bims-medebr 2022-01-23 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–01–23
35 papers selected by
Regina F. Fernández, Johns Hopkins University

Ketogenic diet impairs neurological development of neonatal rats and affects biochemical composition of maternal brains: evidence of functional recovery in pups.
Rates of pyruvate carboxylase, glutamate and GABA neurotransmitter cycling, and glucose oxidation in multiple brain regions of the awake rat using a combination of [2-13C]/[1-13C]glucose infusion and 1H-[13C]NMR ex vivo.
Pathophysiology of Lipid Droplets in Neuroglia.
Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.
Metabolomic Analysis of Carbohydrate and Amino Acid Changes Induced by Hypoxia in Naked Mole-Rat Brain and Liver.
Impaired Brain Mitochondrial Bioenergetics in the Ts65Dn Mouse Model of Down Syndrome Is Restored by Neonatal Treatment with the Polyphenol 7,8-Dihydroxyflavone.
NRF2 Activation Ameliorates Oxidative Stress and Improves Mitochondrial Function and Synaptic Plasticity, and in A53T α-Synuclein Hippocampal Neurons.
Evidence of Energy Metabolism Alterations in Cultured Neonatal Astrocytes Derived from the Ts65Dn Mouse Model of Down Syndrome.
Cyanidin 3-O-β-Galactoside Alleviated Cognitive Impairment in Mice by Regulating Brain Energy Metabolism During Aging.
Aerobic Glycolysis: A DeOxymoron of (Neuro)Biology.
New Insights and Potential Therapeutic Targeting of CB2 Cannabinoid Receptors in CNS Disorders.
Genistein prevents the decrease in ganglioside levels induced by amyloid-beta in the frontal cortex of rats.
Toward the Decipherment of Molecular Interactions in the Diabetic Brain.
Dietary Alpha-Linolenic Acid Supports High Retinal DHA Levels.
Tissue-Specific Content of Polyunsaturated Fatty Acids in (n-3) Deficiency State of Rats.
Impact of fatty acid-binding proteins and dopamine receptors on α-synucleinopathy.
Long-Term High-Fat Diet Consumption Depletes Glial Cells and Tyrosine Hydroxylase-Containing Neurons in the Brain of Middle-Aged Rats.
Liraglutide Regulates Mitochondrial Quality Control System Through PGC-1α in a Mouse Model of Parkinson's Disease.
Disease Outcome and Brain Metabolomics of Cyclophilin-D Knockout Mice in Sepsis.
Regional Brain Analysis of Modified Amino Acids and Dipeptides during the Sleep/Wake Cycle.
Metabolic demands, sensory deficits: Tradeoffs in times of scarcity.
Metabolic Syndrome, Cognitive Impairment and the Role of Diet: A Narrative Review.
Taurine supplementation improves hippocampal metabolism in immature rats with intrauterine growth restriction (IUGR) through protecting neurons and reducing gliosis.
Thiamine-dependent regulation of mammalian brain pyridoxal kinase in vitro and in vivo.
A New Insight into an Alternative Therapeutic Approach to Restore Redox Homeostasis and Functional Mitochondria in Neurodegenerative Diseases.
Evidence for distinct neuro-metabolic phenotypes in humans.
One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration.
Early Blockade of CB1 Receptors Ameliorates Schizophrenia-like Alterations in the Neurodevelopmental MAM Model of Schizophrenia.
Glial Modulation of Energy Balance: The Dorsal Vagal Complex Is No Exception.
Oral Administration of Nicotinamide Mononucleotide Increases Nicotinamide Adenine Dinucleotide Level in an Animal Brain.
Effect of blueberry extract on energetic metabolism, levels of brain-derived neurotrophic factor, and Ca2+-ATPase activity in the hippocampus and cerebral cortex of rats submitted to ketamine-induced mania-like behavior.
Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus.
Insulin-like Growth Factor II Prevents MPP+ and Glucocorticoid Mitochondrial-Oxidative and Neuronal Damage in Dopaminergic Neurons.
The Protective Effects of Mogroside V Against Neuronal Damages by Attenuating Mitochondrial Dysfunction via Upregulating Sirtuin3.
Pyridoxine-Dependent Epilepsy and Antiquitin Deficiency Resulting in Neonatal-Onset Refractory Seizures.

Brain Struct Funct. 2022 Jan 17.

Ketogenic diet impairs neurological development of neonatal rats and affects biochemical composition of maternal brains: evidence of functional recovery in pups.

Kosiek Wojciech, Rauk Zuzanna, Szulc Piotr, Cichy Anna, Rugieł Marzena, Chwiej Joanna, Janeczko Krzysztof, Setkowicz Zuzanna.

  The ketogenic diet (KD) is a type of diet in which the intake of fats significantly increases at the cost of carbohydrates while maintaining an adequate amount of proteins. This kind of diet has been successfully used in clinical therapies of drug-resistant epilepsy, but there is still insufficient evidence on its safety when used in pregnancy. To assess KD effects on the course of gestation and fetal development, pregnant females were fed with: (i) KD during pregnancy and lactation periods (KD group), (ii) KD during pregnancy replaced with ND from the day 2 postpartum (KDND group) and (iii) normal diet alone (ND group). The body mass, ketone and glucose blood levels, and food intake were monitored. In brains of KD-fed females, FTIR biochemical analyses revealed increased concentrations of lipids and ketone groups containing molecules. In offspring of these females, significant reduction of the body mass and delays in neurological development were detected. However, replacement of KD with ND in these females at the beginning of lactation period led to regainment of the body mass in their pups as early as on the postnatal day 14. Moreover, the vast majority of our neurological tests detected functional recovery up to the normal level. It could be concluded that the ketogenic diet undoubtedly affects the brain of pregnant females and impairs the somatic and neurological development of their offspring. However, early postnatal withdrawal of this diet may initiate compensatory processes and considerable functional restitution of the nervous system based on still unrecognized mechanisms.

Keywords:  Betahydroxybutyrate; FTIR spectroscopy; Fetal growth; Ketosis; Undernutrition

DOI:  https://doi.org/10.1007/s00429-021-02450-1
J Cereb Blood Flow Metab. 2022 Jan 20. 271678X221074211

Rates of pyruvate carboxylase, glutamate and GABA neurotransmitter cycling, and glucose oxidation in multiple brain regions of the awake rat using a combination of [2-13C]/[1-13C]glucose infusion and 1H-[13C]NMR ex vivo.

Laura M McNair, Graeme F Mason, Golam Mi Chowdhury, Lihong Jiang, Xiaoxian Ma, Douglas L Rothman, Helle S Waagepetersen, Kevin L Behar.

  Anaplerosis occurs predominately in astroglia through the action of pyruvate carboxylase (PC). The rate of PC (Vpc) has been reported for cerebral cortex (or whole brain) of awake humans and anesthetized rodents, but regional brain rates remain largely unknown and, hence, were subjected to investigation in the current study. Awake male rats were infused with either [2-13C]glucose or [1-13C]glucose (n = 27/30) for 8, 15, 30, 60 or 120 min, followed by rapid euthanasia with focused-beam microwave irradiation to the brain. Blood plasma and extracts of cerebellum, hippocampus, striatum, and cerebral cortex were analyzed by 1H-[13C]-NMR to establish 13C-enrichment time courses for glutamate-C4,C3,C2, glutamine-C4,C3, GABA-C2,C3,C4 and aspartate-C2,C3. Metabolic rates were determined by fitting a three-compartment metabolic model (glutamatergic and GABAergic neurons and astroglia) to the eighteen time courses. Vpc varied by 44% across brain regions, being lowest in the cerebellum (0.087 ± 0.004 µmol/g/min) and highest in striatum (0.125 ± 0.009) with intermediate values in cerebral cortex (0.106 ± 0.005) and hippocampus (0.114 ± 0.005). Vpc constituted 13-19% of the oxidative glucose consumption rate. Combination of cerebral cortical data with literature values revealed a positive correlation between Vpc and the rates of glutamate/glutamine-cycling and oxidative glucose consumption, respectively, consistent with earlier observations.

Keywords:  Anaplerosis; cerebellum; cerebral cortex; hippocampus; striatum

DOI:  https://doi.org/10.1177/0271678X221074211
Antioxidants (Basel). 2021 Dec 23. pii: 22. [Epub ahead of print]11(1):

Pathophysiology of Lipid Droplets in Neuroglia.

Tina Smolič, Robert Zorec, Nina Vardjan.

