bims-medebr 2022-09-11 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–09–11
28 papers selected by
Regina F. Fernández, Johns Hopkins University

Metabolic and Cellular Compartments of Acetyl-CoA in the Healthy and Diseased Brain.
Dynamic FDG-PET demonstration of functional brain abnormalities.
A novel method for Magnetic Resonance Spectroscopy lipid signal suppression using Semi-classical signal analysis and Bidirectional Long short-term memory.
Avian neurons consume three times less glucose than mammalian neurons.
Gray and white matter astrocytes differ in basal metabolism but respond similarly to neuronal activity.
Piezo1 regulates cholesterol biosynthesis to influence neural stem cell fate during brain development.
The Evolution of Ketosis: Potential Impact on Clinical Conditions.
Ketogenic Diet Treatment of Defects in the Mitochondrial Malate Aspartate Shuttle and Pyruvate Carrier.
A High-Fat Diet Disrupts Nerve Lipids and Mitochondrial Function in Murine Models of Neuropathy.
Structural Characterization and Quantitation of Ether-Linked Glycerophospholipids in Peroxisome Biogenesis Disorder Tissue by Ultraviolet Photodissociation Mass Spectrometry.
Lower Availability of Mitochondrial Complex I in Anterior Cingulate Cortex in Autism: A Positron Emission Tomography Study.
Metabolic management of microenvironment acidity in glioblastoma.
Rare cause of ketolysis: Monocarboxylate transporter 1 deficiency.
Mitochondrial dysfunction is a key pathological driver of early stage Parkinson's.
A correlation between Magnetic Resonance Spectroscopy (1-H MRS) and the neurodevelopment of two-year-olds born preterm in an EPIRMEX cohort study.
Mechanical and metabolic interplay in the brain metastatic microenvironment.
Deuterium metabolic imaging of the human brain in vivo at 7 T.
Fatty Acid-Binding Proteins: Their Roles in Ischemic Stroke and Potential as Drug Targets.
Mitochondrial protein synthesis and the bioenergetic cost of neurodevelopment.
High Fat Diet Multigenerationally Affects Hippocampal Neural Stem Cell Proliferation via Epigenetic Mechanisms.
Structural aspects of the glucose and monocarboxylate transporters involved in the Warburg effect.
Lipid-Based Molecules on Signaling Pathways in Autism Spectrum Disorder.
Lysophosphatidic acid as a CSF lipid in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1.
Tracing the lactate shuttle to the mitochondrial reticulum.
A rare case of hypomyelinating leukodystrophy-14 benefiting from ketogenic diet therapy.
Newborn screening and genetic variation of medium chain acyl-CoA dehydrogenase deficiency in the Chinese population.
Dexmedetomidine alleviates olfactory cognitive dysfunction by promoting neurogenesis in the subventricular zone of hypoxic-ischemic neonatal rats.
A potent and selective inhibitor for the modulation of MAGL activity in the neurovasculature.

Int J Mol Sci. 2022 Sep 03. pii: 10073. [Epub ahead of print]23(17):

Metabolic and Cellular Compartments of Acetyl-CoA in the Healthy and Diseased Brain.

Agnieszka Jankowska-Kulawy, Joanna Klimaszewska-Łata, Sylwia Gul-Hinc, Anna Ronowska, Andrzej Szutowicz.

  The human brain is characterised by the most diverse morphological, metabolic and functional structure among all body tissues. This is due to the existence of diverse neurons secreting various neurotransmitters and mutually modulating their own activity through thousands of pre- and postsynaptic interconnections in each neuron. Astroglial, microglial and oligodendroglial cells and neurons reciprocally regulate the metabolism of key energy substrates, thereby exerting several neuroprotective, neurotoxic and regulatory effects on neuronal viability and neurotransmitter functions. Maintenance of the pool of mitochondrial acetyl-CoA derived from glycolytic glucose metabolism is a key factor for neuronal survival. Thus, acetyl-CoA is regarded as a direct energy precursor through the TCA cycle and respiratory chain, thereby affecting brain cell viability. It is also used for hundreds of acetylation reactions, including N-acetyl aspartate synthesis in neuronal mitochondria, acetylcholine synthesis in cholinergic neurons, as well as divergent acetylations of several proteins, peptides, histones and low-molecular-weight species in all cellular compartments. Therefore, acetyl-CoA should be considered as the central point of metabolism maintaining equilibrium between anabolic and catabolic pathways in the brain. This review presents data supporting this thesis.

