bims-medebr 2021-12-12 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2021–12–12
thirty-one papers selected by
Regina F. Fernández, Johns Hopkins University

Brain Intrinsic Functional Activity in Relation to Metabolic Changes in Alzheimer's Disease: A Simultaneous PET/fMRI study.
Mitochondria in Early Forebrain Development: From Neurulation to Mid-Corticogenesis.
Astrocyte Bioenergetics and Major Psychiatric Disorders.
Oleanolic Acid Provides Neuroprotection against Ischemic Stroke through the Inhibition of Microglial Activation and NLRP3 Inflammasome Activation.
Proteomic Identification of an Endogenous Synaptic SUMOylome in the Developing Rat Brain.
Evaluation of radiolabeled acetylcholine synthesis and release in rat striatum.
Autophagy-Induced HDAC6 Activity During Hypoxia Regulates Mitochondrial Energy Metabolism Through the β-Catenin/COUP-TFII Axis in Hepatocellular Carcinoma Cells.
Effects of Post-natal Dietary Milk Fat Globule Membrane Polar Lipid Supplementation on Motor Skills, Anxiety, and Long-Term Memory in Adulthood.
Maternal-fetal transmission of delta-9-tetrahydrocannabinol (THC) and its metabolites following inhalation and injection exposure during pregnancy in rats.
N-Acetyl Cysteine Restores Sirtuin-6 and Decreases HMGB1 Release Following Lipopolysaccharide-Sensitized Hypoxic-Ischemic Brain Injury in Neonatal Mice.
Mitochondrial Transport in Glycolysis and Gluconeogenesis: Achievements and Perspectives.
Expression of PON2 isoforms varies among brain regions in male and female African green monkeys.
α-Lipoic Acid Has the Potential to Normalize Copper Metabolism, Which Is Dysregulated in Alzheimer's Disease.
Evolutionarily Established Palmitoylation-Dependent Regulatory Mechanisms of the Vertebrate Glutamatergic Synapse and Diseases Caused by Their Disruption.
20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis.
Disturbed cerebral circulation and metabolism matters: A preface to the special issue "Stroke and Energy Metabolism".
Potential Crosstalk Between Parkinson's Disease and Energy Metabolism.
Assessment of behavioral, morphological and electrophysiological changes in prenatal and postnatal valproate induced rat models of autism spectrum disorder.
Strategies to protect against age-related mitochondrial decay: Do natural products and their derivatives help?
Loss of monocarboxylate transporter 1 aggravates white matter injury after experimental subarachnoid hemorrhage in rats.
Energy Metabolism Measured by 31P Magnetic Resonance Spectroscopy in the Healthy Human Brain.
Fairly Criticized, or Politicized? Conflicts in the Neuroscience of Sex Differences in the Human Brain.
Dietary Fish Hydrolysate Improves Memory Performance Through Microglial Signature Remodeling During Aging.
Nutrition and cognition across the lifetime: an overview on epigenetic mechanisms.
Comprehensive analysis of protein acetylation and glucose metabolism inmouse brains infected with rabies virus.
Etifoxine Restores Mitochondrial Oxidative Phosphorylation and Improves Cognitive Recovery Following Traumatic Brain Injury.
Ketogenic Diet as a potential treatment for traumatic brain injury in mice.
Preterm nutrition and neurodevelopmental outcomes.
Expression of D5 dopamine receptors in the walls of the lateral ventricles during the post-weaning rat development.
Melatonin as a Potential Regulator of Oxidative Stress, and Neuroinflammation: Mechanisms and Implications for the Management of Brain Injury-Induced Neurodegeneration.
Dietary factors and brain health.

Annu Int Conf IEEE Eng Med Biol Soc. 2021 Nov;2021 3467-3470

Brain Intrinsic Functional Activity in Relation to Metabolic Changes in Alzheimer's Disease: A Simultaneous PET/fMRI study.

Wanqing Sun, Miao Zhang, Yaoyu Zhang, Biao Li, Yao Li.

Previous studies have shown that the intrinsic brain functional activity significantly reduced in a variety of regions of Alzheimer's disease (AD) patients. However, the associated underlying metabolic mechanism remains not clear. Brain activity is primarily driven by the dynamic activity of neurons and their interconnections, which are regulated by synapses and are closely related to glucose uptakes. Simultaneous FDG-PET/fMRI imaging provides a unique opportunity to measure the concurrent brain functional activity and cerebral glucose metabolism information. In this study, using simultaneous resting-state PET/fMRI imaging, we investigated the concurrent global intrinsic activity and metabolic signal changes in AD patients. Twenty-two controls and nineteen AD patients were included. We compared the whole-brain amplitude of low frequency fluctuations (ALFF) measured using fMRI imaging and glucose uptake maps acquired from PET imaging between the two groups. Both maps showed significant reductions in the precuneus and left inferior parietal lobule (IPL) in AD compared to the control groups. Moreover, the ALFF within the precuneus and left IPL were significantly correlated with the colocalized glucose metabolism. The ALFF in the left IPL was significantly correlated with patient cognitive performance evaluated using MMSE or MoCA. Our findings provide useful insights into the understanding of brain intrinsic functional-metabolic activity and its role in AD pathology.

DOI: https://doi.org/10.1109/EMBC46164.2021.9630966
Front Cell Dev Biol. 2021 ;9 780207

Mitochondria in Early Forebrain Development: From Neurulation to Mid-Corticogenesis.

Ryann M Fame, Maria K Lehtinen.

  Function of the mature central nervous system (CNS) requires a substantial proportion of the body's energy consumption. During development, the CNS anlage must maintain its structure and perform stage-specific functions as it proceeds through discrete developmental stages. While key extrinsic signals and internal transcriptional controls over these processes are well appreciated, metabolic and mitochondrial states are also critical to appropriate forebrain development. Specifically, metabolic state, mitochondrial function, and mitochondrial dynamics/localization play critical roles in neurulation and CNS progenitor specification, progenitor proliferation and survival, neurogenesis, neural migration, and neurite outgrowth and synaptogenesis. With the goal of integrating neurodevelopmental biologists and mitochondrial specialists, this review synthesizes data from disparate models and processes to compile and highlight key roles of mitochondria in the early development of the CNS with specific focus on forebrain development and corticogenesis.

Keywords:  corticogenesis; development; forebrain; metabolism; mitochondria; neural tube closure; neurulation

DOI:  https://doi.org/10.3389/fcell.2021.780207
Adv Neurobiol. 2021 ;26 173-227

Astrocyte Bioenergetics and Major Psychiatric Disorders.

Ivan V Maly, Michael J Morales, Mikhail V Pletnikov.

  Ongoing research continues to add new elements to the emerging picture of involvement of astrocyte energy metabolism in the pathophysiology of major psychiatric disorders, including schizophrenia, mood disorders, and addictions. This review outlines what is known about the energy metabolism in astrocytes, the most numerous cell type in the brain, and summarizes the recent work on how specific perturbations of astrocyte bioenergetics may contribute to the neuropsychiatric conditions. The role of astrocyte energy metabolism in mental health and disease is reviewed on the organism, organ, and cell level. Data arising from genomic, metabolomic, in vitro, and neurobehavioral studies is critically analyzed to suggest future directions in research and possible metabolism-focused therapeutic interventions.