  In recent years, increasing evidence regarding the functional importance of lipid droplets (LDs), cytoplasmic storage organelles in the central nervous system (CNS), has emerged. Although not abundantly present in the CNS under normal conditions in adulthood, LDs accumulate in the CNS during development and aging, as well as in some neurologic disorders. LDs are actively involved in cellular lipid turnover and stress response. By regulating the storage of excess fatty acids, cholesterol, and ceramides in addition to their subsequent release in response to cell needs and/or environmental stressors, LDs are involved in energy production, in the synthesis of membranes and signaling molecules, and in the protection of cells against lipotoxicity and free radicals. Accumulation of LDs in the CNS appears predominantly in neuroglia (astrocytes, microglia, oligodendrocytes, ependymal cells), which provide trophic, metabolic, and immune support to neuronal networks. Here we review the most recent findings on the characteristics and functions of LDs in neuroglia, focusing on astrocytes, the key homeostasis-providing cells in the CNS. We discuss the molecular mechanisms affecting LD turnover in neuroglia under stress and how this may protect neural cell function. We also highlight the role (and potential contribution) of neuroglial LDs in aging and in neurologic disorders.

Keywords:  astrocytes; lipid droplets; metabolic and oxidative stress; neuroglia; neurologic disorders; pathophysiology

DOI:  https://doi.org/10.3390/antiox11010022
Neuron. 2022 Jan 13. pii: S0896-6273(21)01046-1. [Epub ahead of print]

Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.

Juliet Goldsmith, Alban Ordureau, J Wade Harper, Erika L F Holzbaur.

  Neurons depend on autophagy to maintain cellular homeostasis, and defects in autophagy are pathological hallmarks of neurodegenerative disease. To probe the role of basal autophagy in the maintenance of neuronal health, we isolated autophagic vesicles from mouse brain tissue and used proteomics to identify the major cargos engulfed within autophagosomes, validating our findings in rodent primary and human iPSC-derived neurons. Mitochondrial proteins were identified as a major cargo in the absence of mitophagy adaptors such as OPTN. We found that nucleoid-associated proteins are enriched compared with other mitochondrial components. In the axon, autophagic engulfment of nucleoid-enriched mitochondrial fragments requires the mitochondrial fission machinery Drp1. We proposed that localized Drp1-dependent fission of nucleoid-enriched fragments in proximity to the sites of autophagosome biogenesis enhances their capture. The resulting efficient autophagic turnover of nucleoids may prevent accumulation of mitochondrial DNA in the neuron, thus mitigating activation of proinflammatory pathways that contribute to neurodegeneration.

Keywords:  Drp1; TFAM; autophagy; mitochondria; mitochondrial division; mitochondrial nucleoids; mitophagy; neurodegeneration; neuronal homeostasis

DOI:  https://doi.org/10.1016/j.neuron.2021.12.029
Metabolites. 2022 Jan 10. pii: 56. [Epub ahead of print]12(1):

Metabolomic Analysis of Carbohydrate and Amino Acid Changes Induced by Hypoxia in Naked Mole-Rat Brain and Liver.

Hang Cheng, Yiming Amy Qin, Rashpal Dhillon, James Dowell, John M Denu, Matthew E Pamenter.

  Hypoxia poses a major physiological challenge for mammals and has significant impacts on cellular and systemic metabolism. As with many other small rodents, naked mole-rats (NMRs; Heterocephalus glaber), who are among the most hypoxia-tolerant mammals, respond to hypoxia by supressing energy demand (i.e., through a reduction in metabolic rate mediated by a variety of cell- and tissue-level strategies), and altering metabolic fuel use to rely primarily on carbohydrates. However, little is known regarding specific metabolite changes that underlie these responses. We hypothesized that NMR tissues utilize multiple strategies in responding to acute hypoxia, including the modulation of signalling pathways to reduce anabolism and reprogram carbohydrate metabolism. To address this question, we evaluated changes of 64 metabolites in NMR brain and liver following in vivo hypoxia exposure (7% O2, 4 h). We also examined changes in matched tissues from similarly treated hypoxia-intolerant mice. We report that, following exposure to in vivo hypoxia: (1) phenylalanine, tyrosine and tryptophan anabolism are supressed both in NMR brain and liver; (2) carbohydrate metabolism is reprogramed in NMR brain and liver, but in a divergent manner; (3) redox state is significantly altered in NMR brain; and (4) the AMP/ATP ratio is elevated in liver. Overall, our results suggest that hypoxia induces significant metabolic remodelling in NMR brain and liver via alterations of multiple metabolic pathways.

Keywords:  AMP; aspartic acid; coenzyme; dopamine; glutamate; glutamine; glutathione; glycogen; pentose phosphate pathway

DOI:  https://doi.org/10.3390/metabo12010056
Antioxidants (Basel). 2021 Dec 28. pii: 62. [Epub ahead of print]11(1):

Impaired Brain Mitochondrial Bioenergetics in the Ts65Dn Mouse Model of Down Syndrome Is Restored by Neonatal Treatment with the Polyphenol 7,8-Dihydroxyflavone.

Daniela Valenti, Fiorenza Stagni, Marco Emili, Sandra Guidi, Renata Bartesaghi, Rosa Anna Vacca.

  Down syndrome (DS), a major genetic cause of intellectual disability, is characterized by numerous neurodevelopmental defects. Previous in vitro studies highlighted a relationship between bioenergetic dysfunction and reduced neurogenesis in progenitor cells from the Ts65Dn mouse model of DS, suggesting a critical role of mitochondrial dysfunction in neurodevelopmental alterations in DS. Recent in vivo studies in Ts65Dn mice showed that neonatal supplementation (Days P3-P15) with the polyphenol 7,8-dihydroxyflavone (7,8-DHF) fully restored hippocampal neurogenesis. The current study was aimed to establish whether brain mitochondrial bioenergetic defects are already present in Ts65Dn pups and whether early treatment with 7,8-DHF positively impacts on mitochondrial function. In the brain and cerebellum of P3 and P15 Ts65Dn pups we found a strong impairment in the oxidative phosphorylation apparatus, resulting in a deficit in mitochondrial ATP production and ATP content. Administration of 7,8-DHF (dose: 5 mg/kg/day) during Days P3-P15 fully restored bioenergetic dysfunction in Ts65Dn mice, reduced the levels of oxygen radicals and reinstated the hippocampal levels of PGC-1α. No pharmacotherapy is available for DS. From current findings, 7,8-DHF emerges as a treatment with a good translational potential for improving mitochondrial bioenergetics and, thus, mitochondria-linked neurodevelopmental alterations in DS.

Keywords:  7,8-dihydroxyflavone; Down syndrome; Ts65Dn mice; brain mitochondria; mitochondrial respiratory chain; oxidative phosphorylation

DOI:  https://doi.org/10.3390/antiox11010062
Antioxidants (Basel). 2021 Dec 24. pii: 26. [Epub ahead of print]11(1):

NRF2 Activation Ameliorates Oxidative Stress and Improves Mitochondrial Function and Synaptic Plasticity, and in A53T α-Synuclein Hippocampal Neurons.

Mikah S Brandes, Jonathan A Zweig, Anita Tang, Nora E Gray.

  In Parkinson's disease (PD), brain oxidative stress and mitochondrial dysfunction contribute to neuronal loss as well as motor and cognitive deficits. The transcription factor NRF2 has emerged as a promising therapeutic target in PD because it sits at the intersection of antioxidant and mitochondrial pathways. Here, we investigate the effects of modulating NRF2 activity in neurons isolated from a A53T α-synuclein (A53TSyn) mouse model of synucleinopathy. Embryonic hippocampal neurons were isolated from A53TSyn mice and their wild type (WT) littermates. Neurons were treated with either the NRF2 activator dimethyl fumarate (DMF) or the NRF2 inhibitor ML385. Reactive oxygen species (ROS), dendritic arborization and dendritic spine density were quantified. Mitochondrial bioenergetics were also profiled in these neurons. A53TSyn neurons had increased ROS and reduced basal and maximal mitochondrial respiration relative to WT neurons. A53TSyn neurons also displayed decreased dendritic arborization and reduced spine density. Treatment with DMF reduced ROS levels and improved both mitochondrial function and arborization, while inhibition of NRF2 with ML385 exacerbated these endpoints. Modulation of NRF2 activity had a significant effect on mitochondrial function, oxidative stress, and synaptic plasticity in A53TSyn neurons. These data suggest that NRF2 may be a viable target for therapeutic interventions in PD.