Keywords:  acetyl-CoA metabolism; aging; neurodegenerative diseases; thiamine deficiency; zinc dyshomeostasis

DOI:  https://doi.org/10.3390/ijms231710073
Ann Clin Transl Neurol. 2022 Sep;9(9): 1487-1497

Dynamic FDG-PET demonstration of functional brain abnormalities.

Mark Quigg, Bijoy Kundu.

Positron emission tomography with fluorine-18 fluorodeoxyglucose (18 F-FDG-PET) has been used over 3 decades to map patterns of brain glucose metabolism to evaluate normal brain function or demonstrate abnormalities of metabolism in brain disorders. Traditional PET maps patterns of absolute tracer uptake but has demonstrated shortcomings in disorders such as brain neoplasm or focal epilepsy in the ability to resolve normally from pathological tissue. In this review, we describe an alternative process of metabolic mapping, dynamic PET. This new technology quantifies the dynamics of tracer uptake and decays with the goal of improving the functional mapping of the desired metabolic activity in the target organ. We discuss technical implementation and findings of initial pilot studies in brain tumor treatment and epilepsy surgery.

DOI: https://doi.org/10.1002/acn3.51546
Annu Int Conf IEEE Eng Med Biol Soc. 2022 Jul;2022 317-320

A novel method for Magnetic Resonance Spectroscopy lipid signal suppression using Semi-classical signal analysis and Bidirectional Long short-term memory.

Maria de Los Angeles Gomez, Hacene Serrai, Sourav Bhaduri, Taous-Meriem Laleg-Kirati.

Magnetic resonance spectroscopy (MRS) is a non-invasive method that enables the analysis and quantification of brain metabolites, which provide useful information about the neuro-biological substrates of brain function. Lactate plays a pivotal role in the diagnosis of various brain diseases. However, accurate lactate quantification is generally difficult to achieve due to the presence of large lipid peaks resonating at a similar spectral position. To overcome this problem several techniques have been proposed. However, most of them suffer from lactate signal loss or poor lipid peak removal. In this paper, a novel method for lipid suppression for MRS signal is proposed. The method combines a semi-classical signal analysis method and a bidirectional long short term memory technique. The method is validated using simulated data that mimics real MRS data.

DOI: https://doi.org/10.1109/EMBC48229.2022.9871645
Curr Biol. 2022 Aug 25. pii: S0960-9822(22)01219-2. [Epub ahead of print]

Avian neurons consume three times less glucose than mammalian neurons.

Kaya von Eugen, Heike Endepols, Alexander Drzezga, Bernd Neumaier, Onur Güntürkün, Heiko Backes, Felix Ströckens.

  Brains are among the most energetically costly tissues in the mammalian body.1 This is predominantly caused by expensive neurons with high glucose demands.2 Across mammals, the neuronal energy budget appears to be fixed, possibly posing an evolutionary constraint on brain growth.3-6 Compared to similarly sized mammals, birds have higher numbers of neurons, and this advantage conceivably contributes to their cognitive prowess.7 We set out to determine the neuronal energy budget of birds to elucidate how they can metabolically support such high numbers of neurons. We estimated glucose metabolism using positron emission tomography (PET) and 2-[18F]fluoro-2-deoxyglucose ([18F]FDG) as the radiotracer in awake and anesthetized pigeons. Combined with kinetic modeling, this is the gold standard to quantify cerebral metabolic rate of glucose consumption (CMRglc).8 We found that neural tissue in the pigeon consumes 27.29 ± 1.57 μmol glucose per 100 g per min in an awake state, which translates into a surprisingly low neuronal energy budget of 1.86 × 10-9 ± 0.2 × 10-9 μmol glucose per neuron per minute. This is approximately 3 times lower than the rate in the average mammalian neuron.3 The remarkably low neuronal energy budget explains how pigeons, and possibly other avian species, can support such high numbers of neurons without associated metabolic costs or compromising neuronal signaling. The advantage in neuronal processing of information at a higher efficiency possibly emerged during the distinct evolution of the avian brain.

Keywords:  PET; bird; brain; energy consumption; evolution; metabolism

DOI:  https://doi.org/10.1016/j.cub.2022.07.070
Glia. 2022 Sep 05.

Gray and white matter astrocytes differ in basal metabolism but respond similarly to neuronal activity.

Susanne Köhler, Ulrike Winkler, Tabea Junge, Kristina Lippmann, Jens Eilers, Johannes Hirrlinger.

