ischemic penumbra metabolic demand

• 8 September 2023

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. 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. This described evidence highlights the capability of IPC in improving mitochondrial efficiency and regulating the reprogramming processes related to mitochondrial function and cellular metabolism. Together, effective IPC metabolic reprogramming may happen and be assumed to sustain during the early and late phases of IPC. Ischemic Penumbra: Evidence From Functional Imaging in Man found that ketone treatment in mice at 30 min after ischemia enhanced mitochondrial function, reduced oxidative stress and, therefore, reduced infarct volume [49]. Furthermore, the level of glycolytic products of lactate in CSF was found to be decreased following IPC [75]. It is well-known that lysine, being an energy-providing amino acid, is necessary for the biosynthesis of L-carnitine. Therefore, given the critical role of these organelles in disease onset and progression, strategies . FOIA Berthet C., Lei H.T., Thevenet J., Gruetter R. Neuroprotective role of lactate after cerebral ischemia. Third, iron deficiency has been associated with an increased risk of ischemic stroke [46]. National Library of Medicine Zong W.X., Rabinowitz J.D., White E. Mitochondria and Cancer. The brain is an unusual organ, having the highest metabolic activity and energy requirement by mass. To the best of our knowledge, no study has assessed whether IPC affects the oxygen delivery ability of erythrocytes. 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). It has been found that direct administration of NADPH can significantly reduce infarct volume, improving post-stroke survival and neurological function recovery in mouse and rat stroke models, with a remarkable increase in the level of the reduced form of glutathione (GSH), while decreasing ROS levels [41]. In 2020, Per E. Andrn et al. Thus, we propose that mitophagy could be developed as an effective and potential target for the treatment of ischemic stroke. Ischemic preconditioning treatment of astrocytes transfers ischemic tolerance to neurons. Sato H., Nomura S., Maebara K., Sato K., Tamba M., Bannai S. Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. Morris-Blanco K.C., Cohan C.H., Neumann J.T., Sick T.J., Perez-Pinzon M.A. ischemic penumbra as a biochemical target (intermittent bioenergetic compromise); (3) the ischemic penumbra as a . Laursen M.R., Hansen J., Elkjaer C., Stavnager N., Nielsen C.B., Pryds K., Johnsen J., Nielsen J.M., Botker H.E., Johannsen M. Untargeted metabolomics reveals a mild impact of remote ischemic conditioning on the plasma metabolome and alpha-hydroxybutyrate as a possible cardioprotective factor and biomarker of tissue ischemia. Oxygen is a crucial substrate in metabolism. Metabolic disorder and metabolic plasticity in ischemic stroke: Upon ischemia onset, a sharp reduction of regional CBF results in oxygen and glucose deprivation, followed by excess excitatory and bloodbrain barrier dysfunction. Ham P.B., Raju R. Mitochondrial function in hypoxic ischemic injury and influence of aging. The concept of the ischemic penumbra was initially proposed by Astrup et al. 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]. 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. 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. These include: NADP+/NADPH. 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. Lactate: Brain fuel in human traumatic brain injury: A comparison with normal healthy control subjects. Dawson T.M., Dawson V.L. (Stroke. MetS patients had a 3.542-fold increased odds ratio (OR) for cognitive impairment. Lemasters J. Significantly lower levels of glutamine and glycine in CSF following IPC have been observed [75], indicating that the replenishment of GSH is accelerated, eventually imposing reductive stress in the ischemic brain tissue. An official website of the United States government. 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. 1 and represented an important milestone for understanding the temporal and spatial evolution of focal ischemic brain injury. 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. Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases. Organic Acids. Iron-Deficiency and Estrogen Are Associated with Ischemic Stroke by Up-Regulating Transferrin to Induce Hypercoagulability. 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). To defend against oxidative stress, cells have developed complex systems that exploit and defend against this dilemma. Meng R., Asmaro K., Meng L., Liu Y., Ma C., Xi C., Li G., Ren C., Luo Y., Ling F., et al. 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). Tang X., Fang M., Cheng R., Zhang Z., Wang Y., Shen C., Han Y., Lu Q., Du Y., Liu Y., et al. In the brain, astrocytes can also generate ketone bodies from fatty acid -oxidation. sharing sensitive information, make sure youre on a federal (2014) Multi-parametric imaging of cerebral hemodynamic and metabolic response followed by ischemic injury . One study showed that neurons made specific metabolic adaptations following IPC (transient OGD) with the regulation of oxygen utilization and lactate production [100]. Notably, neurons and astrocytes preferentially use quite different metabolic pathways in physiological conditions [98]. Collaterals are demonstrated to be strong predictors of both response to endovascular therapy and functional outcomes [11]. Inclusion in an NLM database does not imply endorsement of, or agreement with, 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]. 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. 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. Hou W., Xie Y., Song X., Sun X., Lotze M.T., Zeh H.J., Tang D. Autophagy promotes ferroptosis by degradation of ferritin. Intriguing, the protective effect of IPC can be mimicked pharmacologically. Wu Y., Zhang S., Gong X., Tam S., Xiao D., Liu S., Tao Y. A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. 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. Mitochondria are major contributors to cellular ROS, and there are multiple antioxidant pathways to neutralize ROS, including superoxide dismutase (SOD2), glutathione, thioredoxin, and peroxiredoxins. Mitophagy is also essential in sustaining mitochondrial homeostasis, biogenesis, and the total number and quality of mitochondria. 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]. NAMPT as a Therapeutic Target against Stroke. 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. 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.

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