Keywords:  NRF2; Parkinson’s disease; alpha-synuclein; dimethyl fumarate

DOI:  https://doi.org/10.3390/antiox11010026
Brain Sci. 2022 Jan 06. pii: 83. [Epub ahead of print]12(1):

Evidence of Energy Metabolism Alterations in Cultured Neonatal Astrocytes Derived from the Ts65Dn Mouse Model of Down Syndrome.

Bruna L Zampieri, Alberto C S Costa.

  For many decades, neurons have been the central focus of studies on the mechanisms underlying the neurodevelopmental and neurodegenerative aspects of Down syndrome (DS). Astrocytes, which were once thought to have only a passive role, are now recognized as active participants of a variety of essential physiological processes in the brain. Alterations in their physiological function have, thus, been increasingly acknowledged as likely initiators of or contributors to the pathogenesis of many nervous system disorders and diseases. In this study, we carried out a series of real-time measurements of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in hippocampal astrocytes derived from neonatal Ts65Dn and euploid control mice using a Seahorse XFp Flux Analyzer. Our results revealed a significant basal OCR increase in neonatal Ts65Dn astrocytes compared with those from control mice, indicating increased oxidative phosphorylation. ECAR did not differ between the groups. Given the importance of astrocytes in brain metabolic function and the linkage between astrocytic and neuronal energy metabolism, these data provide evidence against a pure "neurocentric" vision of DS pathophysiology and support further investigations on the potential contribution of disturbances in astrocytic energy metabolism to cognitive deficits and neurodegeneration associated with DS.

Keywords:  Ts65Dn; astrocytes; down syndrome; glycolysis; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.3390/brainsci12010083
J Agric Food Chem. 2022 Jan 18.

Cyanidin 3-O-β-Galactoside Alleviated Cognitive Impairment in Mice by Regulating Brain Energy Metabolism During Aging.

Zhuoyan Fan, Haichao Wen, Xiaoxu Zhang, Jingming Li, Jiachen Zang.

  Metabolic disorder, which commonly happens among senile people worldwide, is an important sign of aging. The early symptoms of neurodegenerative diseases include a decrease in energy metabolism and mitochondrial dysfunction. Comparably, early dietary intervention may be more effective in preventing or delaying brain aging, owing to its role in regulating metabolism. Polyphenol intake has shown its potential in preventing Alzheimer's disease. However, whether there are close connections between polyphenols and the energy metabolism of the brain during aging remains unclear. This study sought to evaluate whether cyanidin 3-O-β-galactoside from black chokeberry (Aronia melanocarpa (Michx.) Elliott) has positive effects on energy metabolism, as well as cognitive function in aging mice. Intragastrical administration of cyanidin 3-O-β-galactoside (25 and 50 mg/kg/day) for 8 weeks effectively alleviated the decline in brain glucose uptake (decline rate 18.29% versus 1.05%, 7.63%) of aging mice. Moreover, cyanidin 3-O-β-galactoside also alleviated neuronal damage in the hippocampus (number of neurons 212.33 ± 16.19 versus 285.33 ± 29.53, 301.67 ± 10.07; p < 0.05) and cortex (number of neurons 82.00 ± 4.58 versus 111.67 ± 6.51, 112.00 ± 1.00; p < 0.05). Furthermore, cyanidin 3-O-β-galactoside reduced β-amyloid load in the brain and significantly increased the crossing-platform number (0.92 ± 1.11 versus 1.83 ± 0.68, 2.08 ± 0.58; p < 0.05) in the Morris water maze test. We further determined that protein kinase B (AKT) might be the target of cyanidin 3-O-β-galactoside, which played a beneficial role in controlling the energy metabolism of the brain. These results suggested that early intervention of anthocyanins could promote neuroprotection under the challenge of brain energy metabolism.

Keywords:  Alzheimer’s disease; aging; cognitive impairment; cyanidin 3-O-β-galactoside; energy metabolism

DOI:  https://doi.org/10.1021/acs.jafc.1c06240
Metabolites. 2022 Jan 13. pii: 72. [Epub ahead of print]12(1):

Aerobic Glycolysis: A DeOxymoron of (Neuro)Biology.

Avital Schurr, Salvatore Passarella.

  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.

Keywords:  BOLD fMRI (blood oxygen level-dependent functional magnetic resonance imaging); CMR (cerebral metabolic rate); L-lactate; aerobic glycolysis; astroglial-neuronal L-lactate shuttle; glucose; mitochondrial oxidative phosphorylation; oxygen

DOI:  https://doi.org/10.3390/metabo12010072
Int J Mol Sci. 2022 Jan 17. pii: 975. [Epub ahead of print]23(2):

New Insights and Potential Therapeutic Targeting of CB2 Cannabinoid Receptors in CNS Disorders.

Berhanu Geresu Kibret, Hiroki Ishiguro, Yasue Horiuchi, Emmanuel S Onaivi.

  The endocannabinoid system (ECS) is ubiquitous in most human tissues, and involved in the regulation of mental health. Consequently, its dysregulation is associated with neuropsychiatric and neurodegenerative disorders. Together, the ECS and the expanded endocannabinoidome (eCBome) are composed of genes coding for CB1 and CB2 cannabinoid receptors (CB1R, CB2R), endocannabinoids (eCBs), and the metabolic enzyme machinery for their synthesis and catabolism. The activation of CB1R is associated with adverse effects on the central nervous system (CNS), which has limited the therapeutic use of drugs that bind this receptor. The discovery of the functional neuronal CB2R raised new possibilities for the potential and safe targeting of the ECS for the treatment of CNS disorders. Previous studies were not able to detect CB2R mRNA transcripts in brain tissue and suggested that CB2Rs were absent in the brain and were considered peripheral receptors. Studies done on the role of CB2Rs as a potential therapeutic target for treating different disorders revealed the important putative role of CB2Rs in certain CNS disorders, which requires further clinical validation. This review addresses recent advances on the role of CB2Rs in neuropsychiatric and neurodegenerative disorders, including, but not limited to, anxiety, depression, schizophrenia, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and addiction.

Keywords:  Alzheimer’s disease; CB2R; Huntington’s disease; addiction; anxiety; endocannabinoid system; endocannabinoidome; neuropsychiatry; schizophrenia

DOI:  https://doi.org/10.3390/ijms23020975
Neurol Res. 2022 Jan 21. 1-7

Genistein prevents the decrease in ganglioside levels induced by amyloid-beta in the frontal cortex of rats.

Fernanda Dos Santos Petry, Juliana Bender Hoppe, Caroline Peres Klein, Bernardo Gindri Dos Santos, Régis Mateus Hözer, Christianne Gazzana Salbego, Vera Maria Treis Trindade.

   OBJECTIVES: In this study, an in vivo model of Aβ toxicity was used to investigate the effects of this peptide and the treatment with genistein on the lipid composition (gangliosides, phospholipids and cholesterol) in the frontal cortex of rats.
METHODS: Male Wistar rats received bilateral intracerebroventricular infusions of Aβ1-42 (2 nmol) and genistein 10 mg/kg orally for 10 days. Frontal cortex was homogenized with chloroform:methanol for lipid extraction and ganglioside, phospholipid and cholesterol levels were evaluated.
RESULTS: The Aβ-infused animals showed a significant decrease in ganglioside concentration and relative reduction of GD1b and GQ1b species. Treatment with genistein prevented the decrease in ganglioside levels. Phospholipid and cholesterol contents did not show significant differences.
DISCUSSION: Considering the roles of gangliosides on neuronal function, findings described here can contribute to the knowledge of the potential neuroprotective mechanisms of genistein against Aβ-induced alterations in the frontal cortex of rats and provide a novel view in the multifaceted scenario associated with its beneficial effects.

Keywords:  Alzheimer’s disease; amyloid-beta; cell membrane; genistein; lipids; neuroprotection

DOI:  https://doi.org/10.1080/01616412.2021.2024731
Biomedicines. 2022 Jan 06. pii: 115. [Epub ahead of print]10(1):

Toward the Decipherment of Molecular Interactions in the Diabetic Brain.

Maria Chomova.

