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]. Rothman D.L., Behar K.L., Hyder F. In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: Implications for brain function. Through neuronal, humoral, and immunological pathways, IPC confers protection against subsequent, more severe, and lethal ischemia. 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]. 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. NAD+ levels and the NAD+/NADH redox couple provide a readout and regulator for cellular energy metabolism [30]. Studies have revealed that inhibitors of ferroptosis, such as ferrostatins, carvacrol, and liproxstatins, could protect against cerebral ischemic injury in rodent models [43,48]. 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]. 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]. Metabolomic Profiling Reveals That Reprogramming of Cerebral Glucose Metabolism is Involved in Ischemic Preconditioning Induced Neuroprotection in a Rodent Model of Ischemic Stroke. In the absence of glutamine (or when glutaminolysis is inhibited), cystine starvation and ferroptosis occur. 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. Intriguing, the protective effect of IPC can be mimicked pharmacologically. 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. 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. There are two major affected zones in an ischemic brain: The infarct core, surrounded by an ischemic penumbra. 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]. (Stroke. Wang G.S., Tong D.M., Chen X.D., Yang T.H., Zhou Y.T., Ma X.B. The .gov means its official. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. This pathway can produce precursors to synthesize nucleotides and aromatic amino acids, generating cytosolic NADPH simultaneously [30]. The brain is an unusual organ, having the highest metabolic activity and energy requirement by mass. Polyzos A.A., Lee D.Y., Datta R., Hauser M., Budworth H., Holt A., Mihalik S., Goldschmidt P., Frankel K., Trego K., et al. To enhance energy reserves, IPC improves mitochondrial efficiency for cellular energy metabolism, boosts glycolysis, and stockpiles and utilizes alternative energy substrates. In the early phase, tissues benefit within minutes of IPC intervention, lasting for 23 h, while the late phase occurs at 1224 h and lasts for 23 days. When the CBF is below 10 mL/100 g per minute, irreversible cellular injury will occur, and the infarct core forms [10]. Bouzat P., Sala N., Suys T., Zerlauth J.B. Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain. The role of ketone bodies in caloric homeostasis. At a practical level, however, this definition is unwieldy. Proteomic analysis of pharmacological preconditioning. An increased understanding of the pathogenic mechanisms of stroke and IPC serves to highlight the importance of metabolic reprogramming. Noteworthy, at the early ischemia-reperfusion (I/R) phase, the impaired mitochondrial function was attenuated by IPC and mediated by adenosine A1 receptors [91,92]. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Ischemic preconditioning treatment of astrocytes transfers ischemic tolerance to neurons. In remote IPC, inflation of a blood-pressure cuff on the arm or leg is used [8]. 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. It has been implied that the neuroprotective ability of IPC may be related with the promotion of ANLS, where lactate serves as a potential agent to protect neurons against lethal ischemic injury. Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. However, in response to changes in the micro-environment, metabolic reprogramming is notably crucial to maintaining metabolic homeostasis. In the ischemic penumbra, a further decrease in CBF leads to neuronal electrical silence and a synaptic activity decrease to preserve energy stores, while energy metabolism is partially preserved to transiently sustain tissue viability. Preservation of the IPC phenotype implicated a unifying endogenous mechanism, possibly involving energy and redox homeostasis maintenance. Rapid NAD+ depletion inevitably disrupts intracellular energy homeostasis. 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 . Hatten M.E. Together, effective IPC metabolic reprogramming may happen and be assumed to sustain during the early and late phases of IPC. L-Carnitine: The level of lysine in human CSF increases following IPC [75]. However, continuing ischemic stress, or additional energy demanding episodes, or both, will exhaust this limited capacity and transform penumbra into necrotic tissue. As the main product of the oxidative PPP (oxPPP), NADPH provides the essential redox equivalent for GSH regeneration, enhancing the antioxidant defense capacity. 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. Ischaemic conditioning and reperfusion 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. 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. To the best of our knowledge, no study has assessed whether IPC affects the oxygen delivery ability of erythrocytes. Thus, we propose that mitophagy could be developed as an effective and potential target for the treatment of ischemic stroke. Whereas in the delayed or the second protect phase of IPC, the brain is again ischemia-tolerant [93]. 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]. 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]. Stroke is one of the leading causes of death and permanent disability worldwide. Banks M.A., Porter D.W., Martin W.G., Castranova V. Ozone-induced lipid-peroxidation and membrane leakage in isolated rat alveolar macrophages- protective effects of taurine. Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice. Meanwhile, exogenous supplementation of lactate has shown remarkable effects in traumatic brain injury therapy [23]. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. In: Murphy S., editor. Therefore, given the critical role of these organelles in disease onset and progression, strategies . Erythrocytes are the only cell type responsible for delivering oxygen. Metabolic Syndrome Is a Strong Risk Factor for Minor Ischemic Stroke and Subsequent Vascular Events. 1 and represented an important milestone for understanding the temporal and spatial evolution of focal ischemic brain injury. 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]. 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. Article. Mitochondria-derived reactive oxygen species dilate cerebral arteries by activating Ca. Mitochondrial Mechanisms of Neuronal Cell Death: Potential Therapeutics. In the brain, astrocytes can also generate ketone bodies from fatty acid -oxidation. 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. Bethesda, MD 20894, Web Policies The ischemic penumbra can maintain metabolic demand with marginal blood flow from collateral circulation for a maximum of _____ before increasing in size. (2) Excitotoxicity. ); nc.ude.aaub@9102gnorgnornah (R.H.), 2School of Engineering Medicine, Beihang University, Beijing 100191, China. However, the underlying neuroprotection mechanisms of IPC remain elusive. Mitochondria are signaling, bioenergetic, and biosynthetic organelles. Dawson T.M., Dawson V.L. The ischemic penumbra has been in the center of ischemic stroke research for the last 40 years. One study showed that neurons made specific metabolic adaptations following IPC (transient OGD) with the regulation of oxygen utilization and lactate production [100]. Here we provide a summary of metabolic mechanism of ischemic preconditioning when it is applied to ischemic stroke. 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). confirmed this: In a Huntington model, they discovered region-specific metabolic reprogramming of astrocytes, which directly induced neuronal susceptibility. 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. Hess D.C., Blauenfeldt R.A., Andersen G., Hougaard K.D., Hoda M.N., Ding Y., Ji X. Mechanisms underlying neuronal death in ischemic stroke (1) Mitochondrial response, including excessive ROS production, mitochondrial calcium overloading, and disrupted mitochondria quality control. MetS patients had a 3.542-fold increased odds ratio (OR) for cognitive impairment. Sato H., Nomura S., Maebara K., Sato K., Tamba M., Bannai S. Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. As a library, NLM provides access to scientific literature. This refinement has potential therapeutic implications.