Keywords:  Astrocyte; Bioenergetics; Glycolysis; Mitochondria; Psychiatric disorders

DOI:  https://doi.org/10.1007/978-3-030-77375-5_9
Biomol Ther (Seoul). 2021 Dec 07.

Oleanolic Acid Provides Neuroprotection against Ischemic Stroke through the Inhibition of Microglial Activation and NLRP3 Inflammasome Activation.

Arjun Sapkota, Ji Woong Choi.

  Oleanolic acid (OA), a natural pentacyclic triterpenoid, has been reported to exert protective effects against several neurological diseases through its anti-oxidative and anti-inflammatory activities. The goal of the present study was to evaluate the therapeutic potential of OA against acute and chronic brain injuries after ischemic stroke using a mouse model of transient middle cerebral artery occlusion (tMCAO, MCAO/reperfusion). OA administration immediately after reperfusion significantly attenuated acute brain injuries including brain infarction, functional neurological deficits, and neuronal apoptosis. Moreover, delayed administration of OA (at 3 h after reperfusion) attenuated brain infarction and improved functional neurological deficits during the acute phase. Such neuroprotective effects were associated with attenuation of microglial activation and lipid peroxidation in the injured brain after the tMCAO challenge. OA also attenuated NLRP3 inflammasome activation in activated microglia during the acute phase. In addition, daily administration of OA for 7 days starting from either immediately after reperfusion or 1 day after reperfusion significantly improved functional neurological deficits and attenuated brain tissue loss up to 21 days after the tMCAO challenge; these findings supported therapeutic effects of OA against ischemic stroke-induced chronic brain injury. Together, these findings showed that OA exerted neuroprotective effects against both acute and chronic brain injuries after tMCAO challenge, suggesting that OA is a potential therapeutic agent to treat ischemic stroke.

Keywords:  Ischemic stroke; Lipid peroxidation; Microglia; NLRP3 inflammasome activation; Oleanolic acid

DOI:  https://doi.org/10.4062/biomolther.2021.154
Front Mol Neurosci. 2021 ;14 780535

Proteomic Identification of an Endogenous Synaptic SUMOylome in the Developing Rat Brain.

Marie Pronot, Félicie Kieffer, Anne-Sophie Gay, Delphine Debayle, Raphaël Forquet, Gwénola Poupon, Lenka Schorova, Stéphane Martin, Carole Gwizdek.

  Synapses are highly specialized structures that interconnect neurons to form functional networks dedicated to neuronal communication. During brain development, synapses undergo activity-dependent rearrangements leading to both structural and functional changes. Many molecular processes are involved in this regulation, including post-translational modifications by the Small Ubiquitin-like MOdifier SUMO. To get a wider view of the panel of endogenous synaptic SUMO-modified proteins in the mammalian brain, we combined subcellular fractionation of rat brains at the post-natal day 14 with denaturing immunoprecipitation using SUMO2/3 antibodies and tandem mass spectrometry analysis. Our screening identified 803 candidate SUMO2/3 targets, which represents about 18% of the synaptic proteome. Our dataset includes neurotransmitter receptors, transporters, adhesion molecules, scaffolding proteins as well as vesicular trafficking and cytoskeleton-associated proteins, defining SUMO2/3 as a central regulator of the synaptic organization and function.

Keywords:  SUMO; SUMOylome; post-translational modification; proteomics; synapse

DOI:  https://doi.org/10.3389/fnmol.2021.780535
J Neurochem. 2021 Dec 08.

Evaluation of radiolabeled acetylcholine synthesis and release in rat striatum.

Ikunobu Muramatsu, Junsuke Uwada, Kazuyasu Chihara, Kiyonao Sada, Mao-Hsien Wang, Takashi Yazawa, Takanobu Taniguchi, Takaharu Ishibashi, Takayoshi Masuoka.

  Cholinergic transmission underlies higher brain functions such as cognition and movement. To elucidate the process whereby acetylcholine (ACh) release is maintained and regulated in the central nervous system, uptake of [3H]choline and subsequent synthesis and release of [3H]ACh were investigated in rat striatal segments. Incubation with [3H]choline elicited efficient uptake via high-affinity choline transporter-1, resulting in accumulation of [3H]choline and [3H]ACh. However, following inhibition of ACh esterase (AChE), incubation with [3H]choline led predominantly to the accumulation of [3H]ACh. Electrical stimulation and KCl depolarization selectively released [3H]ACh but not [3H]choline. [3H]ACh release gradually declined upon repetitive stimulation, whereas the release was reproducible under inhibition of AChE. [3H]ACh release was abolished after treatment with vesamicol, an inhibitor of vesicular ACh transporter. These results suggest that releasable ACh is continually replenished from the cytosol to releasable pools of cholinergic vesicles to maintain cholinergic transmission. [3H]ACh release evoked by electrical stimulation was abolished by tetrodotoxin, but that induced by KCl was largely resistant. ACh release was Ca2+ dependent and exhibited slightly different sensitivities to N- and P-type Ca2+ channel toxins (ω- conotoxin GVIA and ω-agatoxin IVA, respectively) between both stimuli. [3H]ACh release was negatively regulated by M2 muscarinic and D2 dopaminergic receptors. The present results suggest that inhibition of AChE within cholinergic neurons and of presynaptic negative regulation of ACh release contributes to maintenance and facilitation of cholinergic transmission, providing a potentially useful clue for the development of therapies for cholinergic dysfunction-associated disorders, in addition to inhibition of synaptic cleft AChE.

Keywords:  Acetylcholine; acetylcholine esterase; choline; cholinergic release; presynaptic modulation; striatum

DOI:  https://doi.org/10.1111/jnc.15556
Front Oncol. 2021 ;11 742460

Autophagy-Induced HDAC6 Activity During Hypoxia Regulates Mitochondrial Energy Metabolism Through the β-Catenin/COUP-TFII Axis in Hepatocellular Carcinoma Cells.

Xiaoyu Yan, Xianzhi Qu, Buhan Liu, Yuanxin Zhao, Long Xu, Sihang Yu, Jian Wang, Liying Wang, Jing Su.

  Hypoxia is one of the main driving forces that results in poor outcomes and drug resistance in hepatocellular carcinoma (HCC). As the critical cellular oxygen sensor, mitochondria respond to hypoxic stress by sending retrograde signals to the nucleus that initiate adaptive metabolic responses and maintain the survival of HCC cells. Increasing evidence suggested autophagy contributes to sustain mitochondrial metabolic and quality control. Understanding how mitochondria communicate with the nucleus and alter transcription may provide promising targets for HCC treatment. In this study, we found mitochondrial undergoes selective degradation by autophagy under hypoxia. Furthermore, autophagy-activated HDAC6 not only promoted the nuclear translocation of β-catenin but also increased the affinity of β-catenin to the transcription repressor chicken ovalbumin upstream promoter-transcription factor 2 (COUP-TF II), which suppressed mitochondrial oxidative phosphorylation-related genes transcription. Our data showed that autophagy served as a critical mediator of integrating mitochondrial energy metabolism and nuclear transcription. HDAC6 may be a potential target for reducing the survival of HCC cells by interrupting mitochondria-nucleus crosstalk.

