bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2024–10–06
fiveteen papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Metabolic preferences of astrocytes: Functional metabolic mapping reveals butyrate outcompetes acetate.
  2. Classic ketogenic diet-induced ketoacidosis in the treatment of pyruvate dehydrogenase deficiency: a case report and literature review.
  3. Glucose metabolism impairment as a hallmark of progressive myoclonus epilepsies: a focus on neuronal ceroid lipofuscinoses.
  4. Neuronal lipid droplets play a conserved and sex-biased role in maintaining whole-body energy homeostasis.
  5. Metabolic impairments in neurodegeneration with brain iron accumulation.
  6. Measuring cerebral enzymatic activity, brain pH and extracranial muscle metabolism with hyperpolarized 13C-pyruvate.
  7. Analysis of the Mammalian Lipidome by DMS Shotgun Lipidomics.
  8. Developmental maturation and regional heterogeneity but no sexual dimorphism of the murine CNS myelin proteome.
  9. Astrocyte-neuron crosstalk in neurodevelopmental disorders.
  10. Neonatal wellbeing and timing of brain injury in term and late preterm cerebral palsy.
  11. Findings from the individualized management of a patient with Acyl-CoA Oxidase-1 (ACOX1) deficiency: A bedside-to-bench-to-bedside strategy.
  12. Lipid metabolism: Novel approaches for managing idiopathic epilepsy.
  13. Prenatal exposure to undernutrition is associated with a specific lipid profile predicting future brain aging.
  14. The role of PINK1-Parkin in mitochondrial quality control.
  15. Neuroregeneration Improved by Sodium-D,L-Beta-Hydroxybutyrate in Primary Neuronal Cultures.
  1. J Cereb Blood Flow Metab. 2024 Sep 28. 271678X241270457
    Metabolic preferences of astrocytes: Functional metabolic mapping reveals butyrate outcompetes acetate.
    Aishat O Ameen, Sebastian W Nielsen, Martin W Kjær, Jens V Andersen, Emil W Westi, Kristine K Freude, Blanca I Aldana.
      Disruptions to the gut-brain-axis have been linked to neurodegenerative disorders. Of these disruptions, reductions in the levels of short-chain fatty acids (SCFAs), like butyrate, have been observed in mouse models of Alzheimer's disease (AD). Butyrate supplementation in mice has shown promise in reducing neuroinflammation, amyloid-β accumulation, and enhancing memory. However, the underlying mechanisms remain unclear. To address this, we investigated the impact of butyrate on energy metabolism in mouse brain slices, primary cultures of astrocytes and neurons and in-vivo by dynamic isotope labelling with [U-13C]butyrate and [1,2-13C]acetate to map metabolism via mass spectrometry. Metabolic competition assays in cerebral cortical slices revealed no competition between butyrate and the ketone body, β-hydroxybutyrate, but competition with acetate. Astrocytes favoured butyrate metabolism compared to neurons, suggesting that the astrocytic compartment is the primary site of butyrate metabolism. In-vivo metabolism investigated in the 5xFAD mouse, an AD pathology model, showed no difference in 13C-labelling of TCA cycle metabolites between wild-type and 5xFAD brains, but butyrate metabolism remained elevated compared to acetate in both groups, indicating sustained uptake and metabolism in 5xFAD mice. Overall, these findings highlight the role of astrocytes in butyrate metabolism and the potential use of butyrate as an alternative brain fuel source.
    Keywords:  Alzheimer’s disease; astrocytes; brain energy metabolism; gut-brain axis; short-chain fatty acids
    DOI:  https://doi.org/10.1177/0271678X241270457
  2. BMC Pediatr. 2024 Sep 28. 24(1): 603
    Classic ketogenic diet-induced ketoacidosis in the treatment of pyruvate dehydrogenase deficiency: a case report and literature review.
    Rongrong Li, Mingsheng Ma, Wei Chen, Zhengqing Qiu.
       BACKGROUND: As a rare mitochondrial disorder, the pyruvate dehydrogenase complex (PDC) deficiency is a rare inborn disease characterized with glucose metabolism defects, which leads to neurological dysfunction, serum lactic acid buildup and a resultant trend of metabolic acidosis. Although the ketogenic diet (KD) is the first-line treatment for PDC deficiency, there is currently no widely accepted consensus on specific implementation of KD for this condition. Due to the combined effect of pre-existing hyperlactacidemia and KD-induced ketoacidosis that can further exacerbate metabolic disturbances, maintaining metabolic homeostasis should be prioritized during the implementation of KD.
