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Metabolites
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Biochemical and Physiological Perspectives of Brain Energy Metabolism
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Biochemical and Physiological Perspectives of Brain Energy Metabolism

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Advances in Metabolomics".

Deadline for manuscript submissions: closed (15 October 2022) | Viewed by 16845

Special Issue Editor

Prof. Dr. Avital Schurr

E-Mail Website
Guest Editor
School of Medicine, University of Louisville, Louisville, KY, USA
Interests: brain energy metabolism; cerebral ischemia; glycolysis; mitochondrial transport; neuroprotection

Special Issue Information

Dear Colleagues,

Over the past three decades we have gained a great deal of knowledge and understanding of the cellular processes  involved in brain energy metabolism. From the discovery that lactate is an oxidative energy substrate for neuronal function to the operation of inter-lactate shuttle between astrocytes and neurons and intra-lactate shuttle between the cytosol and mitochondria; from the presence of monocarboxylate transporters in brain cell and mitochondrial membranes to the  possible existence of a lactate receptor in the brain. Consequently, we are better equipped today to explore the possible changes in these processes that could be responsible for myriad brain disorders and diseases. Hence, this Special Isssue will include, but will not be limited to: Brain energy metabolic pathways; inter- and intra-cellular transporting and shuttling of metabolites; the role such metabolites may play in cellular signaling; energy metabolic processes of CNS disorders and diseases such as cancer, cerebral ischemia, Amyotrophic Lateral Sclerosis (ALS), Alzheimer Disease, Traumatic Brain Injury (TBI) and the potential pharmacological and other treatments to alleviate and/or cure them. Last, but not least, this issue will include methods and techniques for the measurement of CNS cellular metabolism under physiological and disease conditions.

Prof. Dr. Avital Schurr
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Central Nervous System (CNS)
  • cellular neuroenergetics
  • glycolysis
  • oxidative phosphorylation
  • lactate
  • metabolite transport
  • mitochondrial transport
  • shuttles
  • NAD+/NADH
  • CNS disorders
  • neuroprotection
  • functional brain imaging

Published Papers (7 papers)