Keywords:  HDAC6; autophagy; hepatocellular carcinoma; hypoxia; mitochondrial energy metabolism; β-catenin

DOI:  https://doi.org/10.3389/fonc.2021.742460
Front Nutr. 2021 ;8 737731

Effects of Post-natal Dietary Milk Fat Globule Membrane Polar Lipid Supplementation on Motor Skills, Anxiety, and Long-Term Memory in Adulthood.

Sébastien Sultan, Jonas Hauser, Manuel Oliveira, Andreas Rytz, Nicolas Preitner, Nora Schneider.

  Early life nutrition critically impacts post-natal brain maturation and cognitive development. Post-natal dietary deficits in specific nutrients, such as lipids, minerals or vitamins are associated with brain maturation and cognitive impairments. Specifically, polar lipids (PL), such as sphingolipids and phospholipids, are important cellular membrane building blocks and are critical for brain connectivity due to their role in neurite outgrowth, synaptic formation, and myelination. In this preclinical study, we assessed the effects of a chronic supplementation with a source of PL extracted from an alpha-lactalbumin enriched whey protein containing 10% lipids from early life (post-natal day (PND) 7) to adulthood (PND 72) on adult motor skills, anxiety, and long-term memory. The motor skills were assessed using open field and rotarod test. Anxiety was assessed using elevated plus maze (EPM). Long-term object and spatial memory were assessed using novel object recognition (NOR) and Morris water maze (MWM). Our results suggest that chronic PL supplementation improved measures of spatial long-term memory accuracy and cognitive flexibility in the MWM in adulthood, with no change in general mobility, anxiety and exploratory behavior. Our results indicate memory specific functional benefits of long-term dietary PL during post-natal brain development.

Keywords:  learning; memory; neurodevelopment; nutrition; polar lipids

DOI:  https://doi.org/10.3389/fnut.2021.737731
J Neurosci Res. 2021 Dec 09.

Maternal-fetal transmission of delta-9-tetrahydrocannabinol (THC) and its metabolites following inhalation and injection exposure during pregnancy in rats.

Samantha L Baglot, Jonathan W VanRyzin, Ashley E Marquardt, Robert J Aukema, Gavin N Petrie, Catherine Hume, Erin L Reinl, John B Bieber, Ryan J McLaughlin, Margaret M McCarthy, Matthew N Hill.

  Cannabis use during pregnancy has increased over the past few decades, with recent data indicating that, in youth and young adults especially, up to 22% of people report using cannabis during pregnancy. Animal models provide the ability to study prenatal cannabis exposure (PCE) with control over timing and dosage; however, these studies utilize both injection and inhalation approaches. While it is known that Δ9-tetrahydrocannabinol (THC; primary psychoactive component of cannabis) can cross the placenta, examination of the transmission and concentration of THC and its metabolites from maternal blood into the placenta and fetal brain remains relatively unknown, and the influence of route of administration has never been examined. Pregnant female rats were exposed to either vaporized THC-dominant cannabis extract for pulmonary consumption or subcutaneous injection of THC repeatedly during the gestational period. Maternal blood, placenta, and fetal brains were collected following the final administration of THC for analysis of THC and its metabolites, as well as endocannabinoid concentrations, through mass spectrometry. Both routes of administration resulted in the transmission of THC and its metabolites in placenta and fetal brain. Repeated exposure to inhaled THC vapor resulted in fetal brain THC concentrations that were about 30% of those seen in maternal blood, whereas repeated injections resulted in roughly equivalent concentrations of THC in maternal blood and fetal brain. Neither inhalation nor injection of THC during pregnancy altered fetal brain endocannabinoid concentrations. Our data provide the first characterization of maternal-fetal transmission of THC and its metabolites following both vaporized delivery and injection routes of administration. These data are important to establish the maternal-fetal transmission in preclinical injection and inhalation models of PCE and may provide insight into predicting fetal exposure in human studies.

Keywords:  THC; cannabis; fetal; inhalation; injection; pharmacokinetics; pregnancy; rat; vapor

DOI:  https://doi.org/10.1002/jnr.24992
Front Cell Neurosci. 2021 ;15 743093

N-Acetyl Cysteine Restores Sirtuin-6 and Decreases HMGB1 Release Following Lipopolysaccharide-Sensitized Hypoxic-Ischemic Brain Injury in Neonatal Mice.

Gagandeep Singh-Mallah, Takuya Kawamura, Maryam Ardalan, Tetyana Chumak, Pernilla Svedin, Peter G Arthur, Christopher James, Henrik Hagberg, Mats Sandberg, Carina Mallard.

  Inflammation and neonatal hypoxia-ischemia (HI) are important etiological factors of perinatal brain injury. However, underlying mechanisms remain unclear. Sirtuins are a family of nicotinamide adenine dinucleotide (NAD)+-dependent histone deacetylases. Sirtuin-6 is thought to regulate inflammatory and oxidative pathways, such as the extracellular release of the alarmin high mobility group box-1 (HMGB1). The expression and role of sirtuin-6 in neonatal brain injury are unknown. In a well-established model of neonatal brain injury, which encompasses inflammation (lipopolysaccharide, LPS) and hypoxia-ischemia (LPS+HI), we investigated the protein expression of sirtuin-6 and HMGB1, as well as thiol oxidation. Furthermore, we assessed the effect of the antioxidant N-acetyl cysteine (NAC) on sirtuin-6 expression, nuclear to cytoplasmic translocation, and release of HMGB1 in the brain and blood thiol oxidation after LPS+HI. We demonstrate reduced expression of sirtuin-6 and increased release of HMGB1 in injured hippocampus after LPS+HI. NAC treatment restored sirtuin-6 protein levels, which was associated with reduced extracellular HMGB1 release and reduced thiol oxidation in the blood. The study suggests that early reduction in sirtuin-6 is associated with HMGB1 release, which may contribute to neonatal brain injury, and that antioxidant treatment is beneficial for the alleviation of these injurious mechanisms.

Keywords:  high-mobility group box 1 protein; hypoxia-ischemia; lipopolysaccharide; n-acetyl cysteine; sirtuins

DOI:  https://doi.org/10.3389/fncel.2021.743093
Int J Mol Sci. 2021 Nov 23. pii: 12620. [Epub ahead of print]22(23):

Mitochondrial Transport in Glycolysis and Gluconeogenesis: Achievements and Perspectives.

Salvatore Passarella, Avital Schurr, Piero Portincasa.