  Diabetes mellitus (DM) has been associated with cognitive complications in the brain resulting from acute and chronic metabolic disturbances happening peripherally and centrally. Numerous studies have reported on the morphological, electrophysiological, biochemical, and cognitive changes in the brains of diabetic individuals. The detailed pathophysiological mechanisms implicated in the development of the diabetic cognitive phenotype remain unclear due to intricate molecular changes evolving over time and space. This review provides an insight into recent advances in understanding molecular events in the diabetic brain, focusing on cerebral glucose and insulin uptake, insulin action in the brain, and the role of the brain in the regulation of glucose homeostasis. Fully competent mitochondria are essential for energy metabolism and proper brain function; hence, the potential contribution of mitochondria to the DM-induced impairment of the brain is also discussed.

Keywords:  ROS; brain; diabetes; insulin; mitochondria; proteostasis

DOI:  https://doi.org/10.3390/biomedicines10010115
Nutrients. 2022 Jan 12. pii: 301. [Epub ahead of print]14(2):

Dietary Alpha-Linolenic Acid Supports High Retinal DHA Levels.

Andrew J Sinclair, Xiao-Fei Guo, Lavinia Abedin.

  The retina requires docosahexaenoic acid (DHA) for optimal function. Alpha-linolenic acid (ALA) and DHA are dietary sources of retinal DHA. This research investigated optimizing retinal DHA using dietary ALA. Previous research identified 19% DHA in retinal phospholipids was associated with optimal retinal function in guinea pigs. Pregnant guinea pigs were fed dietary ALA from 2.8% to 17.3% of diet fatty acids, at a constant level of linoleic acid (LA) of 18% for the last one third of gestation and retinal DHA levels were assessed in 3-week-old offspring maintained on the same diets as their mothers. Retinal DHA increased in a linear fashion with the maximum on the diet with LA:ALA of 1:1. Feeding diets with LA:ALA of 1:1 during pregnancy and assessing retinal DHA in 3-week-old offspring was associated with optimized retinal DHA levels. We speculate that the current intakes of ALA in human diets, especially in relation to LA intakes, are inadequate to support high DHA levels in the retina.

Keywords:  22:5n-6; alpha-linolenic acid; biomarker; brain; diet; docosahexaenoic acid; docosapentaenoic acid n-6; equivalence; guinea pigs; linoleic acid; linoleic acid to linolenic acid ratio; liver; omega-3; retina; vegans; vegetarians

DOI:  https://doi.org/10.3390/nu14020301
Foods. 2022 Jan 12. pii: 208. [Epub ahead of print]11(2):

Tissue-Specific Content of Polyunsaturated Fatty Acids in (n-3) Deficiency State of Rats.

Amruta Kulkarni, Ai Zhao, Baoru Yang, Yumei Zhang, Kaisa M Linderborg.

  The dietary intake of fatty acids (FAs) affects the composition and distribution of FAs in the body. Here, a first-generation (n-3)-deficiency study was conducted by keeping young (age 21 ± 2 days) Sprague-Dawley male rats on a peanut-oil-based diet for 33 days after weaning in order to compare the effect of mild (n-3)-deficiency on the lipid composition of different organs and feces. Soybean-oil-based diet was used as a control. The plasma FA levels corresponded to FAs levels in the organs. Lower docosahexaenoic acid (DHA) content was detected in the plasma, brain, testis, visceral fat, heart, and lungs of the (n-3)-deficient group, whereas the DHA content of the eye and feces did not differ between the experimental groups. The DHA content of the brains of the (n-3)-deficient group was 86% of the DHA content of the brains of the (n-3)-adequate group. The DHA level of the organs was affected in the order of visceral fat > liver triacylglycerols > lung > heart > liver phospholipids > testis > eye > brain, with brain being least affected. The low levels of (n-3) FAs in the liver, brain, eye, heart, and lung were offset by an increase in the (n-6) FAs, mainly arachidonic acid. These results indicate that, in rats, adequate maternal nutrition during pregnancy and weaning does not provide enough (n-3) FAs for 33 days of an (n-3)-deficient diet. Results of this study can be used also to evaluate the conditions needed to reach mild (n-3) deficiency in the first generation of rats and to evaluate the feasibility to collect data from a variety of organs or only selected ones.

Keywords:  (n-3) deficiency; (n-3) polyunsaturated fatty acids; docosahexaenoic acid; fatty acid composition; lipid metabolism; α-linolenic acid

DOI:  https://doi.org/10.3390/foods11020208
J Pharmacol Sci. 2022 Feb;pii: S1347-8613(21)00118-3. [Epub ahead of print]148(2): 248-254

Impact of fatty acid-binding proteins and dopamine receptors on α-synucleinopathy.

Ichiro Kawahata, Kohji Fukunaga.

  An aging society leads to an increased number of patients with cognitive and movement disorders, such as Parkinson's disease and dementia with Lewy bodies. α-Synuclein accumulation in neuronal cells is a pathological hallmark of α-synucleinopathies. Aberrant soluble oligomeric units of α-synuclein are toxic and disrupt neuronal homeostasis. Fatty acids partially regulate α-synuclein accumulation as well as oligomerization, and fatty acid-binding protein (FABP) associates with the α-synuclein aggregates. Heart-type FABP (hFABP, FABP3) is rich in dopaminergic neurons and interacts with dopamine D2 receptors, specifically the long type (D2L), which is abundant in caveolae. We recently demonstrated that mesencephalic neurons require FABP3 and dopamine D2L receptors for the caveolae-mediated α-synuclein uptake. Accumulated α-synuclein gets fibrillized and tightly co-localizes with FABP3 and dopamine D2L receptors, which leads to mitochondrial dysfunction and loss of tyrosine hydroxylase, a rate-limiting enzyme in dopamine production. Furthermore, the inhibition of FABP3 using small-molecule ligands successfully prevents FABP3-induced neurotoxicity. In this review, we focus on the impact of FABP3, dopamine receptors, and other FABP family proteins in the process of α-synuclein propagation and the subsequent aggregate-induced cytotoxicity. We also propose the potential of FABP as a therapeutic target for α-synucleinopathies.

Keywords:  Dopamine D(2) receptor; Fatty acid-binding protein; Mitochondria; Parkinson's disease; Tyrosine Hydroxylase; α-Synucleinopathy

DOI:  https://doi.org/10.1016/j.jphs.2021.12.003
Cells. 2022 Jan 15. pii: 295. [Epub ahead of print]11(2):

Long-Term High-Fat Diet Consumption Depletes Glial Cells and Tyrosine Hydroxylase-Containing Neurons in the Brain of Middle-Aged Rats.

Mei-Chuan Chou, Hsiang-Chun Lee, Yen-Chin Liu, Patrick Szu-Ying Yen, Ching-Kuan Liu, Chu-Huang Chen, Tzu-Han Hsieh, Shiou-Lan Chen.

  Epidemiologic studies have indicated that dyslipidemia may facilitate the progression of neuronal degeneration. However, the effects of chronic dyslipidemia on brain function, especially in older individuals, remain unclear. In this study, middle-aged 37-week-old male Wistar-Kyoto rats were fed a normal diet (ND) or a 45% high-fat diet (HFD) for 30 weeks (i.e., until 67 weeks of age). To study the effects of chronic dyslipidemia on the brain, we analyzed spontaneous locomotor activity, cognitive function, and brain tissues in both groups of rats after 30 weeks. Compared with age-matched rats fed a ND, Wistar-Kyoto rats fed a HFD had dyslipidemia and showed decreased movement but normal recognition of a novel object. In our brain analyses, we observed a significant decrease in astrocytes and tyrosine hydroxylase-containing neurons in the substantia nigra and locus coeruleus of rats fed a HFD compared with rats fed a ND. However, hippocampal pyramidal neurons were not affected. Our findings indicate that the long-term consumption of a HFD may cause lipid metabolism overload in the brain and damage to glial cells. The decrease in astrocytes may lead to reduced protection of the brain and affect the survival of tyrosine hydroxylase-containing neurons but not pyramidal neurons of the hippocampus.

Keywords:  cognitive function; dopamine neuron; glial cell; lipids; locomotor activity

DOI:  https://doi.org/10.3390/cells11020295
Neurotox Res. 2022 Jan 18.

Liraglutide Regulates Mitochondrial Quality Control System Through PGC-1α in a Mouse Model of Parkinson's Disease.

Pengyue Wu, Yuxuan Dong, Jinhu Chen, Tianyuan Guan, Bing Cao, Yanqiu Zhang, Yueyan Qi, Zhenlong Guan, Yanqin Wang.