    CASE PRESENTATION: Herein, the authors present a 6-year-old boy with lactic acidosis, ataxia, hypotonia and neuromotor development retardation. The KD was started after the patient was diagnosed with PDC deficiency based on genetic testing. The initiation with classic KD resulted in severe non-diabetic ketoacidosis with elevated anion gap, which was promptly alleviated by dextrose supplementation and dietary modification to a less-restrictive KD. Long-term supervision demonstrated the efficacy of a modified KD in improving both clinical course and metabolic acidosis of the patient.
    CONCLUSIONS: This rare case adds to the limited evidence of KD application in PDC deficiency, and provides valuable insights into the importance of reasonably lowering the ketogenic ratio of KD at the start of treatment to reduce the risk of metabolic acidosis.
    Keywords:  Acidosis; Ketogenic diet; Lactic acid; Non-diabetic ketoacidosis; Pyruvate dehydrogenase complex deficiency
    DOI:  https://doi.org/10.1186/s12887-024-05054-w
  3. Front Cell Neurosci. 2024 ;18 1445003
    Glucose metabolism impairment as a hallmark of progressive myoclonus epilepsies: a focus on neuronal ceroid lipofuscinoses.
    Lorenzo Santucci, Sara Bernardi, Rachele Vivarelli, Filippo Maria Santorelli, Maria Marchese.
      Glucose is the brain's main fuel source, used in both energy and molecular production. Impaired glucose metabolism is associated with adult and pediatric neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), GLUT1 deficiency syndrome, and progressive myoclonus epilepsies (PMEs). PMEs, a group of neurological disorders typical of childhood and adolescence, account for 1% of all epileptic diseases in this population worldwide. Diffuse glucose hypometabolism is observed in the brains of patients affected by PMEs such as Lafora disease (LD), dentatorubral-pallidoluysian (DRPLA) atrophy, Unverricht-Lundborg disease (ULD), and myoclonus epilepsy with ragged red fibers (MERRFs). PMEs also include neuronal ceroid lipofuscinoses (NCLs), a subgroup in which lysosomal and autophagy dysfunction leads to progressive loss of vision, brain atrophy, and cognitive decline. We examine the role of impaired glucose metabolism in neurodegenerative diseases, particularly in the NCLs. Our literature review, which includes findings from case reports and animal studies, reveals that glucose hypometabolism is still poorly characterized both in vitro and in vivo in the different NCLs. Better identification of the glucose metabolism pathway impaired in the NCLs may open new avenues for evaluating the therapeutic potential of anti-diabetic agents in this population and thus raise the prospect of a therapeutic approach able to delay or even halt disease progression.
    Keywords:  anti-diabetics; glucose metabolism; neurodegeneration; neuronal ceroid lipofuscinosis; progressive myoclonic epilepsies
    DOI:  https://doi.org/10.3389/fncel.2024.1445003
  4. bioRxiv. 2024 Sep 20. pii: 2024.09.19.613929. [Epub ahead of print]
    Neuronal lipid droplets play a conserved and sex-biased role in maintaining whole-body energy homeostasis.
    Romane Manceau, Danie Majeur, Celena M Cherian, Colin J Miller, Lianna W Wat, Jasper D Fisher, Audrey Labarre, Serena Hollman, Sanjana Prakash, Sébastien Audet, Charlotte F Chao, Lewis Depaauw-Holt, Benjamin Rogers, Anthony Bosson, Joyce J Y Xi, Catrina A S Callow, Niyoosha Yoosefi, Niki Shahraki, Yi Han Xia, Alisa Hui, Jared VanderZwaag, Khalil Bouyakdan, Demetra Rodaros, Pavel Kotchetkov, Caroline Daneault, Ghazal Fallahpour, Martine Tetreault, Marie-Ève Tremblay, Matthieu Ruiz, Baptiste Lacoste, J A Parker, Ciaran Murphy-Royal, Tao Huan, Stephanie Fulton, Elizabeth J Rideout, Thierry Alquier.