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Research

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15 pages, 2839 KiB  
Article
Metabolism of Exogenous [2,4-13C]β-Hydroxybutyrate following Traumatic Brain Injury in 21-22-Day-Old Rats: An Ex Vivo NMR Study
by Susanna Scafidi, Jennifer Jernberg, Gary Fiskum and Mary C. McKenna
Metabolites 2022, 12(8), 710; https://doi.org/10.3390/metabo12080710 - 29 Jul 2022
Cited by 4 | Viewed by 1647
Abstract
Traumatic brain injury (TBI) is leading cause of morbidity in young children. Acute dysregulation of oxidative glucose metabolism within the first hours after injury is a hallmark of TBI. The developing brain relies on ketones as well as glucose for energy. Thus, the [...] Read more.
Traumatic brain injury (TBI) is leading cause of morbidity in young children. Acute dysregulation of oxidative glucose metabolism within the first hours after injury is a hallmark of TBI. The developing brain relies on ketones as well as glucose for energy. Thus, the aim of this study was to determine the metabolism of ketones early after TBI injury in the developing brain. Following the controlled cortical impact injury model of TBI, 21-22-day-old rats were infused with [2,4-13C]β-hydroxybutyrate during the acute (4 h) period after injury. Using ex vivo 13C-NMR spectroscopy, we determined that 13C-β-hydroxybutyrate (13C-BHB) metabolism was increased in both the ipsilateral and contralateral sides of the brain after TBI. Incorporation of the label was significantly higher in glutamate than glutamine, indicating that 13C-BHB metabolism was higher in neurons than astrocytes in both sham and injured brains. Our results show that (i) ketone metabolism was significantly higher in both the ipsilateral and contralateral sides of the injured brain after TBI; (ii) ketones were extensively metabolized by both astrocytes and neurons, albeit higher in neurons; (iii) the pyruvate recycling pathway determined by incorporation of the label from the metabolism of 13C-BHB into lactate was upregulated in the immature brain after TBI. Full article
(This article belongs to the Special Issue Biochemical and Physiological Perspectives of Brain Energy Metabolism)
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13 pages, 2657 KiB  
Article
Energy Metabolism in Mouse Sciatic Nerve A Fibres during Increased Energy Demand
by Laura R. Rich, Bruce R. Ransom and Angus M. Brown
Metabolites 2022, 12(6), 505; https://doi.org/10.3390/metabo12060505 - 31 May 2022
Cited by 2 | Viewed by 1331
Abstract
The ability of sciatic nerve A fibres to conduct action potentials relies on an adequate supply of energy substrate, usually glucose, to maintain necessary ion gradients. Under our ex vivo experimental conditions, the absence of exogenously applied glucose triggers Schwann cell glycogen metabolism [...] Read more.
The ability of sciatic nerve A fibres to conduct action potentials relies on an adequate supply of energy substrate, usually glucose, to maintain necessary ion gradients. Under our ex vivo experimental conditions, the absence of exogenously applied glucose triggers Schwann cell glycogen metabolism to lactate, which is transported to axons to fuel metabolism, with loss of the compound action potential (CAP) signalling glycogen exhaustion. The CAP failure is accelerated if tissue energy demand is increased by high-frequency stimulation (HFS) or by blocking lactate uptake into axons using cinnemate (CIN). Imposing HFS caused CAP failure in nerves perfused with 10 mM glucose, but increasing glucose to 30 mM fully supported the CAP and promoted glycogen storage. A combination of glucose and lactate supported the CAP more fully than either substrate alone, indicating the nerve is capable of simultaneously metabolising each substrate. CAP loss resulting from exposure to glucose-free artificial cerebrospinal fluid (aCSF) could be fully reversed in the absence of glycogen by addition of glucose or lactate when minimally stimulated, but imposing HFS resulted in only partial CAP recovery. The delayed onset of CAP recovery coincided with the release of lactate by Schwann cells, suggesting that functional Schwann cells are a prerequisite for CAP recovery. Full article
(This article belongs to the Special Issue Biochemical and Physiological Perspectives of Brain Energy Metabolism)
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9 pages, 1534 KiB  
Article
Lactate Neuroprotection against Transient Ischemic Brain Injury in Mice Appears Independent of HCAR1 Activation
by Lara Buscemi, Melanie Price, Julia Castillo-González, Jean-Yves Chatton and Lorenz Hirt
Metabolites 2022, 12(5), 465; https://doi.org/10.3390/metabo12050465 - 21 May 2022
Cited by 7 | Viewed by 2155
Abstract
Lactate can protect against damage caused by acute brain injuries both in rodents and in human patients. Besides its role as a metabolic support and alleged preferred neuronal fuel in stressful situations, an additional signaling mechanism mediated by the hydroxycarboxylic acid receptor 1 [...] Read more.
Lactate can protect against damage caused by acute brain injuries both in rodents and in human patients. Besides its role as a metabolic support and alleged preferred neuronal fuel in stressful situations, an additional signaling mechanism mediated by the hydroxycarboxylic acid receptor 1 (HCAR1) was proposed to account for lactate’s beneficial effects. However, the administration of HCAR1 agonists to mice subjected to middle cerebral artery occlusion (MCAO) at reperfusion did not appear to exert any relevant protective effect. To further evaluate the involvement of HCAR1 in the protection against ischemic damage, we looked at the effect of HCAR1 absence. We subjected wild-type and HCAR1 KO mice to transient MCAO followed by treatment with either vehicle or lactate. In the absence of HCAR1, the ischemic damage inflicted by MCAO was less pronounced, with smaller lesions and a better behavioral outcome than in wild-type mice. The lower susceptibility of HCAR1 KO mice to ischemic injury suggests that lactate-mediated protection is not achieved or enhanced by HCAR1 activation, but rather attributable to its metabolic effects or related to other signaling pathways. Additionally, in light of these results, we would disregard HCAR1 activation as an interesting therapeutic strategy for stroke patients. Full article
(This article belongs to the Special Issue Biochemical and Physiological Perspectives of Brain Energy Metabolism)
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Review