  Astrocytes are a heterogeneous population of glial cells in the brain, which adapt their properties to the requirements of the local environment. Two major groups of astrocytes are protoplasmic astrocytes residing in gray matter as well as fibrous astrocytes of white matter. Here, we compared the energy metabolism of astrocytes in the cortex and corpus callosum as representative gray matter and white matter regions, in acute brain slices taking advantage of genetically encoded fluorescent nanosensors for the NADH/NAD+ redox ratio and for ATP. Astrocytes of the corpus callosum presented a more reduced basal NADH/NAD+ redox ratio, and a lower cytosolic concentration of ATP compared to cortical astrocytes. In cortical astrocytes, the neurotransmitter glutamate and increased extracellular concentrations of K+ , typical correlates of neuronal activity, induced a more reduced NADH/NAD+ redox ratio. While application of glutamate decreased [ATP], K+ as well as the combination of glutamate and K+ resulted in an increase of ATP levels. Strikingly, a very similar regulation of metabolism by K+ and glutamate was observed in astrocytes in the corpus callosum. Finally, strong intrinsic neuronal activity provoked by application of bicuculline and withdrawal of Mg2+ caused a shift of the NADH/NAD+ redox ratio to a more reduced state as well as a slight reduction of [ATP] in gray and white matter astrocytes. In summary, the metabolism of astrocytes in cortex and corpus callosum shows distinct basal properties, but qualitatively similar responses to neuronal activity, probably reflecting the different environment and requirements of these brain regions.

Keywords:  astrocyte; energy metabolism; gray matter; heterogeneity; white matter

DOI:  https://doi.org/10.1002/glia.24268
J Gen Physiol. 2022 Oct 03. pii: e202213084. [Epub ahead of print]154(10):

Piezo1 regulates cholesterol biosynthesis to influence neural stem cell fate during brain development.

Jamison L Nourse, Vivian M Leung, Hamid Abuwarda, Elizabeth L Evans, Esmeralda Izquierdo-Ortiz, Alan T Ly, Nguyen Truong, Samantha Smith, Harsh Bhavsar, Gabriella Bertaccini, Edwin S Monuki, Mitradas M Panicker, Medha M Pathak.

Mechanical forces and tissue mechanics influence the morphology of the developing brain, but the underlying molecular mechanisms have been elusive. Here, we examine the role of mechanotransduction in brain development by focusing on Piezo1, a mechanically activated ion channel. We find that Piezo1 deletion results in a thinner neuroepithelial layer, disrupts pseudostratification, and reduces neurogenesis in E10.5 mouse embryos. Proliferation and differentiation of Piezo1 knockout (KO) mouse neural stem cells (NSCs) isolated from E10.5 embryos are reduced in vitro compared to littermate WT NSCs. Transcriptome analysis of E10.5 Piezo1 KO brains reveals downregulation of the cholesterol biosynthesis superpathway, in which 16 genes, including Hmgcr, the gene encoding the rate-limiting enzyme of the cholesterol biosynthesis pathway, are downregulated by 1.5-fold or more. Consistent with this finding, membrane lipid composition is altered, and the cholesterol levels are reduced in Piezo1 KO NSCs. Cholesterol supplementation of Piezo1 KO NSCs partially rescues the phenotype in vitro. These findings demonstrate a role for Piezo1 in the neurodevelopmental process that modulates the quantity, quality, and organization of cells by influencing cellular cholesterol metabolism. Our study establishes a direct link in NSCs between PIEZO1, intracellular cholesterol levels, and neural development.

DOI: https://doi.org/10.1085/jgp.202213084
Nutrients. 2022 Sep 01. pii: 3613. [Epub ahead of print]14(17):

The Evolution of Ketosis: Potential Impact on Clinical Conditions.

Latha Nagamani Dilliraj, Giovanna Schiuma, Djidjell Lara, Giovanni Strazzabosco, James Clement, PierPaolo Giovannini, Claudio Trapella, Marco Narducci, Roberta Rizzo.

  Ketone bodies are small compounds derived from fatty acids that behave as an alternative mitochondrial energy source when insulin levels are low, such as during fasting or strenuous exercise. In addition to the metabolic function of ketone bodies, they also have several signaling functions separate from energy production. In this perspective, we review the main current data referring to ketone bodies in correlation with nutrition and metabolic pathways as well as to the signaling functions and the potential impact on clinical conditions. Data were selected following eligibility criteria accordingly to the reviewed topic. We used a set of electronic databases (Medline/PubMed, Scopus, Web of Sciences (WOS), Cochrane Library) for a systematic search until July 2022 using MeSH keywords/terms (i.e., ketone bodies, BHB, acetoacetate, inflammation, antioxidant, etc.). The literature data reported in this review need confirmation with consistent clinical trials that might validate the results obtained in in vitro and in vivo in animal models. However, the data on exogenous ketone consumption and the effect on the ketone bodies' brain uptake and metabolism might spur the research to define the acute and chronic effects of ketone bodies in humans and pursue the possible implication in the prevention and treatment of human diseases. Therefore, additional studies are required to examine the potential systemic and metabolic consequences of ketone bodies.