      Lipids are essential for neuron development and physiology. Yet, the central hubs that coordinate lipid supply and demand in neurons remain unclear. Here, we combine invertebrate and vertebrate models to establish the presence and functional significance of neuronal lipid droplets (LD) in vivo . We find that LD are normally present in neurons in a non-uniform distribution across the brain, and demonstrate triglyceride metabolism enzymes and lipid droplet-associated proteins control neuronal LD formation through both canonical and recently-discovered pathways. Appropriate LD regulation in neurons has conserved and male-biased effects on whole-body energy homeostasis across flies and mice, specifically neurons that couple environmental cues with energy homeostasis. Mechanistically, LD-derived lipids support neuron function by providing phospholipids to sustain mitochondrial and endoplasmic reticulum homeostasis. Together, our work identifies a conserved role for LD as the organelle that coordinates lipid management in neurons, with implications for our understanding of mechanisms that preserve neuronal lipid homeostasis and function in health and disease.
    HIGHLIGHTS: Lipid droplets (LD) normally form in neurons across species Neuronal LD are regulated by a conserved gene networkNeuronal LD regulation plays a conserved and sex-biased role in maintaining energy homeostasisLD regulation supports ER and mitochondrial function in hunger-activated neurons.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.1101/2024.09.19.613929
  5. Biochim Biophys Acta Bioenerg. 2024 Oct 02. pii: S0005-2728(24)00487-0. [Epub ahead of print] 149517
    Metabolic impairments in neurodegeneration with brain iron accumulation.
    Agata Wydrych, Barbara Pakuła, Justyna Janikiewicz, Aneta M Dobosz, Patrycja Jakubek-Olszewska, Marta Skowrońska, Iwona Kurkowska-Jastrzębska, Maciej Cwyl, Mariola Popielarz, Paolo Pinton, Barbara Zavan, Agnieszka Dobrzyń, Magdalena Lebiedzińska-Arciszewska, Mariusz R Więckowski.
      Neurodegeneration with brain iron accumulation (NBIA) is a broad, heterogeneous group of rare inherited diseases (1-3 patients/1,000,000 people) characterized by progressive symptoms associated with excessive abnormal iron deposition in the brain. Approximately 15,000-20,000 individuals worldwide are estimated to be affected by NBIA. NBIA is usually associated with slowly progressive pyramidal and extrapyramidal symptoms, axonal motor neuropathy, optic nerve atrophy, cognitive impairment and neuropsychiatric disorders. To date, eleven subtypes of NBIA have been described and the most common ones include pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN) and beta-propeller protein-associated neurodegeneration (BPAN). We present a comprehensive overview of the evidence for disturbed cellular homeostasis and metabolic alterations in NBIA variants, with a careful focus on mitochondrial bioenergetics and lipid metabolism which drives a new perspective in understanding the course of this infrequent malady.
    Keywords:  Bioenergetics; Iron accumulation in the brain; Lipid metabolism; Mitochondria; NBIA; Rare disease
    DOI:  https://doi.org/10.1016/j.bbabio.2024.149517
  6. NMR Biomed. 2024 Oct 05. e5271
    Measuring cerebral enzymatic activity, brain pH and extracranial muscle metabolism with hyperpolarized 13C-pyruvate.
    Alixander S Khan, Mary A McLean, Joshua D Kaggie, Ines Horvat-Menih, Tomasz Matys, Rolf F Schulte, Matthew J Locke, Ashley Grimmer, Pascal Wodtke, Elizabeth Latimer, Amy Frary, Martin J Graves, Ferdia A Gallagher.
      Hyperpolarized carbon-13 (13C) magnetic resonance imaging (MRI) has shown promise for non-invasive assessment of the cerebral metabolism of [1-13C]pyruvate in both healthy volunteers and patients. The exchange of pyruvate to lactate catalysed by lactate dehydrogenase (LDH) and that of pyruvate flux to bicarbonate through pyruvate dehydrogenase (PDH) are the most widely studied reactions in vivo. Here we show the potential of the technique to probe additional enzymatic activity within the brain. Approximately 50 s after intravenous injection of hyperpolarized pyruvate, high-flip-angle pulses were used to detect cerebral 13C-labelled carbon dioxide (13CO2), in addition to the 13C-bicarbonate (H13CO3 -) subsequently formed by carbonic anhydrase (CA). Brain pH measurements, which were weighted towards the extracellular compartment, were calculated from the ratio of H13CO3 - to 13CO2 in seven volunteers using the Henderson-Hasselbalch equation, demonstrating an average pH ± SD of 7.40 ± 0.02, with inter-observer reproducibility of 0.04. In addition, hyperpolarized [1-13C]aspartate was also detected, demonstrating irreversible pyruvate carboxylation to oxaloacetate by pyruvate carboxylase (PC) and subsequent transamination by aspartate aminotransferase (AST), with the average flux being on average 11% ± 3% of that through PDH. A hyperpolarized [1-13C]alanine signal was also detected, but this was localized to extracranial muscle tissue in keeping with skeletal alanine aminotransferase (ALT) activity. The results demonstrate the potential of hyperpolarized 13C-MRI to assess cerebral and extracerebral [1-13C]pyruvate metabolism in addition to LDH and PDH activity. Non-invasive measurements of brain pH could be particularly important in assessing cerebral pathology given the wide range of disease processes that alter acid-base balance.