  Some metabolic pathways involve two different cell components, for instance, cytosol and mitochondria, with metabolites traffic occurring from cytosol to mitochondria and vice versa, as seen in both glycolysis and gluconeogenesis. However, the knowledge on the role of mitochondrial transport within these two glucose metabolic pathways remains poorly understood, due to controversial information available in published literature. In what follows, we discuss achievements, knowledge gaps, and perspectives on the role of mitochondrial transport in glycolysis and gluconeogenesis. We firstly describe the experimental approaches for quick and easy investigation of mitochondrial transport, with respect to cell metabolic diversity. In addition, we depict the mitochondrial shuttles by which NADH formed in glycolysis is oxidized, the mitochondrial transport of phosphoenolpyruvate in the light of the occurrence of the mitochondrial pyruvate kinase, and the mitochondrial transport and metabolism of L-lactate due to the L-lactate translocators and to the mitochondrial L-lactate dehydrogenase located in the inner mitochondrial compartment.

Keywords:  L-lactate; gluconeogenesis; glycolysis; mitochondrial shuttles; mitochondrial transport; phosphoenolpyruvate

DOI:  https://doi.org/10.3390/ijms222312620
Free Radic Biol Med. 2021 Dec 07. pii: S0891-5849(21)00856-X. [Epub ahead of print]

Expression of PON2 isoforms varies among brain regions in male and female African green monkeys.

Sumit Jamwal, Jennifer K Blackburn, John D Elsworth.

  Mitochondrial dysfunction and oxidative stress contribute to the neuropathology of neurodegenerative disorders such as Parkinson's disease (PD). Paraoxonase-2 (PON2) is a mitochondrial protein that mitigates oxidative stress, enhances mitochondrial function and exhibits anti-inflammatory properties. Previously, we have documented sex-based variation in PON2 with higher brain PON2 expression in female (2-fold) as compared to male African green monkeys. This aim of this study is to identify PON2 isoforms and explore the region-based variations in the protein level of PON2 in brain of African green monkeys. Male and female brain tissue samples (striatum, hippocampus, occipital cortex, dorsolateral prefrontal cortex) from African green monkeys (Chlorocebus sabaeus) were analyzed by western blotting technique for PON2 expression. We found two PON2 isoforms (39 and 41 kDa) in each examined brain region of male and female monkeys. Male monkeys showed no significant difference in the expression level of PON2 isoforms among different brain regions whereas female monkeys showed a significant difference in the expression level of PON2 isoforms in all examined regions except dorsolateral prefrontal cortex. In addition, the result revealed highest expression of PON2 protein in striatum compared to other brain regions in both male and female monkeys. This report is the first to quantify expression of PON2 isoforms in different brain regions and it also establishes the existence of sex as well as region-based variation in PON2 protein expression in primate brain. Since PON2 serves a protective role for dopaminergic neurons it should be considered as a druggable target for oxidative stress-related neurodegenerative disorders like PD. We anticipate that the outcome of this study will contribute to the development of neuroprotective stratergies in PD.

Keywords:  Mitochondria; Neuroprotection; Oxidative stress; Paraoxonase-2; Parkinson's disease; Striatum

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.12.005
J Alzheimers Dis. 2021 Nov 30.

α-Lipoic Acid Has the Potential to Normalize Copper Metabolism, Which Is Dysregulated in Alzheimer's Disease.

Kristel Metsla, Sigrid Kirss, Katrina Laks, Gertrud Sildnik, Mari Palgi, Teele Palumaa, Vello Tõugu, Peep Palumaa.

   BACKGROUND: Alzheimer's disease (AD) is an age-dependent progressive neurodegenerative disorder and the most common cause of dementia. The treatment and prevention of AD present immense yet unmet needs. One of the hallmarks of AD is the formation of extracellular amyloid plaques in the brain, composed of amyloid-β (Aβ) peptides. Besides major amyloid-targeting approach there is the necessity to focus also on alternative therapeutic strategies. One factor contributing to the development of AD is dysregulated copper metabolism, reflected in the intracellular copper deficit and excess of extracellular copper.
OBJECTIVE: In the current study, we follow the widely accepted hypothesis that the normalization of copper metabolism leads to the prevention or slowing of the disease and search for new copper-regulating ligands.
METHODS: We used cell culture, ICP MS, and Drosophila melanogaster models of AD.
RESULTS: We demonstrate that the natural intracellular copper chelator, α-lipoic acid (LA) translocates copper from extracellular to intracellular space in an SH-SY5Y-based neuronal cell model and is thus suitable to alleviate the intracellular copper deficit characteristic of AD neurons. Furthermore, we show that supplementation with LA protects the Drosophila melanogaster models of AD from developing AD phenotype by improving locomotor activity of fruit fly with overexpression of human Aβ with Iowa mutation in the fly brain. In addition, LA slightly weakens copper-induced smooth eye phenotype when amyloid-β protein precursor (AβPP) and beta-site AβPP cleaving enzyme 1 (BACE1) are overexpressed in eye photoreceptor cells.
CONCLUSION: Collectively, these results provide evidence that LA has the potential to normalize copper metabolism in AD.

Keywords:  Alzheimer’s disease; copper metabolism; metalloneurochemistry; α-lipoic acid

DOI:  https://doi.org/10.3233/JAD-215026
Front Mol Neurosci. 2021 ;14 796912

Evolutionarily Established Palmitoylation-Dependent Regulatory Mechanisms of the Vertebrate Glutamatergic Synapse and Diseases Caused by Their Disruption.

Takashi Hayashi.

  Glutamate is the major excitatory neurotransmitter in the vertebrate brain and various modifications have been established in the glutamatergic synapses. Generally, many neuronal receptors and ion channels are regulated by S-palmitoylation, a reversible post-translational protein modification. Genome sequence databases show the evolutionary acquisition and conservation concerning vertebrate-specific palmitoylation of synaptic proteins including glutamate receptors. Moreover, palmitoylation of some glutamate receptor-binding proteins is subsequently acquired only in some mammalian lineages. Recent progress in genome studies has revealed that some palmitoylation-catalyzing enzymes are the causative genes of neuropsychiatric disorders. In this review, I will summarize the evolutionary development of palmitoylation-dependent regulation of glutamatergic synapses and their dysfunctions which are caused by the disruption of palmitoylation mechanism.

Keywords:  PDZ protein; eutherian; evolution; excitatory synapse; glutamate receptor (GluR); palmitoylation; vertebrate

DOI:  https://doi.org/10.3389/fnmol.2021.796912
Front Neurol. 2021 ;12 763419

20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis.

Ranran Han, Jieru Wan, Xiaoning Han, Honglei Ren, John R Falck, Sailu Munnuri, Zeng-Jin Yang, Raymond C Koehler.