Keywords:  anti-inflammatory; beta-hydroxybutyrate; evolution; ketogenesis

DOI:  https://doi.org/10.3390/nu14173613
Nutrients. 2022 Aug 31. pii: 3605. [Epub ahead of print]14(17):

Ketogenic Diet Treatment of Defects in the Mitochondrial Malate Aspartate Shuttle and Pyruvate Carrier.

Bigna K Bölsterli, Eugen Boltshauser, Luigi Palmieri, Johannes Spenger, Michaela Brunner-Krainz, Felix Distelmaier, Peter Freisinger, Tobias Geis, Andrea L Gropman, Johannes Häberle, Julia Hentschel, Bruno Jeandidier, Daniela Karall, Boris Keren, Annick Klabunde-Cherwon, Vassiliki Konstantopoulou, Raimund Kottke, Francesco M Lasorsa, Christine Makowski, Cyril Mignot, Ruth O'Gorman Tuura, Vito Porcelli, René Santer, Kuntal Sen, Katja Steinbrücker, Steffen Syrbe, Matias Wagner, Andreas Ziegler, Thomas Zöggeler, Johannes A Mayr, Holger Prokisch, Saskia B Wortmann.

  The mitochondrial malate aspartate shuttle system (MAS) maintains the cytosolic NAD+/NADH redox balance, thereby sustaining cytosolic redox-dependent pathways, such as glycolysis and serine biosynthesis. Human disease has been associated with defects in four MAS-proteins (encoded by MDH1, MDH2, GOT2, SLC25A12) sharing a neurological/epileptic phenotype, as well as citrin deficiency (SLC25A13) with a complex hepatopathic-neuropsychiatric phenotype. Ketogenic diets (KD) are high-fat/low-carbohydrate diets, which decrease glycolysis thus bypassing the mentioned defects. The same holds for mitochondrial pyruvate carrier (MPC) 1 deficiency, which also presents neurological deficits. We here describe 40 (18 previously unreported) subjects with MAS-/MPC1-defects (32 neurological phenotypes, eight citrin deficiency), describe and discuss their phenotypes and genotypes (presenting 12 novel variants), and the efficacy of KD. Of 13 MAS/MPC1-individuals with a neurological phenotype treated with KD, 11 experienced benefits-mainly a striking effect against seizures. Two individuals with citrin deficiency deceased before the correct diagnosis was established, presumably due to high-carbohydrate treatment. Six citrin-deficient individuals received a carbohydrate-restricted/fat-enriched diet and showed normalisation of laboratory values/hepatopathy as well as age-adequate thriving. We conclude that patients with MAS-/MPC1-defects are amenable to dietary intervention and that early (genetic) diagnosis is key for initiation of proper treatment and can even be lifesaving.

Keywords:  AGC1; Citrullinemia; aspartate glutamate carrier 1 deficiency; citrin deficiency; epilepsy; hepatopathy; mitochondrial disease; modified Atkins diet; serine; treatment

DOI:  https://doi.org/10.3390/nu14173605
Front Physiol. 2022 ;13 921942

A High-Fat Diet Disrupts Nerve Lipids and Mitochondrial Function in Murine Models of Neuropathy.

Amy E Rumora, Kai Guo, Lucy M Hinder, Phillipe D O'Brien, John M Hayes, Junguk Hur, Eva L Feldman.

  As the prevalence of prediabetes and type 2 diabetes (T2D) continues to increase worldwide, accompanying complications are also on the rise. The most prevalent complication, peripheral neuropathy (PN), is a complex process which remains incompletely understood. Dyslipidemia is an emerging risk factor for PN in both prediabetes and T2D, suggesting that excess lipids damage peripheral nerves; however, the precise lipid changes that contribute to PN are unknown. To identify specific lipid changes associated with PN, we conducted an untargeted lipidomics analysis comparing the effect of high-fat diet (HFD) feeding on lipids in the plasma, liver, and peripheral nerve from three strains of mice (BL6, BTBR, and BKS). HFD feeding triggered distinct strain- and tissue-specific lipid changes, which correlated with PN in BL6 mice versus less robust murine models of metabolic dysfunction and PN (BTBR and BKS mice). The BL6 mice showed significant changes in neutral lipids, phospholipids, lysophospholipids, and plasmalogens within the nerve. Sphingomyelin (SM) and lysophosphatidylethanolamine (LPE) were two lipid species that were unique to HFD BL6 sciatic nerve compared to other strains (BTBR and BKS). Plasma and liver lipids were significantly altered in all murine strains fed a HFD independent of PN status, suggesting that nerve-specific lipid changes contribute to PN pathogenesis. Many of the identified lipids affect mitochondrial function and mitochondrial bioenergetics, which were significantly impaired in ex vivo sural nerve and dorsal root ganglion sensory neurons. Collectively, our data show that consuming a HFD dysregulates the nerve lipidome and mitochondrial function, which may contribute to PN in prediabetes.