  Parkinson's disease (PD) is a multifactorial disorder, and there is strong evidence that mitochondria play an essential role in the disorder. Factors that regulate the mechanism of the mitochondrial quality control system have been drawing more and more attention. PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1α) is a powerful transcription factor involved in regulation of mitochondrial function. Glucagon-like peptide 1 (GLP-1), a brain-gut peptide, can enter the central nervous system through the blood-brain barrier and play neuroprotective role. However, whether the GLP-1R agonist liraglutide regulates mitochondrial quality control system through PGC-1α is still unclear. We administered different doses of liraglutide to intervene MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD model, and then immunofluorescence, Western blot, and stereotactic injection of lentivirus to downregulate PGC-1α were used to explore the mechanisms underlying the protective effect of liraglutide in PD. The results showed that MPTP lead to decreased mitochondrial biogenesis, disrupted mitochondrial dynamics, inhibited mitochondrial autophagy, and promoted cell apoptosis. While liraglutide effectively attenuated the neurotoxicity of MPTP, including reversing the dyskinesia caused by MPTP and preserving the expression of GLP-1R, TH, and PGC-1α in the substantia nigra (SN), further experiments showed that downregulation of PGC-1α expression via stereotactic injection PGC-1α lentivirus into the SN reversed the liraglutide protective effects. By PGC-1α downregulation, we found that PGC-1α can not only regulate mitochondria biogenesis, mitochondria dynamics, and autophagy, but also regulate cell apoptosis. In summary, liraglutide has a neuroprotective effect in the PD model induced by MPTP. This protective effect is accomplished by activating PGC-1α, which regulates the mitochondrial quality control system.

Keywords:  Autophagy; Mitochondria quality control; Mitochondrial biogenesis; Mitochondrial dynamics; PGC-1α; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12640-021-00460-9
Int J Mol Sci. 2022 Jan 16. pii: 961. [Epub ahead of print]23(2):

Disease Outcome and Brain Metabolomics of Cyclophilin-D Knockout Mice in Sepsis.

Takayuki Kobayashi, Hiroyuki Uchino, Eskil Elmér, Yukihiko Ogihara, Hidetoshi Fujita, Shusuke Sekine, Yusuke Ishida, Iwao Saiki, Shoichiro Shibata, Aya Kawachi.

  Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction resulting from a systemic inflammatory response to infection, but the mechanism remains unclear. The mitochondrial permeability transition pore (MPTP) could play a central role in the neuronal dysfunction, induction of apoptosis, and cell death in SAE. The mitochondrial isomerase cyclophilin D (CypD) is known to control the sensitivity of MPTP induction. We, therefore, established a cecal ligation and puncture (CLP) model, which is the gold standard in sepsis research, using CypD knockout (CypD KO) mice, and analyzed the disease phenotype and the possible molecular mechanism of SAE through metabolomic analyses of brain tissue. A comparison of adult, male wild-type, and CypD KO mice demonstrated statistically significant differences in body temperature, mortality, and histological changes. In the metabolomic analysis, the main finding was the maintenance of reduced glutathione (GSH) levels and the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio in the KO animals following CLP. In conclusion, we demonstrate that CypD is implicated in the pathogenesis of SAE, possibly related to the inhibition of MPTP induction and, as a consequence, the decreased production of ROS and other free radicals, thereby protecting mitochondrial and cellular function.

Keywords:  cyclophilin D; encephalopathy; glutathione; mitochondria; oxidative stress

DOI:  https://doi.org/10.3390/ijms23020961
Metabolites. 2021 Dec 27. pii: 21. [Epub ahead of print]12(1):

Regional Brain Analysis of Modified Amino Acids and Dipeptides during the Sleep/Wake Cycle.

Theodosia Vallianatou, Nicholas B Bèchet, Mario S P Correia, Iben Lundgaard, Daniel Globisch.

  Sleep is a state in which important restorative and anabolic processes occur. Understanding changes of these metabolic processes during the circadian rhythm in the brain is crucial to elucidate neurophysiological mechanisms important for sleep function. Investigation of amino acid modifications and dipeptides has recently emerged as a valuable approach in the metabolic profiling of the central nervous system. Nonetheless, very little is known about the effects of sleep on the brain levels of amino acid analogues. In the present study, we examined brain regional sleep-induced alterations selective for modified amino acids and dipeptides using Ultra-high performance liquid chromatography-MS/MS (UHPLC-MS/MS) based metabolomics. Our approach enabled the detection and identification of numerous amino acid-containing metabolites in the cortex, the hippocampus, the midbrain, and the cerebellum. In particular, analogues of the aromatic amino acids phenylalanine, tyrosine and tryptophan were significantly altered during sleep in the investigated brain regions. Cortical levels of medium and long chain N-acyl glycines were higher during sleep. Regional specific changes were also detected, especially related to tyrosine analogues in the hippocampus and the cerebellum. Our findings demonstrate a strong correlation between circadian rhythms and amino acid metabolism specific for different brain regions that provide previously unknown insights in brain metabolism.

Keywords:  amino acids; brain regions; dipeptides; mass spectrometry; metabolomics; modifications; sleep/wake cycle

DOI:  https://doi.org/10.3390/metabo12010021
Neuron. 2022 Jan 19. pii: S0896-6273(21)01028-X. [Epub ahead of print]110(2): 183-184

Metabolic demands, sensory deficits: Tradeoffs in times of scarcity.

Alexa D Faulkner, Christian R Burgess.

The brain requires a lot of energy to carry out its functions at peak performance. In times of energy deficit, something has to give. In this issue of Neuron, Padamsey et al. (2021) explore how metabolic demands impact cortical coding by demonstrating the effects of food restriction on visual processing.

DOI: https://doi.org/10.1016/j.neuron.2021.12.011
Nutrients. 2022 Jan 13. pii: 333. [Epub ahead of print]14(2):

Metabolic Syndrome, Cognitive Impairment and the Role of Diet: A Narrative Review.

Matina Kouvari, Nathan M D'Cunha, Nikolaj Travica, Domenico Sergi, Manja Zec, Wolfgang Marx, Nenad Naumovski.

   BACKGROUND: This narrative review presents the association between metabolic syndrome (MetS), along with its components, and cognition-related disorders, as well as the potential reversal role of diet against cognitive impairment by modulating MetS.
METHODS: An electronic research in Medline (Pubmed) and Scopus was conducted.
RESULTS: MetS and cognitive decline share common cardiometabolic pathways as MetS components can trigger cognitive impairment. On the other side, the risk factors for both MetS and cognitive impairment can be reduced by optimizing the nutritional intake. Clinical manifestations such as dyslipidemia, hypertension, diabetes and increased central body adiposity are nutrition-related risk factors present during the prodromal period before cognitive impairment. The Mediterranean dietary pattern stands among the most discussed predominantly plant-based diets in relation to cardiometabolic disorders that may prevent dementia, Alzheimer's disease and other cognition-related disorders. In addition, accumulating evidence suggests that the consumption of specific dietary food groups as a part of the overall diet can improve cognitive outcomes, maybe due to their involvement in cardiometabolic paths.
CONCLUSIONS: Early MetS detection may be helpful to prevent or delay cognitive decline. Moreover, this review highlights the importance of healthy nutritional habits to reverse such conditions and the urgency of early lifestyle interventions.

Keywords:  cognition; cognitive impairment; dementia; healthy aging; metabolic syndrome; nutrition

DOI:  https://doi.org/10.3390/nu14020333
Metab Brain Dis. 2022 Jan 20.

Taurine supplementation improves hippocampal metabolism in immature rats with intrauterine growth restriction (IUGR) through protecting neurons and reducing gliosis.

Qiong Fang, Jing Liu, Lang Chen, Qiaobin Chen, Yan Wang, Zuanfang Li, Wei Fu, Ying Liu.