  Intracerebral hemorrhage (ICH) is a highly fatal type of stroke that leads to various types of neuronal death. Recently, ferroptosis, a form of cell death resulting from iron-dependent lipid peroxide accumulation, was observed in a mouse ICH model. N-hydroxy-N'-(4-n-butyl-2-methylphenyl)-formamidine (HET0016), which inhibits synthesis of the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE), has shown a protective effect after ICH. However, the underlying mechanisms of the neuroprotective effect need further investigation. We explored whether 20-HETE participates in ICH-induced ferroptosis ex vivo by using hemoglobin-treated organotypic hippocampal slice cultures (OHSCs) and in vivo by using a collagenase-induced ICH mouse model. Ex vivo, we found that the 20-HETE synthesis inhibitor HET0016 and antagonist 20-6,15-HEDGE reduced hemoglobin-induced cell death, iron deposition, and lipid reactive oxygen species levels in OHSCs. Furthermore, 20-HETE inhibition in OHSCs increased the expression of glutathione peroxidase (GPX) 4, an antioxidant enzyme that serves as a main regulator of ferroptosis. In contrast, exposure of OHSCs to the 20-HETE stable mimetic 20-5,14-HEDGE induced cell death that was significantly inhibited by the ferroptosis inhibitor ferrostatin-1. In vivo, HET0016 treatment ameliorated focal deficits, reduced lesion volume, and decreased iron accumulation around the lesion at day 3 and 7 after ICH. In addition, lipid peroxidation was decreased and expression of GPX4 was increased in the HET0016-treated ICH group. The mitogen-activated protein kinase pathway also was inhibited by HET0016 in vivo. These results indicate that 20-HETE contributes to ICH-induced acute brain injury in part by activating ferroptosis pathways, thereby providing an upstream target for inhibiting ferroptosis.

Keywords:  20-hydroxyeicosatetraenoic acid; ferroptosis; glutathione peroxidase; intracerebral hemorrhage; lipid peroxide

DOI:  https://doi.org/10.3389/fneur.2021.763419
J Neurochem. 2021 Dec 11.

Disturbed cerebral circulation and metabolism matters: A preface to the special issue "Stroke and Energy Metabolism".

Yujie Chen.

  Stroke is a serious neurological disorder caused by blockage or rupture of cerebral blood vessels. Two main aims in acute stroke therapy include the restoration of cerebral blood flow in order to preserve energy supply to neurons and other brain cells, and minimizing neuronal loss. Maintenance of energy homeostasis in the brain drives neural network dynamics, which preserves normal brain function under physiological conditions. As such, cerebral energy homeostasis is a key target in stroke therapy. The various articles in this special issue highlight energy metabolism changes following stroke, including disturbed cerebral blood circulation, mitochondrial dysfunction, programmed neuronal cell death and cell-cell communication in brain metabolism. Collectively, this series of articles provides insight and presents new avenues for further research to improve the clinical management of stroke patients.

Keywords:  cerebral blood circulation; energy metabolism; mitochondrial dysfunction; programmed neuronal cell death; stroke; vascular neural network

DOI:  https://doi.org/10.1111/jnc.15552
Aging Dis. 2021 Dec;12(8): 2003-2015

Potential Crosstalk Between Parkinson's Disease and Energy Metabolism.

Meiqiu Liu, Qian Jiao, Xixun Du, Mingxia Bi, Xi Chen, Hong Jiang.

  Parkinson's disease (PD) is characterized by the accumulation of alpha-synuclein (α-Syn) in the substantia nigra (SN) and the degeneration of nigrostriatal dopaminergic (DAergic) neurons. Some studies have reported that the pathology of PD originates from the gastrointestinal (GI) tract, which also serves as an energy portal, and develops upward along the neural pathway to the central nervous system (CNS), including the dorsal motor nucleus of vagus (DMV), SN, and hypothalamus, which are also involved in energy metabolism control. Therefore, we discuss the alterations of nuclei that regulate energy metabolism in the development of PD. In addition, due to their anti-inflammatory, antiapoptotic and antioxidative roles, metabolism-related peptides are involved in the progression of PD. Furthermore, abnormal glucose and lipid metabolism are common in PD patients and exacerbate the pathological changes in PD. Therefore, in this review, we attempt to explain the correlation between PD and energy metabolism, which may provide possible strategies for PD treatment.

Keywords:  Energy metabolism; Hypercholesterolemia; Metabolism-related peptides; Obesity; Parkinson’s disease; T2DM

DOI:  https://doi.org/10.14336/AD.2021.0422
Sci Rep. 2021 Dec 06. 11(1): 23471

Assessment of behavioral, morphological and electrophysiological changes in prenatal and postnatal valproate induced rat models of autism spectrum disorder.

Katarine Fereshetyan, Vergine Chavushyan, Margarita Danielyan, Konstantin Yenkoyan.

Autism spectrum disorders (ASD) are neurodevelopmental disorders, that are characterized by core symptoms, such as alterations of social communication and restrictive or repetitive behavior. The etiology and pathophysiology of disease is still unknown, however, there is a strong interaction between genetic and environmental factors. An intriguing point in autism research is identification the vulnerable time periods of brain development that lack compensatory homeostatic corrections. Valproic acid (VPA) is an antiepileptic drug with a pronounced teratogenic effect associated with a high risk of ASD, and its administration to rats during the gestation is used for autism modeling. It has been hypothesized that valproate induced damage and functional alterations of autism target structures may occur and evolve during early postnatal life. Here, we used prenatal and postnatal administrations of VPA to investigate the main behavioral features which are associated with autism spectrum disorders core symptoms were tested in early juvenile and adult rats. Neuroanatomical lesion of autism target structures and electrophysiological studies in specific neural circuits. Our results showed that prenatal and early postnatal administration of valproate led to the behavioral alterations that were similar to ASD. Postnatally treated group showed tendency to normalize in adulthood. We found pronounced structural changes in the brain target regions of prenatally VPA-treated groups, and an absence of abnormalities in postnatally VPA-treated groups, which confirmed the different severity of VPA across different stages of brain development. The results of this study clearly show time dependent effect of VPA on neurodevelopment, which might be explained by temporal differences of brain regions' development process. Presumably, postnatal administration of valproate leads to the dysfunction of synaptic networks that is recovered during the lifespan, due to the brain plasticity and compensatory ability of circuit refinement. Therefore, investigations of compensatory homeostatic mechanisms activated after VPA administration and directed to eliminate the defects in postnatal brain, may elucidate strategies to improve the course of disease.

DOI: https://doi.org/10.1038/s41598-021-02994-6
Free Radic Biol Med. 2021 Dec 07. pii: S0891-5849(21)00859-5. [Epub ahead of print]

Strategies to protect against age-related mitochondrial decay: Do natural products and their derivatives help?

Francesco Visioli, Avery Ingram, Joseph S Beckman, Kathy R Magnusson, Tory M Hagen.

  Mitochondria serve vital roles critical for overall cellular function outside of energy transduction. Thus, mitochondrial decay is postulated to be a key factor in aging and in age-related diseases. Mitochondria may be targets of their own decay through oxidative damage. However, treating animals with antioxidants has been met with only limited success in rejuvenating mitochondrial function or in increasing lifespan. A host of nutritional strategies outside of using traditional antioxidants have been devised to promote mitochondrial function. Dietary compounds are under study that induce gene expression, enhance mitochondrial biogenesis, and mitophagy, or replenish key metabolites that decline with age. Moreover, redox-active compounds may now be targeted to mitochondria which improve their effectiveness. Herein we review the evidence that representative dietary effectors modulate mitochondrial function by stimulating their renewal or reversing the age-related loss of key metabolites. While in vitro evidence continues to accumulate that many of these compounds benefit mitochondrial function and/or prevent their decay, the results using animal models and, in some instances human clinical trials, are more mixed and sometimes even contraindicated. Thus, further research on optimal dosage and age of intervention are warranted before recommending potential mitochondrial rejuvenating compounds for human use.