    Keywords:  MRI; amino acids; hyperpolarized 13C; metabolic imaging; pH; pyruvate
    DOI:  https://doi.org/10.1002/nbm.5271
  7. Methods Mol Biol. 2025 ;2855 357-372
    Analysis of the Mammalian Lipidome by DMS Shotgun Lipidomics.
    Baolong Su, Kevin J Williams.
      Shotgun Lipidomics is a robust methodology for the characterization of the lipidome of complex biological samples. This assay is among the most quantitative lipidomics methods and is capable of surveying a wide breadth of lipid subclasses, both neutral and polar. The shortfalls of the technique include limitations in lipid species characterization and computationally demanding data analysis requiring isotopic and isobaric overlap correction. Differential Mobility Spectrometry (DMS) has demonstrated its utility in enabling acyl tail characterization within a Shotgun Lipidomics experiment. Here, we present a workflow for DMS Shotgun Lipidomics that measures 1400 possible lipid species. It utilizes the Shotgun Lipidomics Assistant (SLA) application, an open-source application that supervises the data analysis for an expansive Shotgun Lipidomics experiment.
    Keywords:  DMS; Direct infusion; Mammalian lipidome; Shotgun lipidomics; Shotgun lipidomics assistant
    DOI:  https://doi.org/10.1007/978-1-0716-4116-3_21
  8. Glia. 2024 Sep 30.
    Developmental maturation and regional heterogeneity but no sexual dimorphism of the murine CNS myelin proteome.
    Sophie B Siems, Vasiliki-Ilya Gargareta, Leonie C Schadt, Vinicius Daguano Gastaldi, Ramona B Jung, Lars Piepkorn, Patrizia Casaccia, Ting Sun, Olaf Jahn, Hauke B Werner.
      The molecules that constitute myelin are critical for the integrity of axon/myelin-units and thus speed and precision of impulse propagation. In the CNS, the protein composition of oligodendrocyte-derived myelin has evolutionarily diverged and differs from that in the PNS. Here, we hypothesized that the CNS myelin proteome also displays variations within the same species. We thus used quantitative mass spectrometry to compare myelin purified from mouse brains at three developmental timepoints, from brains of male and female mice, and from four CNS regions. We find that most structural myelin proteins are of approximately similar abundance across all tested conditions. However, the abundance of multiple other proteins differs markedly over time, implying that the myelin proteome matures between P18 and P75 and then remains relatively constant until at least 6 months of age. Myelin maturation involves a decrease of cytoskeleton-associated proteins involved in sheath growth and wrapping, along with an increase of all subunits of the septin filament that stabilizes mature myelin, and of multiple other proteins which potentially exert protective functions. Among the latter, quinoid dihydropteridine reductase (QDPR) emerges as a highly specific marker for mature oligodendrocytes and myelin. Conversely, female and male mice display essentially similar myelin proteomes. Across the four CNS regions analyzed, we note that spinal cord myelin exhibits a comparatively high abundance of HCN2-channels, required for particularly long sheaths. These findings show that CNS myelination involves developmental maturation of myelin protein composition, and regional differences, but absence of evidence for sexual dimorphism.
    Keywords:  axon/glia‐interaction; myelin maturation; oligodendrocyte; quantitative proteomics; white matter
    DOI:  https://doi.org/10.1002/glia.24614
  9. Curr Opin Neurobiol. 2024 Oct 01. pii: S0959-4388(24)00087-4. [Epub ahead of print]89 102925
    Astrocyte-neuron crosstalk in neurodevelopmental disorders.
    Gabrielle Séjourné, Cagla Eroglu.