  Taurine as an essential amino acid in the brain could play an important role in protecting the fetal brain of intrauterine growth restriction (IUGR). The hippocampus with IUGR showed neural metabolic disorder and structure changed that affected memory and learning ability. This study was aimed to identify the effect of taurine supplementation on the metabolism alterations and cellular composition changes of the hippocampus in IUGR immature rats. Metabolite concentrations were determined by magnetic resonance spectroscopy (MRS) in the hippocampus of juvenile rats with IUGR following taurine supplementation with antenatal or postnatal supply. The composition of neural cells in the hippocampus was observed by immunohistochemical staining (IHC) and western blotting (WB). Antenatal taurine supplementation increased the ratios of N-acetylaspartate (NAA) /creatine (Cr) and glutamate (Glu) /Cr of the hippocampus in the IUGR immature rats, but reduced the ratios of choline (Cho) /Cr and myoinositol (mI) /Cr. At the same time, the protein expression of NeuN in the IUGR rats was increased through intrauterine taurine supplementation, and the GFAP expression was reduced. Especially the effect of antenatal taurine was better than postpartum. Furthermore, there existed a positive correlation between the NAA/Cr ratio and the NeuN protein expression (R = 0.496 p < 0.001 IHC; R = 0.568 p < 0.001 WB), the same results existed in the relationship between the mI/Cr ratio and the GFAP protein expression (R = 0.338 p = 0.019 IHC; R = 0.440 p = 0.002 WB). Prenatal taurine supplementation can better improve hippocampal neuronal metabolism by increasing NAA / Cr ratio related to the number of neurons and reducing Cho / Cr ratio related to the number of glial cells.

Keywords:  Hippocampus; Immature rats; Intrauterine growth restriction; Magnetic resonance spectroscopy; Taurine

DOI:  https://doi.org/10.1007/s11011-021-00896-0
J Neurochem. 2022 Jan 20.

Thiamine-dependent regulation of mammalian brain pyridoxal kinase in vitro and in vivo.

Victoria Bunik, Vasily Aleshin, Isabel Nogues, Thilo Kähne, Alessia Parroni, Roberto Contestabile, Martino Luigi di Salvo, Anastasia Graf, Angela Tramonti.

  Vitamins B1 (thiamine) and B6 (pyridox(al/ine/amine)) are crucial for CNS function and neurogenesis due to the coenzyme action of their phosphorylated derivatives in the brain metabolism of glucose and neurotransmitters. Here, the non-coenzyme action of thiamine on the major mammalian producers of pyridoxal-5'-phosphate (PLP), such as pyridoxal kinase (PdxK) and pyridoxine 5'-phosphate oxidase (PNPO), is characterized. Among the natural thiamine compounds, thiamine triphosphate (ThTP) is the best effector of recombinant human PdxK (hPdxK) in vitro, inhibiting hPdxK in the presence of Mg2+ , but activating the Zn2+ -dependent reaction. Inhibition of hPdxK by thiamine antagonists decreases from amprolium to pyrithiamine to oxythiamine, highlighting possible dysregulation of both the B1 - and B6 -dependent metabolism in the chemical models of thiamine deficiency. Compared to the canonical hPdxK, the D87H and V128I variants show a 2-fold increase in Kapp of thiamine inhibition, and the V128I and H246Q variants show a 4-fold and a 2-fold decreased Kapp of ThDP, respectively. Thiamine administration changes diurnal regulation of PdxK activity and phosphorylation at Ser213 and Ser285, expression of the PdxK-related circadian kinases / phosphatases in the rat brain, and ECG. In contrast to PdxK, PNPO is not affected by thiamine or its derivatives, either in vitro, or in vivo. Dephosphorylation of the PdxK Ser285, potentially affecting mobility of the ATP-binding loop, inversely correlates with the enzyme activity. Dephosphorylation of the PdxK Ser213, which is far away from the active site, does not correlate with the activity. The correlations analysis suggests the PdxK Ser213 to be a target of kinase MAP2K1 and phosphatase Ppp1ca. Diurnal effects of thiamine administration on the metabolically linked ThDP- and PLP-dependent enzymes may support the brain homeostatic mechanisms and physiological fitness.

Keywords:  MAP kinases; Ppp1ca; diurnal rhythms; pyridoxal kinase; thiamine antagonists; thiamine triphosphate

DOI:  https://doi.org/10.1111/jnc.15576
Antioxidants (Basel). 2021 Dec 21. pii: 7. [Epub ahead of print]11(1):

A New Insight into an Alternative Therapeutic Approach to Restore Redox Homeostasis and Functional Mitochondria in Neurodegenerative Diseases.

Dong-Hoon Hyun, Jaewang Lee.

  Neurodegenerative diseases are accompanied by oxidative stress and mitochondrial dysfunction, leading to a progressive loss of neuronal cells, formation of protein aggregates, and a decrease in cognitive or motor functions. Mitochondrial dysfunction occurs at the early stage of neurodegenerative diseases. Protein aggregates containing oxidatively damaged biomolecules and other misfolded proteins and neuroinflammation have been identified in animal models and patients with neurodegenerative diseases. A variety of neurodegenerative diseases commonly exhibits decreased activity of antioxidant enzymes, lower amounts of antioxidants, and altered cellular signalling. Although several molecules have been approved clinically, there is no known cure for neurodegenerative diseases, though some drugs are focused on improving mitochondrial function. Mitochondrial dysfunction is caused by oxidative damage and impaired cellular signalling, including that of peroxisome proliferator-activated receptor gamma coactivator 1α. Mitochondrial function can also be modulated by mitochondrial biogenesis and the mitochondrial fusion/fission cycle. Mitochondrial biogenesis is regulated mainly by sirtuin 1, NAD+, AMP-activated protein kinase, mammalian target of rapamycin, and peroxisome proliferator-activated receptor γ. Altered mitochondrial dynamics, such as increased fission proteins and decreased fusion products, are shown in neurodegenerative diseases. Due to the restrictions of a target-based approach, a phenotype-based approach has been performed to find novel proteins or pathways. Alternatively, plasma membrane redox enzymes improve mitochondrial function without the further production of reactive oxygen species. In addition, inducers of antioxidant response elements can be useful to induce a series of detoxifying enzymes. Thus, redox homeostasis and metabolic regulation can be important therapeutic targets for delaying the progression of neurodegenerative diseases.

Keywords:  mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; neurodegenerative diseases; neuroinflammation; oxidative stress; plasma membrane redox enzymes

DOI:  https://doi.org/10.3390/antiox11010007
Neuroimage. 2022 Jan 13. pii: S1053-8119(22)00032-5. [Epub ahead of print] 118902

Evidence for distinct neuro-metabolic phenotypes in humans.

Bofan Wu, Andrew P Bagshaw, Clayton Hickey, Simone Kühn, Martin Wilson.

  Advances in magnetic resonance imaging have shown how individual differences in the structure and function of the human brain relate to health and cognition. The relationship between individual differences and the levels of neuro-metabolites, however, remains largely unexplored - despite the potential for the discovery of novel behavioural and disease phenotypes. In this study, we measured 14 metabolite levels, normalised as ratios to total-creatine, with 1H magnetic resonance spectroscopy (MRS) acquired from the bilateral anterior cingulate cortices of six healthy participants, repeatedly over a period of four months. ANOVA tests revealed statistically significant differences of 3 metabolites and 3 commonly used combinations (total-choline, glutamate + glutamine and total-N-acetylaspartate) between the participants, with scyllo-inositol (F=85, p=6e-26) and total-choline (F=39, p=1e-17) having the greatest discriminatory power. This was not attributable to structural differences. When predicting individuals from the repeated MRS measurements, a leave-one-out classification accuracy of 88% was achieved using a support vector machine based on scyllo-inositol and total-choline levels. Accuracy increased to 98% with the addition of total-N-acetylaspartate and myo-inositol - demonstrating the efficacy of combining MRS with machine learning and metabolomic methodology. These results provide evidence for the existence of neuro-metabolic phenotypes, which may be non-invasively measured using widely available 3 Tesla MRS. Establishing these phenotypes in a larger cohort and investigating their connection to brain health and function presents an important area for future study.

Keywords:  ABfit; Individual differences; MR spectroscopy; MRS; Neurochemical; Spant

DOI:  https://doi.org/10.1016/j.neuroimage.2022.118902
Cells. 2022 Jan 09. pii: 214. [Epub ahead of print]11(2):

One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration.

Eirini Lionaki, Christina Ploumi, Nektarios Tavernarakis.

  One-carbon metabolism (OCM) is a network of biochemical reactions delivering one-carbon units to various biosynthetic pathways. The folate cycle and methionine cycle are the two key modules of this network that regulate purine and thymidine synthesis, amino acid homeostasis, and epigenetic mechanisms. Intersection with the transsulfuration pathway supports glutathione production and regulation of the cellular redox state. Dietary intake of micronutrients, such as folates and amino acids, directly contributes to OCM, thereby adapting the cellular metabolic state to environmental inputs. The contribution of OCM to cellular proliferation during development and in adult proliferative tissues is well established. Nevertheless, accumulating evidence reveals the pivotal role of OCM in cellular homeostasis of non-proliferative tissues and in coordination of signaling cascades that regulate energy homeostasis and longevity. In this review, we summarize the current knowledge on OCM and related pathways and discuss how this metabolic network may impact longevity and neurodegeneration across species.