Keywords:  (poly)phenols; Aging; Essential fatty acids; Glutathione; Mitochondria; NAD; Nrf2; Nutritional supplements; Oxidative stress; Sirtuins; Triphenylphosphonium

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.12.008
Front Med. 2021 Dec 06.

Loss of monocarboxylate transporter 1 aggravates white matter injury after experimental subarachnoid hemorrhage in rats.

Xin Wu, Zongqi Wang, Haiying Li, Xueshun Xie, Jiang Wu, Haitao Shen, Xiang Li, Zhong Wang, Gang Chen.

  Monocarboxylic acid transporter 1 (MCT1) maintains axonal function by transferring lactic acid from oligodendrocytes to axons. Subarachnoid hemorrhage (SAH) induces white matter injury, but the involvement of MCT1 is unclear. In this study, the SAH model of adult male Sprague-Dawley rats was used to explore the role of MCT1 in white matter injury after SAH. At 48 h after SAH, oligodendrocyte MCT1 was significantly reduced, and the exogenous overexpression of MCT1 significantly improved white matter integrity and long-term cognitive function. Motor training after SAH significantly increased the number of ITPR2+SOX10+ oligodendrocytes and upregulated the level of MCT1, which was positively correlated with the behavioral ability of rats. In addition, miR-29b and miR-124 levels were significantly increased in SAH rats compared with non-SAH rats. Further intervention experiments showed that miR-29b and miR-124 could negatively regulate the level of MCT1. This study confirmed that the loss of MCT1 may be one of the mechanisms of white matter damage after SAH and may be caused by the negative regulation of miR-29b and miR-124. MCT1 may be involved in the neurological improvement of rehabilitation training after SAH.

Keywords:  microRNAs; monocarboxylate transporter 1; motor training; subarachnoid hemorrhage; white matter injury

DOI:  https://doi.org/10.1007/s11684-021-0879-9
J Neuroradiol. 2021 Dec 03. pii: S0150-9861(21)00170-X. [Epub ahead of print]

Energy Metabolism Measured by 31P Magnetic Resonance Spectroscopy in the Healthy Human Brain.

Andreas Rietzler, Ruth Steiger, Stephanie Mangesius, Lisa-Maria Walchhofer, Raffaella Matteucci Gothe, Michael Schocke, Elke Ruth Gizewski, Astrid Ellen Grams.

   BACKGROUND AND PURPOSE: Phosphorous magnetic resonance spectroscopy (31P-MRS) allows a non-invasive analysis of phosphorus-containing compounds in vivo. The present study investigated the influence of brain region, hemisphere, age, sex and brain volume on 31P-MRS metabolites in healthy adults.
MATERIALS AND METHODS: Supratentorial brain 31P-MRS spectra of 125 prospectively recruited healthy volunteers (64 female, 61 male) aged 20 to 85 years (mean: 49.4 ± 16.9 years) were examined with a 3D-31P-MRS sequence at 3T, and the compounds phosphocreatine (PCr), inorganic phosphate (Pi) and adenosine triphosphate (ATP) were measured. From this data, the metabolite ratios PCr/ATP, Pi/ATP and PCr/Pi were calculated for different brain regions. In addition, volumes of grey matter, white matter and cerebrospinal fluid were determined.
RESULTS: For all metabolite ratios significant regional differences and in several regions sex differences were found. In some brain regions and for some metabolites hemispheric differences were detected. In addition, changes with ageing were found, which differed between women and men.
CONCLUSIONS: The present results indicate that 31P-MRS metabolism varies throughout the brain, with age and between sexes, and therefore have important practical implications for the design and the interpretation of future 31P-MRS studies under physiological conditions and in patients with various cerebral diseases.

Keywords:  31P; Cerebral Energy Metabolism, ATP; Phosphorous Magnetic Resonance Spectroscopy

DOI:  https://doi.org/10.1016/j.neurad.2021.11.006
Cold Spring Harb Perspect Biol. 2021 Dec 06. pii: a039115. [Epub ahead of print]

Fairly Criticized, or Politicized? Conflicts in the Neuroscience of Sex Differences in the Human Brain.

Cordelia Fine.

Investigations of sex differences in the human brain take place on politically sensitive terrain. While some scholars express concern that gendered biases and stereotypes remain embedded in scientific research, others are alarmed about the politicization of science. To help better understand these debates, this review sets out three kinds of conflicts that can arise in the neuroscience of sex differences: academic freedom versus gender equality; frameworks, background assumptions, and dominant methodologies; and inductive risk and social values. The boundaries between fair criticism and politicization are explored for each kind of conflict, pointing to ways in which the academic community can facilitate fair criticism while protecting against politicization.

DOI: https://doi.org/10.1101/cshperspect.a039115
Front Nutr. 2021 ;8 750292

Dietary Fish Hydrolysate Improves Memory Performance Through Microglial Signature Remodeling During Aging.

Mathilde Chataigner, Céline Lucas, Mathieu Di Miceli, Véronique Pallet, Sophie Laye, Alexis Mehaignerie, Elodie Bouvret, Anne-Laure Dinel, Corinne Joffre.

  Brain aging is characterized by a chronic low-grade inflammation, which significantly impairs cognitive function. Microglial cells, the immunocompetent cells of the brain, present a different phenotype, switching from a homeostatic signature (M0) to a more reactive phenotype called "MGnD" (microglial neurodegenerative phenotype), leading to a high production of pro-inflammatory cytokines. Furthermore, microglial cells can be activated by age-induced gut dysbiosis through the vagus nerve or the modulation of the peripheral immune system. Nutrients, in particular n-3 long chain polyunsaturated fatty acids (LC-PUFAs) and low molecular weight peptides, display powerful immunomodulatory properties, and can thus prevent age-related cognitive decline. The objective of this study was to investigate the effects of n-3 LC-PUFAs and low molecular weight peptides contained in a marine by-product-derived hydrolysate on microglial phenotypes and intestinal permeability and their consequences on cognition in mice. We demonstrated that the hydrolysate supplementation for 8 weeks prevented short- and long-term memory decline during aging. These observations were linked to the modulation of microglial signature. Indeed, the hydrolysate supplementation promoted homeostatic microglial phenotype by increasing TGF-β1 expression and stimulated phagocytosis by increasing Clec7a expression. Moreover, the hydrolysate supplementation promoted anti-inflammatory intestinal pathway and tended to prevent intestinal permeability alteration occurring during aging. Therefore, the fish hydrolysate appears as an interesting candidate to prevent cognitive decline during aging.

Keywords:  aging; cognitive decline; hydrolysate; low molecular weight peptides; memory; microglia; n-3 long chain PUFA

DOI:  https://doi.org/10.3389/fnut.2021.750292
AIMS Neurosci. 2021 ;8(4): 448-476

Nutrition and cognition across the lifetime: an overview on epigenetic mechanisms.