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22 pages, 4561 KiB  
Review
Monitoring Neurochemistry in Traumatic Brain Injury Patients Using Microdialysis Integrated with Biosensors: A Review
by Chisomo Zimphango, Farah C. Alimagham, Keri L. H. Carpenter, Peter J. Hutchinson and Tanya Hutter
Metabolites 2022, 12(5), 393; https://doi.org/10.3390/metabo12050393 - 26 Apr 2022
Cited by 8 | Viewed by 3777
Abstract
In a traumatically injured brain, the cerebral microdialysis technique allows continuous sampling of fluid from the brain’s extracellular space. The retrieved brain fluid contains useful metabolites that indicate the brain’s energy state. Assessment of these metabolites along with other parameters, such as intracranial [...] Read more.
In a traumatically injured brain, the cerebral microdialysis technique allows continuous sampling of fluid from the brain’s extracellular space. The retrieved brain fluid contains useful metabolites that indicate the brain’s energy state. Assessment of these metabolites along with other parameters, such as intracranial pressure, brain tissue oxygenation, and cerebral perfusion pressure, may help inform clinical decision making, guide medical treatments, and aid in the prognostication of patient outcomes. Currently, brain metabolites are assayed on bedside analysers and results can only be achieved hourly. This is a major drawback because critical information within each hour is lost. To address this, recent advances have focussed on developing biosensing techniques for integration with microdialysis to achieve continuous online monitoring. In this review, we discuss progress in this field, focusing on various types of sensing devices and their ability to quantify specific cerebral metabolites at clinically relevant concentrations. Important points that require further investigation are highlighted, and comments on future perspectives are provided. Full article
(This article belongs to the Special Issue Biochemical and Physiological Perspectives of Brain Energy Metabolism)
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Other