      A fundamental feature shared across neurodevelopmental disorders (NDDs) is the disruption of synaptic circuit formation and homeostasis. During early life, non-neuronal cells called astrocytes tightly regulate the establishment of circuits by controlling formation, remodeling, stabilization, and maturation of synapses. Concurrently, astrocytes mature to meet the evolving needs of the developing brain. Bidirectional astrocyte-neuron communication synchronizes astrocyte maturation with synapse development. An emerging body of evidence supports the hypothesis that in NDDs, deficits in astrocyte-neuron communication underlie errors in synaptic circuit development. Here we will review and discuss these findings, with the aim of inspiring future research and guiding translational studies.
    DOI:  https://doi.org/10.1016/j.conb.2024.102925
  10. Dev Med Child Neurol. 2024 Oct 01.
    Neonatal wellbeing and timing of brain injury in term and late preterm cerebral palsy.
      
    DOI:  https://doi.org/10.1111/dmcn.16103
  11. Mol Genet Metab. 2024 Sep 28. pii: S1096-7192(24)00465-7. [Epub ahead of print]143(3): 108581
    Findings from the individualized management of a patient with Acyl-CoA Oxidase-1 (ACOX1) deficiency: A bedside-to-bench-to-bedside strategy.
    Camille Moreau, Adrien Paquot, Gustavo Soto Ares, Anne-Frédérique Dessein, Benoit Deprez, Terence Beghyn, Dries Dobbelaere.
      Acyl-CoA Oxidase-1 (ACOX1) deficiency (MIM 264470) is an autosomal recessive disease characterized by impairments in the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs, which is the first step in the catalysis of the β-oxidative breakdown of very long chain fatty acids (VLCFA) occuring in peroxisomes. The deleterious accumulation of VLCFA in several organs, including the brain, is a key biochemical feature of this disease which has devastating neurological consequences. ACOX1 deficiency is ultra-rare; as such, few studies have been conducted to determine the leading causes of symptoms or uncover new therapeutics. When confronted with one such case, we decided to bring drug discovery tools to the patient's bedside in an attempt to identify a cure. A skin biopsy was performed on a young patient with ACOX1 deficiency, following which screening technologies and mass spectrometry analysis techniques were applied to design a cellular assay that enabled the direct measurement of the effect of small molecules on the patient's primary fibroblasts. This approach is particularly well adapted to inherited metabolic disorders such as ACOX1 deficiency. Through the evaluation of a proprietary library of repurposable drugs, we found that the anthelmintic drug niclosamide led to a significant reduction in VLCFA in vitro. This drug was subsequently administered to the patient for more than six years. This study outlines the screening and drug selection processes. Additionally, we present our comprehensive clinical and biochemical findings that aided in understanding the patient's natural history and analysis of the progression of the patient's symptoms throughout the treatment period. Although the patient's overall lifespan was extended compared to the average age at death in severe early onset cases of ACOX1 deficiency, we did not observe any definitive evidence of clinical or biochemical improvement during niclosamide treatment. Nonetheless, our study shows a good safety profile of long-term niclosamide administration in a child with a rare neurodegenerative disease, and illustrates the potential of individualized therapeutic strategies in the management of inherited metabolic disorders, which could benefit both patients and the broader scientific and medical communities.
    Keywords:  ACOX1; Drug repurposing; High-throughput screening; Individualized medicine; Peroxisomal disorder
    DOI:  https://doi.org/10.1016/j.ymgme.2024.108581
  12. Neuropeptides. 2024 Sep 29. pii: S0143-4179(24)00074-X. [Epub ahead of print]108 102475
    Lipid metabolism: Novel approaches for managing idiopathic epilepsy.
    Chao Wang, Jinxia Zhai, Xuemei Zhou, Yongjun Chen.
      Epilepsy is a common neurological condition characterized by abnormal neuronal activity, often leading to cellular damage and death. There is evidence to suggest that lipid imbalances resulting in cellular death play a key role in the development of epilepsy, including changes in triglycerides, cholesterol, sphingolipids, phospholipids, lipid droplets, and bile acids (BAs). Disrupted lipid metabolism acts as a crucial pathological mechanism in epilepsy, potentially linked to processes such as cellular ferroptosis, lipophagy, and immune modulation of gut microbiota (thus influencing the gut-brain axis). Understanding these mechanisms could open up new avenues for epilepsy treatment. This study investigates the association between disturbances in lipid metabolism and the onset of epilepsy.