Arianna Polverino, Pierpaolo Sorrentino, Matteo Pesoli, Laura Mandolesi.

  The functioning of our brain depends on both genes and their interactions with environmental factors. The close link between genetics and environmental factors produces structural and functional cerebral changes early on in life. Understanding the weight of environmental factors in modulating neuroplasticity phenomena and cognitive functioning is relevant for potential interventions. Among these, nutrition plays a key role. In fact, the link between gut and brain (the gut-brain axis) is very close and begins in utero, since the Central Nervous System (CNS) and the Enteric Nervous System (ENS) originate from the same germ layer during the embryogenesis. Here, we investigate the epigenetic mechanisms induced by some nutrients on the cognitive functioning, which affect the cellular and molecular processes governing our cognitive functions. Furthermore, epigenetic phenomena can be positively affected by specific healthy nutrients from diet, with the possibility of preventing or modulating cognitive impairments. Specifically, we described the effects of several nutrients on diet-dependent epigenetic processes, in particular DNA methylation and histones post-translational modifications, and their potential role as therapeutic target, to describe how some forms of cognitive decline could be prevented or modulated from the early stages of life.

Keywords:  cognitive functioning; environmental factors; epigenetics; neuroplasticity; nutrition

DOI:  https://doi.org/10.3934/Neuroscience.2021024
J Virol. 2021 Dec 08. JVI0194221

Comprehensive analysis of protein acetylation and glucose metabolism inmouse brains infected with rabies virus.

Jie Pei, Yueming Yuan, Dayong Tian, Fei Huang, Chengguang Zhang, Caiqian Wang, Ming Zhou, Huanchun Chen, Zhenfang Fu, Ling Zhao.

Rabies, caused by rabies virus (RABV), is a widespread zoonosis that is nearly 100% fatal. Alteration of the metabolic environment affects viral replication and the immune response during viral infection. In this study, glucose uptake was increased in mouse brains at the late stage of infection with different RABV strains (lab-attenuated CVS strain and wild-type DRV strain). To illustrate the mechanism underlying glucose metabolism alteration, comprehensive analysis of lysine acetylation and target analysis of energy metabolites in mouse brains infected with CVS and DRV strains were performed. A total of 156 acetylated sites and 115 acetylated proteins were identified as significantly different during RABV infection. Compared to CVS- and mock-infected mice, the lysine acetylation levels of glycolysis and tricarboxylic acid (TCA) cycle enzymes were decreased, and enzyme activity was upregulated in DRV-infected mouse brains. Metabolomic analysis revealed that high levels of oxaloacetate (OAA) in RABV-infected mouse brains. Specifically, the OAA level in CVS-infected mouse brains was higher than that in DRV-infected mouse brains, which contributed to the enhancement of the metabolic rate at the substrate level. Finally, we confirmed that OAA could reduce excessive neuroinflammation in CVS-infected mouse brains by inhibiting JNK and P38 phosphorylation. Taken together, this study provides fresh insight into the different strategies the host adapts to regulate glucose metabolism for energy requirements after different RABV strain infection and suggest that OAA treatment could be a potential strategy to prevent neural damage during RABV infection. IMPORTANCE Both viral replication and the host immune response are highly energy-dependent. It is important to understand how the rabies virus affects energy metabolism in the brain. Glucose is the direct energy source for cell metabolism. Previous studies have revealed that there is some association between acetylation and metabolic processes. In this study, comprehensive protein acetylation and glucose metabolism analysis were conducted to compare glucose metabolism in mouse brains infected with different RABV strains. Our study demonstrates that the regulation of enzyme activity by acetylation and OAA accumulation at the substrate level are two strategies for the host to respond to the energy requirements after RABV infection. Our study also indicates the potential role OAA could play in neuronal protection by suppressing excessive neuroinflammation.

DOI: https://doi.org/10.1128/JVI.01942-21
Int J Mol Sci. 2021 Nov 28. pii: 12881. [Epub ahead of print]22(23):

Etifoxine Restores Mitochondrial Oxidative Phosphorylation and Improves Cognitive Recovery Following Traumatic Brain Injury.

Eilam Palzur, Doron Edelman, Reem Sakas, Jean Francois Soustiel.

  The opening of the mitochondrial permeability transition pore (mPTP) has emerged as a pivotal event following traumatic brain injury (TBI). Evidence showing the impact of the translocator protein (TSPO) over mPTP activity has prompted several studies exploring the effect of TSPO ligands, including etifoxine, on the outcome of traumatic brain injury (TBI). Mitochondrial respiration was assessed by respirometry in isolated rat brain mitochondria (RBM) by measurements of oxidative phosphorylation capacity (OXPHOS). The addition of calcium to RBM was used to induce mitochondrial injury and resulted in significant OXPHOS reduction that could be reversed by preincubation of RBM with etifoxine. Sensorimotor and cognitive functions were assessed following controlled cortical impact and compared in vehicle and etifoxine-treated animals. There was no difference between the vehicle and etifoxine groups for sensorimotor functions as assessed by rotarod. In contrast, etifoxine resulted in a significant improvement of cognitive functions expressed by faster recovery in Morris water maze testing. The present findings show a significant neuroprotective effect of etifoxine in TBI through restoration of oxidative phosphorylation capacity associated with improved behavioral and cognitive outcomes. Since etifoxine is a registered drug used in common clinical practice, implementation in a phase II study may represent a reasonable step forward.

Keywords:  etifoxine; mitochondria; mitochondrial permeability transition pore; translocator protein; traumatic brain injury

DOI:  https://doi.org/10.3390/ijms222312881
Sci Rep. 2021 Dec 07. 11(1): 23559

Ketogenic Diet as a potential treatment for traumatic brain injury in mice.

Meirav Har-Even, Vardit Rubovitch, Whitney A Ratliff, Bar Richmond-Hacham, Bruce A Citron, Chaim G Pick.

Traumatic brain injury (TBI) is a brain dysfunction without present treatment. Previous studies have shown that animals fed ketogenic diet (KD) perform better in learning tasks than those fed standard diet (SD) following brain injury. The goal of this study was to examine whether KD is a neuroprotective in TBI mouse model. We utilized a closed head injury model to induce TBI in mice, followed by up to 30 days of KD/SD. Elevated levels of ketone bodies were confirmed in the blood following KD. Cognitive and behavioral performance was assessed post injury and molecular and cellular changes were assessed within the temporal cortex and hippocampus. Y-maze and Novel Object Recognition tasks indicated that mTBI mice maintained on KD displayed better cognitive abilities than mTBI mice maintained on SD. Mice maintained on SD post-injury demonstrated SIRT1 reduction when compared with uninjured and KD groups. In addition, KD management attenuated mTBI-induced astrocyte reactivity in the dentate gyrus and decreased degeneration of neurons in the dentate gyrus and in the cortex. These results support accumulating evidence that KD may be an effective approach to increase the brain's resistance to damage and suggest a potential new therapeutic strategy for treating TBI.

DOI: https://doi.org/10.1038/s41598-021-02849-0
World J Methodol. 2021 Nov 20. 11(6): 278-293

Preterm nutrition and neurodevelopmental outcomes.