Keywords:  Alzheimer’s disease; Parkinson disease; aging; diet; folate; metabolism; methionine; mitochondria; neurodegeneration; one-carbon vitamins

DOI:  https://doi.org/10.3390/cells11020214
Biomolecules. 2022 Jan 10. pii: 108. [Epub ahead of print]12(1):

Early Blockade of CB1 Receptors Ameliorates Schizophrenia-like Alterations in the Neurodevelopmental MAM Model of Schizophrenia.

Tibor Stark, Fabio Arturo Iannotti, Serena Di Martino, Martina Di Bartolomeo, Jana Ruda-Kucerova, Fabiana Piscitelli, Carsten T Wotjak, Claudio D'Addario, Filippo Drago, Vincenzo Di Marzo, Vincenzo Micale.

  In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of Sprague-Dawley rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produces long-lasting behavioral alterations such as social withdrawal and cognitive impairment in adulthood, mimicking a schizophrenia-like phenotype. These abnormalities were preceded at neonatal age both by the delayed appearance of neonatal reflexes, an index of impaired brain maturation, and by higher 2-arachidonoylglycerol (2-AG) brain levels. Schizophrenia-like deficits were reversed by early treatment [from postnatal day (PND) 2 to PND 8] with the CB1 antagonist/inverse agonist AM251 (0.5 mg/kg/day). By contrast, early CB1 blockade affected the behavioral performance of control rats which was paralleled by enhanced 2-AG content in the prefrontal cortex (PFC). These results suggest that prenatal MAM insult leads to premorbid anomalies at neonatal age via altered tone of the endocannabinoid system, which may be considered as an early marker preceding the development of schizophrenia-like alterations in adulthood.

Keywords:  2-arachidonoylglycerol (2-AG); AM251; MAM model; cannabinoid CB1 receptor; endocannabinoid system; schizophrenia

DOI:  https://doi.org/10.3390/biom12010108
Int J Mol Sci. 2022 Jan 16. pii: 960. [Epub ahead of print]23(2):

Glial Modulation of Energy Balance: The Dorsal Vagal Complex Is No Exception.

Jean-Denis Troadec, Stéphanie Gaigé, Manon Barbot, Bruno Lebrun, Rym Barbouche, Anne Abysique.

  The avoidance of being overweight or obese is a daily challenge for a growing number of people. The growing proportion of people suffering from a nutritional imbalance in many parts of the world exemplifies this challenge and emphasizes the need for a better understanding of the mechanisms that regulate nutritional balance. Until recently, research on the central regulation of food intake primarily focused on neuronal signaling, with little attention paid to the role of glial cells. Over the last few decades, our understanding of glial cells has changed dramatically. These cells are increasingly regarded as important neuronal partners, contributing not just to cerebral homeostasis, but also to cerebral signaling. Our understanding of the central regulation of energy balance is part of this (r)evolution. Evidence is accumulating that glial cells play a dynamic role in the modulation of energy balance. In the present review, we summarize recent data indicating that the multifaceted glial compartment of the brainstem dorsal vagal complex (DVC) should be considered in research aimed at identifying feeding-related processes operating at this level.

Keywords:  NTS; area postrema; astrocytes; food intake; glucose; leptin; metabolism; microglia; obesity; oligodendrocytes; vagliocytes

DOI:  https://doi.org/10.3390/ijms23020960
Nutrients. 2022 Jan 12. pii: 300. [Epub ahead of print]14(2):

Oral Administration of Nicotinamide Mononucleotide Increases Nicotinamide Adenine Dinucleotide Level in an Animal Brain.

Chidambaram Ramanathan, Thomas Lackie, Drake H Williams, Paul S Simone, Yufeng Zhang, Richard J Bloomer.

  As a redox-sensitive coenzyme, nicotinamide adenine dinucleotide (NAD+) plays a central role in cellular energy metabolism and homeostasis. Low NAD+ levels are linked to multiple disease states, including age-related diseases, such as metabolic and neurodegenerative diseases. Consequently, restoring/increasing NAD+ levels in vivo has emerged as an important intervention targeting age-related neurodegenerative diseases. One of the widely studied approaches to increase NAD+ levels in vivo is accomplished by using NAD+ precursors, such as nicotinamide mononucleotide (NMN). Oral administration of NMN has been shown to successfully increase NAD+ levels in a variety of tissues; however, it remains unclear whether NMN can cross the blood-brain barrier to increase brain NAD+ levels. This study evaluated the effects of oral NMN administration on NAD+ levels in C57/B6J mice brain tissues. Our results demonstrate that oral gavage of 400 mg/kg NMN successfully increases brain NAD+ levels in mice after 45 min. These findings provide evidence that NMN may be used as an intervention to increase NAD+ levels in the brain.

Keywords:  NAD+; NMN; brain; mice; oral gavage

DOI:  https://doi.org/10.3390/nu14020300
Metab Brain Dis. 2022 Jan 19.

Effect of blueberry extract on energetic metabolism, levels of brain-derived neurotrophic factor, and Ca2+-ATPase activity in the hippocampus and cerebral cortex of rats submitted to ketamine-induced mania-like behavior.

Luiza Spohr, Mayara Sandrielly Pereira Soares, Natália Pontes Bona, Nathalia Stark Pedra, Alethéa Gatto Barschak, Rafaela Martins Alvariz, Marcia Vizzotto, Claiton Leoneti Lencina, Francieli Moro Stefanello, Roselia Maria Spanevello.

  Bipolar disorder (BD) is a psychiatric disease characterized by mood episodes. Blueberry is rich in bioactive compounds and shows excellent therapeutic potential against chronic diseases. The aim of this study was to evaluate the effects of blueberry extract on behavior, energetic metabolism, Ca2+-ATPase activity, and levels of brain-derived neurotrophic factor (BDNF) in the cerebral cortex and hippocampus of rats submitted to an animal model of mania induced by ketamine. Vehicle, lithium (45 mg/kg, twice a day), or blueberry extract (200 mg/kg), was orally administered to Wistar rats for 14 days. Ketamine (25 mg/kg) or vehicle was administered intraperitoneally, once a day, between the 8th and 14th day. On the 15th day, animals received ketamine or vehicle and were subjected to the open field test. Our results demonstrated that the administration of lithium and blueberry extract prevented ketamine-induced hyperlocomotion (P < 0.01). Blueberry extract attenuated the ketamine-induced reduction in the activity of complex I in the cerebral cortex (P < 0.05). Additionally, the administration of ketamine reduced the activities of complexes I and IV (P < 0.05) and citrate synthase in the hippocampus (P < 0.01). However, blueberry extract attenuated the inhibition in the activity of complex IV (P < 0.01). Furthermore, ketamine reduced the Ca2+-ATPase activity in the cerebral cortex and hippocampus (P < 0.05); however, blueberry extract prevented the change in the cerebral cortex (P < 0.05). There were no significant alterations in the levels of BDNF (P > 0.05). In conclusion, this suggested that the blueberry extract can serve as a potential therapeutic strategy for studies searching for novel therapeutic alternatives for BD patients.

Keywords:  Anthocyanins; Behavior; Bipolar disorder; Manic-like; Mitochondria

DOI:  https://doi.org/10.1007/s11011-022-00904-x
Front Cell Neurosci. 2021 ;15 788262

Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus.

Theresa S Rimmele, Shaomin Li, Jens Velde Andersen, Emil W Westi, Alexander Rotenberg, Jianlin Wang, Blanca Irene Aldana, Dennis J Selkoe, Chiye J Aoki, Chris G Dulla, Paul Allen Rosenberg.

