would promote -HB formation. Targeting the Ischemic Penumbra | Stroke the ischemic penumbra can maintain metabolic demand with marginal blood flow from collateral circulation for a maximum of __ before increasing in size? Before Ying W.H., Wei G.W., Wang D.M., Wang Q., Tang X.N., Shi J., Zhang P., Lu H.F. Intranasal administration with NAD+ profoundly decreases brain injury in a rat model of transient focal ischemia. Ardito S., Oudin A., Ahmed S.U., Fack F., Keunen O., Zheng L., Miletic H., Sakariassen P.., Weinstock A., Wagner A., et al. 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]. Efficacy of remote ischemic conditioning on improving WMHs and cognition in very elderly patients with intracranial atherosclerotic stenosis. Reduced Nicotinamide Adenine Dinucleotide Phosphate, a Pentose Phosphate Pathway Product, Might Be a Novel Drug Candidate for Ischemic Stroke. 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. Direct NAD+ repletion, either in animal or in cultured neurons, markedly reduced ischemic cell death and DNA damage [32,33]. Effects of ischemic preconditioning on mitochondrial and metabolic neruoprotection: 5 adenosine monophosphate-activated protein kinase and sirtuins. In 2014, Gary used laser desorptionionization mass (LDI/MS) spectrometry to create maps of the spatial distributions of glutamine, DHA, and other metabolites across the brain and within each sub-region [87]. Metabolic reprogramming by ischemic preconditioning (IPC). 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. Ischemic Penumbra: Evidence From Functional Imaging in Man IPC is neuroprotective for ischemic stroke, but the precise mechanisms through which it exerts protection against ischemic insults remain unclear at present.