Alyson Margaret Skinner, Hassib Narchi.

  Survival of preterm infants has been steadily improving in recent years because of many recent advances in perinatal and neonatal medicine. Despite these advances, the growth of survivors does not reach the ideal target level of the normal fetus of the same gestational age. Postnatal weight gain is often not achieved because extrauterine growth has higher energy requirements than intrauterine growth, due to the intensive care environment, illness and inadequate nutrition. Although many other factors influence infant brain development, including family socioeconomic and educational background, the role of nutrition is considerable and fortunately, amenable to intervention. In the preterm neonate, the brain is the most metabolically demanding organ, consuming the largest proportions of energy and nutrient intake for its function and programmed growth and maturation. Weight gain, linear and head circumference growth are all markers of nutritional status and are independently associated with long-term neurodevelopment. Brain development is not only the result of nutrients intake, but in addition, of the interaction with growth factors which depend on adequate nutrient supply and overall health status. This explains why conditions such as sepsis, necrotizing enterocolitis and chronic lung disease alter the distribution and accretion of nutrients thereby suppressing growth factor synthesis. In this review, we will focus on the direct role of nutrition on neurodevelopment, emphasizing why it should be started without delay. The nutritional requirements of the preterm infant will be discussed, followed by the effects of general nutritional interventions and specific nutrients, as well as the role of nutritional supplements on neurodevelopment. The primordial role of human breast milk, breast milk fortifiers and human milk oligosaccharides will be discussed in detail. We will also examine the role of nutrition in preventing neonatal complications which can affect neurodevelopment in their own right.

Keywords:  Brain; Breast milk; Neurodevelopmental outcomes; Newborn; Nutrition; Preterm infants

DOI:  https://doi.org/10.5662/wjm.v11.i6.278
Int J Dev Biol. 2021 Oct 26.

Expression of D5 dopamine receptors in the walls of the lateral ventricles during the post-weaning rat development.

Antonis Prosilis, Vassilios Mesiakaris, Antonios Stamatakis.

Even before the first synapses appear, neurotransmitters and their receptors are present in the developing brain regulating the cell fate of neuronal progenitors in neurogenic niches, such as the lateral ventricle. In particular, dopamine appears to play a pivotal role in the neurogenesis of the subventricular zone by controlling the proliferation and differentiation of progenitors through activation of different receptors. Although, dopamine receptor 5 (D5R) is expressed prenatally, there is little information regarding its role in either pre- or postnatal forebrain development. To examine the role of D5Rs on neurogenesis in the rat lateral ventricle subventricular zone (V-SVZ), we defined immunohistochemically D5R expression as well as BrdU incorporation in progenitor cells of various post-weaning stages (Post-natal day (P) 20 until P80). We found that the level of proliferating cells is stable from postnatal day 20 until 50 and then sharply declines on P80. Concomitantly, D5R is expressed in all ages examined, but we detected a progressive decrease in the density of D5R+ cells from P40 until P80. Moreover, double immunostaining for BrdU and D5R, revealed that proliferating cells in V-SVZ also express the D5R. Collectively, our data suggest that D5R is expressed in the post-weaning V-SVZ of rat at least until P80 and its expression pattern coincides that of proliferating cells in the V-SVZ, hinting to a possible role of D5Rs in the regulation of neuronal progenitor division/differentiation.

DOI: https://doi.org/10.1387/ijdb.210163as
J Inflamm Res. 2021 ;14 6251-6264

Melatonin as a Potential Regulator of Oxidative Stress, and Neuroinflammation: Mechanisms and Implications for the Management of Brain Injury-Induced Neurodegeneration.

Muhammad Ikram, Hyun Young Park, Tahir Ali, Myeong Ok Kim.

  This review covers the preclinical and clinical literature supporting the role of melatonin in the management of brain injury-induced oxidative stress, neuroinflammation, and neurodegeneration, and reviews the past and current therapeutic strategies. Traumatic brain injury (TBI) is a neurodegenerative condition, unpredictably and potentially progressing into chronic neurodegeneration, with permanent cognitive, neurologic, and motor dysfunction, having no standard therapies. Due to its complex and multi-faceted nature, the TBI has highly heterogeneous pathophysiology, characterized by the highest mortality and disability worldwide. Mounting evidence suggests that the TBI induces oxidative and nitrosative stress, which is involved in the progression of chronic and acute neurodegenerative diseases. Defenses against such conditions are mostly dependent on the usage of antioxidant compounds, the majority of whom are ingested as nutraceuticals or as dietary supplements. A large amount of literature is available regarding the efficacy of antioxidant compounds to counteract the TBI-associated damage in animal and cellular models of the TBI and several clinical studies. Collectively, the studies have suggested that TBI induces oxidative stress, by suppressing the endogenous antioxidant system, such as nuclear factor erythroid 2-related factor-2 (Nrf-2) increasing the lipid peroxidation and elevation of oxidative damage. Moreover, elevated oxidative stress may induce neuroinflammation by activating the microglial cells, releasing and activating the inflammatory cytokines and inflammatory mediators, and energy dyshomeostasis. Thus, melatonin has shown regulatory effects against the TBI-induced autophagic dysfunction, regulation of mitogen-activated protein kinases, such as ERK, activation of the NLRP-3 inflammasome, and release of the inflammatory cytokines. The collective findings strongly suggest that melatonin may regulate TBI-induced neurodegeneration, although further studies should be conducted to better facilitate future therapeutic windows.

Keywords:  antioxidants; brain injury; melatonin; neurodegeneration; oxidative and nitrosative stress

DOI:  https://doi.org/10.2147/JIR.S334423
Curr Opin Lipidol. 2021 Dec 09.

Dietary factors and brain health.

Sophie Lefèvre-Arbogast, Aline Thomas, Cécilia Samieri.

PURPOSE OF REVIEW: Nutrition is a complex exposure (i.e., the food exposome) that influences brain function and health through multiple pathways. We review recent epidemiological studies that have improved the characterization of the food exposome and brain health in humans and have revealed promising nutrition-based strategies to prevent cognitive aging.
RECENT FINDINGS: A selection of epidemiological research from the past 18 months of both observational and clinical studies is presented, with a focus on novel findings, including novel nutrient and diet patterns, diet-related approaches to rescue brain energetics defects in aging, and biomarker-based studies to decipher specific neurobiological pathways of nutrition and brain health.
SUMMARY: Although healthy diets such as the Mediterranean diet promote brain health throughout life, specific diets, such as the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay diet, or specific nutrients (LC n-3 polyunsaturated fatty acids, carotenoids, vitamin D, B vitamins, polyphenols) alone or in combination, may prevent cognitive aging. Diet management approaches to rescue brain energetics defects such as the Modified Mediterranean-ketogenic diet may be promising to prevent neurodegenerative diseases. Expanding research also suggests that promotion of a healthy gut microbiome through prebiotic foods may preserve the diet-gut-brain axis with aging. Future studies should explore more individualized preventive approaches through a 'precision nutrition' framework.

DOI: https://doi.org/10.1097/MOL.0000000000000803