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11 pages, 791 KiB  
Protocol
Fractional Gluconeogenesis: A Biomarker of Dietary Energy Adequacy in a Rat Brain Injury Model
by Casey C. Curl, Anika Kumar, Austin J. Peck, Jose A. Arevalo, Allison Gleason, Robert G. Leija, Adam D. Osmond, Justin J. Duong, Benjamin F. Miller, Michael A. Horning and George A. Brooks
Metabolites 2022, 12(12), 1163; https://doi.org/10.3390/metabo12121163 - 23 Nov 2022
Cited by 1 | Viewed by 1385
Abstract
Patients treated for traumatic brain injury (TBI) are in metabolic crises because of the trauma and underfeeding. We utilized fractional gluconeogenesis (fGNG) to assess nutritional adequacy in ad libitum-fed and calorically-restricted rats following TBI. Male Sprague–Dawley individually housed rats 49 days of age [...] Read more.
Patients treated for traumatic brain injury (TBI) are in metabolic crises because of the trauma and underfeeding. We utilized fractional gluconeogenesis (fGNG) to assess nutritional adequacy in ad libitum-fed and calorically-restricted rats following TBI. Male Sprague–Dawley individually housed rats 49 days of age were randomly assigned into four groups: ad libitum (AL) fed control (AL-Con, sham), AL plus TBI (AL+TBI), caloric restriction (CR) control (CR-Con, sham), and CR plus TBI (CR+TBI). From days 1–7 animals were given AL access to food and water containing 6% deuterium oxide (D2O). On day 8, a pre-intervention blood sample was drawn from each animal, and TBI, sham injury, and CR protocols were initiated. On day 22, the animals were euthanized, and blood was collected to measure fGNG. Pre-intervention, there was no significant difference in fGNG among groups (p ≥ 0.05). There was a significant increase in fGNG due to caloric restriction, independent of TBI (p ≤ 0.05). In addition, fGNG may provide a real-time, personalized biomarker for assessing patient dietary caloric needs. Full article
(This article belongs to the Special Issue Biochemical and Physiological Perspectives of Brain Energy Metabolism)
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9 pages, 287 KiB  
Opinion
Should We Void Lactate in the Pathophysiology of Delayed Onset Muscle Soreness? Not So Fast! Let’s See a Neurocentric View!
by Balázs Sonkodi
Metabolites 2022, 12(9), 857; https://doi.org/10.3390/metabo12090857 - 13 Sep 2022
Cited by 13 | Viewed by 2928
Abstract
The pathophysiology of delayed onset muscle soreness is not entirely known. It seems to be a simple, exercise-induced delayed pain condition, but has remained a mystery for over 120 years. The buildup of lactic acid used to be blamed for muscle fatigue and [...] Read more.
The pathophysiology of delayed onset muscle soreness is not entirely known. It seems to be a simple, exercise-induced delayed pain condition, but has remained a mystery for over 120 years. The buildup of lactic acid used to be blamed for muscle fatigue and delayed onset muscle soreness; however, studies in the 1980s largely refuted the role of lactate in delayed onset muscle soreness. Regardless, this belief is widely held even today, not only in the general public, but within the medical and scientific community as well. Current opinion is highlighting lactate’s role in delayed onset muscle soreness, if neural dimension and neuro-energetics are not overlooked. By doing so, lactate seems to have an essential role in the initiation of the primary damage phase of delayed onset muscle soreness within the intrafusal space. Unaccustomed or strenuous eccentric contractions are suggested to facilitate lactate nourishment of proprioceptive sensory neurons in the muscle spindle under hyperexcitation. However, excessive acidosis and lactate could eventually contribute to impaired proprioception and increased nociception under pathological condition. Furthermore, lactate could also contribute to the secondary damage phase of delayed onset muscle soreness in the extrafusal space, primarily by potentiating the role of bradykinin. After all, neural interpretation may help us to dispel a 40-year-old controversy about lactate’s role in the pathophysiology of delayed onset muscle soreness. Full article
(This article belongs to the Special Issue Biochemical and Physiological Perspectives of Brain Energy Metabolism)
11 pages, 668 KiB  
Opinion
Aerobic Glycolysis: A DeOxymoron of (Neuro)Biology
by Avital Schurr and Salvatore Passarella
Metabolites 2022, 12(1), 72; https://doi.org/10.3390/metabo12010072 - 13 Jan 2022
Cited by 7 | Viewed by 2442
Abstract
The term ‘aerobic glycolysis’ has been in use ever since Warburg conducted his research on cancer cells’ proliferation and discovered that cells use glycolysis to produce adenosine triphosphate (ATP) rather than the more efficient oxidative phosphorylation (oxphos) pathway, despite an abundance of oxygen. [...] Read more.
The term ‘aerobic glycolysis’ has been in use ever since Warburg conducted his research on cancer cells’ proliferation and discovered that cells use glycolysis to produce adenosine triphosphate (ATP) rather than the more efficient oxidative phosphorylation (oxphos) pathway, despite an abundance of oxygen. When measurements of glucose and oxygen utilization by activated neural tissue indicated that glucose was consumed without an accompanied oxygen consumption, the investigators who performed those measurements also termed their discovery ‘aerobic glycolysis’. Red blood cells do not contain mitochondria and, therefore, produce their energy needs via glycolysis alone. Other processes within the central nervous system (CNS) and additional organs and tissues (heart, muscle, and so on), such as ion pumps, are also known to utilize glycolysis only for the production of ATP necessary to support their function. Unfortunately, the phenomenon of ‘aerobic glycolysis’ is an enigma wherever it is encountered, thus several hypotheses have been produced in attempts to explain it; that is, whether it occurs in cancer cells, in activated neural tissue, or during postprandial or exercise metabolism. Here, it is argued that, where the phenomenon in neural tissue is concerned, the prefix ‘aerobic’ in the term ‘aerobic glycolysis’ should be removed. Data collected over the past three decades indicate that L-lactate, the end product of the glycolytic pathway, plays an essential role in brain energy metabolism, justifying the elimination of the prefix ‘aerobic’. Similar justification is probably appropriate for other tissues as well. Full article
(This article belongs to the Special Issue Biochemical and Physiological Perspectives of Brain Energy Metabolism)
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