  GLT-1, the major glutamate transporter in the mammalian central nervous system, is expressed in presynaptic terminals that use glutamate as a neurotransmitter, in addition to astrocytes. It is widely assumed that glutamate homeostasis is regulated primarily by glutamate transporters expressed in astrocytes, leaving the function of GLT-1 in neurons relatively unexplored. We generated conditional GLT-1 knockout (KO) mouse lines to understand the cell-specific functions of GLT-1. We found that stimulus-evoked field extracellular postsynaptic potentials (fEPSPs) recorded in the CA1 region of the hippocampus were normal in the astrocytic GLT-1 KO but were reduced and often absent in the neuronal GLT-1 KO at 40 weeks. The failure of fEPSP generation in the neuronal GLT-1 KO was also observed in slices from 20 weeks old mice but not consistently from 10 weeks old mice. Using an extracellular FRET-based glutamate sensor, we found no difference in stimulus-evoked glutamate accumulation in the neuronal GLT-1 KO, suggesting a postsynaptic cause of the transmission failure. We hypothesized that excitotoxicity underlies the failure of functional recovery of slices from the neuronal GLT-1 KO. Consistent with this hypothesis, the non-competitive NMDA receptor antagonist MK801, when present in the ACSF during the recovery period following cutting of slices, promoted full restoration of fEPSP generation. The inclusion of an enzymatic glutamate scavenging system in the ACSF conferred partial protection. Excitotoxicity might be due to excess release or accumulation of excitatory amino acids, or to metabolic perturbation resulting in increased vulnerability to NMDA receptor activation. Previous studies have demonstrated a defect in the utilization of glutamate by synaptic mitochondria and aspartate production in the synGLT-1 KO in vivo, and we found evidence for similar metabolic perturbations in the slice preparation. In addition, mitochondrial cristae density was higher in synaptic mitochondria in the CA1 region in 20-25 weeks old synGLT-1 KO mice in the CA1 region, suggesting compensation for loss of axon terminal GLT-1 by increased mitochondrial efficiency. These data suggest that GLT-1 expressed in presynaptic terminals serves an important role in the regulation of vulnerability to excitotoxicity, and this regulation may be related to the metabolic role of GLT-1 expressed in glutamatergic axon terminals.

Keywords:  Alzheimer’s disease; aging; excitotoxicity glutamatergic; homeostasis; mitochondria; neurodegeneration; repair

DOI:  https://doi.org/10.3389/fncel.2021.788262
Antioxidants (Basel). 2021 Dec 24. pii: 41. [Epub ahead of print]11(1):

Insulin-like Growth Factor II Prevents MPP+ and Glucocorticoid Mitochondrial-Oxidative and Neuronal Damage in Dopaminergic Neurons.

Silvia Claros, Pablo Cabrera, Nadia Valverde, Silvana Y Romero-Zerbo, Manuel Víctor López-González, Kirill Shumilov, Alicia Rivera, Jose Pavia, Elisa Martín-Montañez, María Garcia-Fernandez.

  Stress seems to contribute to Parkinson's disease (PD) neuropathology, probably by dysregulation of the hypothalamic-pituitary-adrenal axis. Key factors in this pathophysiology are oxidative stress and mitochondrial dysfunction and neuronal glucocorticoid-induced toxicity. The insulin-like growth factor II (IGF-II), a pleiotropic hormone, has shown antioxidant and neuroprotective effects in some neurodegenerative disorders. Our aim was to examine the protective effect of IGF-II on a dopaminergic cellular combined model of PD and mild to moderate stress measuring oxidative stress parameters, mitochondrial and neuronal markers, and signalling pathways. IGF-II counteracts the mitochondrial-oxidative damage produced by the toxic synergistic effect of corticosterone and 1-methyl-4-phenylpyridinium, protecting dopaminergic neurons from death and neurodegeneration. IGF-II promotes PKC activation and nuclear factor (erythroid-derived 2)-like 2 antioxidant response in a glucocorticoid receptor-dependent pathway, preventing oxidative cell damage and maintaining mitochondrial function. Thus, IGF-II is a potential therapeutic tool for treatment and prevention of disease progression in PD patients suffering mild to moderate emotional stress.

Keywords:  Parkinson’s disease; hormonal stress; insulin-like growth factor II; mitochondria; neuroprotection; oxidative stress

DOI:  https://doi.org/10.3390/antiox11010041
Mol Neurobiol. 2022 Jan 18.

The Protective Effects of Mogroside V Against Neuronal Damages by Attenuating Mitochondrial Dysfunction via Upregulating Sirtuin3.

Hanjiang Luo, Caixia Peng, Xiaofeng Xu, Yuntao Peng, Fang Shi, Qinghua Li, Jianghui Dong, Min Chen.

  Mitochondrial dysfunction and oxidative stress are thought to play a dominant role in the pathogenesis of Parkinson's disease (PD). Mogroside V (MV), extracted from Siraitia grosvenorii, exhibits antioxidant-like activities. The aim of this study was to investigate the function of MV in neuroprotection in PD and to reveal its mechanism of action. To that end, we firstly set up mice models of PD with unilateral striatum injection of 0.25 mg/kg rotenone (Rot) and co-treated with 2.5 mg/kg, 5 mg/kg, and 10 mg/kg MV by gavage. Results showed that Rot-induced motor impairments and dopaminergic neuronal damage were reversed by treatment of 10 mg/kg MV. Then, we established cellular models of PD using Rot-treated SH-SY5Y cells, which were divided into six groups, including control, Rot, and co-enzyme Q10 (CQ10), as well as MV groups, MV25, MV50, and MV100 treated with 25 μM, 50 μM, and 100 μM MV doses, respectively. Results demonstrated that MV effectively attenuates Rot neurotoxicity through a ROS-related intrinsic mitochondrial pathway. MV reduced overproduction of reactive oxygen species (ROS), recovered the mitochondrial membrane potential (MMP), and increased the oxygen consumption rate and adenosine triphosphate (ATP) production in a dose-dependent manner. Hence, treatment with MV led to a reduction in the number of apoptotic cells, as reflected by Annexin-V/propidium iodide co-staining using flow cytometry and TdT-mediated dUTP Nick-End Labeling (TUNEL) assay. In addition, the Sirtuin3 (SIRT3) protein level and activity were decreased upon exposure to Rot both in substantia nigra (SN) of mice and SH-SY5Y cells. SIRT3 impairment hyperacetylated a key mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2). MV alleviates SIRT3 and SOD2 molecular changes. However, after successfully inhibiting SIRT3 by its specific inhibitor 3-1H-1, 2, 3-triazol-4-yl pyridine (3TYP), MV was not able to reduce ROS levels, reverse abnormal MMP, or decrease apoptotic cells. Motor impairments and dopaminergic neuronal injury in the SN were alleviated with the oral administration of MV in Rot-treated PD mice, indicating a relationship between protection against defective motility and preservation of dopaminergic neurons. Therefore, we conclude that MV can alleviate Rot-induced neurotoxicity in a PD model, and that SIRT3 may be an important regulator in the protection of MV.

Keywords:  Mitochondria-dependent apoptosis; Mogroside V; Parkinson’s disease; Rotenone; Sirtuin3

DOI:  https://doi.org/10.1007/s12035-021-02689-z
Brain Sci. 2021 Dec 31. pii: 65. [Epub ahead of print]12(1):

Pyridoxine-Dependent Epilepsy and Antiquitin Deficiency Resulting in Neonatal-Onset Refractory Seizures.

Konrad Kaminiów, Magdalena Pająk, Renata Pająk, Justyna Paprocka.

  Pyridoxine-dependent epilepsy (PDE) is an autosomal recessive neurometabolic disorder due to a deficiency of α-aminoadipic semialdehyde dehydrogenase (mutation in ALDH7A1 gene), more commonly known as antiquitin (ATQ). ATQ is one of the enzymes involved in lysine oxidation; thus, its deficiency leads to the accumulation of toxic metabolites in body fluids. PDE is characterized by persistent, recurrent neonatal seizures that cannot be well controlled by antiepileptic drugs but are responsive clinically and electrographically to daily pyridoxine (vitamin B6) supplementation. Although the phenotypic spectrum distinguishes between typical and atypical, pyridoxine-dependent is true for each. Diagnosis may pose a challenge mainly due to the rarity of the disorder and the fact that seizures may not occur until childhood or even late adolescence. Moreover, patients may not demonstrate an obvious clinical or electroencephalography response to the initial dose of pyridoxine. Effective treatment requires lifelong pharmacologic supplements of pyridoxine, and dietary lysine restriction and arginine enrichment should improve prognosis and avoid developmental delay and intellectual disability. The purpose of this review is to summarize briefly the latest reports on the etiology, clinical symptoms, diagnosis, and management of patients suffering from pyridoxine-dependent epilepsy.

Keywords:  ALDH7A1; inborn errors of metabolism; metabolic epilepsy; pyridoxine-dependent epilepsy; seizures

DOI:  https://doi.org/10.3390/brainsci12010065