    Keywords:  Cell death; Epilepsy; Ferroptosis; Lipid; Metabolism
    DOI:  https://doi.org/10.1016/j.npep.2024.102475
  13. NPJ Aging. 2024 Sep 30. 10(1): 42
    Prenatal exposure to undernutrition is associated with a specific lipid profile predicting future brain aging.
    Stuart G Snowden, Albert Koulman, Christian Gaser, Susanne E la Fleur, Tessa J Roseboom, Aniko Korosi, Susanne R de Rooij.
      Prenatal adversity affects cognitive and brain aging. Both lipid and leptin concentrations may be involved. We investigated if prenatal undernutrition is associated with a specific blood lipid profile and/or leptin concentrations, and if these relate to cognitive function and brain aging. 801 plasma samples of members of the Dutch famine birth cohort were assessed for lipidomics and leptin at age 58. Cognitive performance was measured with a Stroop task at 58, and MRI-based BrainAGE was derived in a subsample at 68. Out of 259 lipid signals, a signature of five identified individuals who were undernourished prenatally. These five lipids were not associated with cognitive performance, but three were predictive of BrainAGE. Leptin was not associated with prenatal famine exposure, Stroop performance, or BrainAGE. In conclusion, prenatal undernutrition was associated with an altered lipid profile predictive of BrainAGE 10 years later, demonstrating the potential of lipid profiles as early biomarkers for accelerated brain aging.
    DOI:  https://doi.org/10.1038/s41514-024-00169-x
  14. Nat Cell Biol. 2024 Oct 02.
    The role of PINK1-Parkin in mitochondrial quality control.
    Derek P Narendra, Richard J Youle.
      Mitophagy mediated by the recessive Parkinson's disease genes PINK1 and Parkin responds to mitochondrial damage to preserve mitochondrial function. In the pathway, PINK1 is the damage sensor, probing the integrity of the mitochondrial import pathway, and activating Parkin when import is blocked. Parkin is the effector, selectively marking damaged mitochondria with ubiquitin for mitophagy and other quality-control processes. This selective mitochondrial quality-control pathway may be especially critical for dopamine neurons affected in Parkinson's disease, in which the mitochondrial network is widely distributed throughout a highly branched axonal arbor. Here we review the current understanding of the role of PINK1-Parkin in the quality control of mitophagy, including sensing of mitochondrial distress by PINK1, activation of Parkin by PINK1 to induce mitophagy, and the physiological relevance of the PINK1-Parkin pathway.
    DOI:  https://doi.org/10.1038/s41556-024-01513-9
  15. Pharmaceuticals (Basel). 2024 Aug 31. pii: 1160. [Epub ahead of print]17(9):
    Neuroregeneration Improved by Sodium-D,L-Beta-Hydroxybutyrate in Primary Neuronal Cultures.
    Csilla Ari, Dominic P D'Agostino, Byeong J Cha.
      Ketone bodies are considered alternative fuels for the brain when glucose availability is limited. To determine the neuroregenerative potential of D,L-sodium-beta-hydroxybutyrate (D/L-BHB), Sprague Dawley rat primary cortical neurons were exposed to simulated central nervous system injury using a scratch assay. The neuronal cell migration, cell density and degree of regeneration in the damaged areas (gaps) in the absence (control) and presence of BHB (2 mM) were documented with automated live-cell imaging by the CytoSMART system over 24 h, which was followed by immunocytochemistry, labeling synapsin-I and β3-tubulin. The cell density was significantly higher in the gaps with BHB treatment after 24 h compared to the control. In the control, only 1.5% of the measured gap areas became narrower over 24 h, while in the BHB-treated samples 49.23% of the measured gap areas became narrower over 24 h. In the control, the gap expanded by 63.81% post-injury, while the gap size decreased by 10.83% in response to BHB treatment, compared to the baseline. The cell density increased by 97.27% and the gap size was reduced by 74.64% in response to BHB, compared to the control. The distance travelled and velocity of migrating cells were significantly higher with BHB treatment, while more synapsin-I and β3-tubulin were found in the BHB-treated samples after 24 h, compared to the control. The results demonstrate that D/L-BHB enhanced neuronal migration and molecular processes associated with neural regeneration and axonogenesis. These results may have clinical therapeutic applications in the future for nervous system injuries, such as for stroke, concussion and TBI patients.
    Keywords:  BHB; beta-hydroxybutyrate; cell migration; exogenous ketones; ketone salt; neural injury; neuroplasticity; scratch assay; synapsin; tubulin
    DOI:  https://doi.org/10.3390/ph17091160
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