Keywords:  dyslipidemia; high-fat diet; lipidomics; metabolic syndrome; mitochondria; neuropathy; obesity; prediabetes

DOI:  https://doi.org/10.3389/fphys.2022.921942
Anal Chem. 2022 Sep 07.

Structural Characterization and Quantitation of Ether-Linked Glycerophospholipids in Peroxisome Biogenesis Disorder Tissue by Ultraviolet Photodissociation Mass Spectrometry.

Molly S Blevins, Samuel W J Shields, Wei Cui, Wedad Fallatah, Ann B Moser, Nancy E Braverman, Jennifer S Brodbelt.

The biological impact of ether glycerophospholipids (GP) in peroxisomal disorders and other diseases makes them significant targets as biomarkers for diagnostic assays or deciphering pathology of the disorders. Ether lipids include both plasmanyl and plasmenyl lipids, which each contain an ether or a vinyl ether bond at the sn-1 linkage position, respectively. This linkage, in contrast to traditional diacyl GPs, precludes their detailed characterization by mass spectrometry via traditional collisional-based MS/MS techniques. Additionally, the isomeric nature of plasmanyl and plasmenyl pairs of ether lipids introduces a further level of complexity that impedes analysis of these species. Here, we utilize 213 nm ultraviolet photodissociation mass spectrometry (UVPD-MS) for detailed characterization of phosphatidylethanolamine (PE) and phosphatidylcholine (PC) plasmenyl and plasmanyl lipids in mouse brain tissue. 213 nm UVPD-MS enables the successful differentiation of these four ether lipid subtypes for the first time. We couple this UVPD-MS methodology to reversed-phase liquid chromatography (RPLC) for characterization and relative quantitation of ether lipids from normal and diseased (Pex7 deficiency modeling the peroxisome biogenesis disorder, RCDP) mouse brain tissue, highlighting the ability to pinpoint specific structural features of ether lipids that are important for monitoring aberrant lipid metabolism in peroxisomal disorders.

DOI: https://doi.org/10.1021/acs.analchem.2c01274
Am J Psychiatry. 2022 Sep 07. appiajp22010014

Lower Availability of Mitochondrial Complex I in Anterior Cingulate Cortex in Autism: A Positron Emission Tomography Study.

Yasuhiko Kato, Masamichi Yokokura, Toshiki Iwabuchi, Chihiro Murayama, Taeko Harada, Takafumi Goto, Taishi Tamayama, Yosuke Kameno, Tomoyasu Wakuda, Hitoshi Kuwabara, Seico Benner, Atsushi Senju, Hideo Tsukada, Sadahiko Nishizawa, Yasuomi Ouchi, Hidenori Yamasue.

   OBJECTIVE: Mitochondrial dysfunction has been implicated in the pathophysiology of autism spectrum disorder (ASD) in previous studies of postmortem brain or peripheral samples. The authors investigated whether and where mitochondrial dysfunction occurs in the living brains of individuals with ASD and to identify the clinical correlates of detected mitochondrial dysfunction.
METHODS: This case-control study used positron emission tomography (PET) with 2-tert-butyl-4-chloro-5-{6-[2-(2-[18F]fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([18F]BCPP-EF), a radioligand that binds to the mitochondrial electron transport chain complex I, to examine the topographical distribution of mitochondrial dysfunction in living brains of individuals with ASD. Twenty-three adult males with high-functioning ASD, with no psychiatric comorbidities and free of psychotropic medication, and 24 typically developed males with no psychiatric diagnoses, matched with the ASD group on age, parental socioeconomic background, and IQ, underwent [18F]BCPP-EF PET measurements. Individuals with mitochondrial disease were excluded by clinical evaluation and blood tests for abnormalities in lactate and pyruvate levels.
RESULTS: Among the brain regions in which mitochondrial dysfunction has been reported in postmortem studies of autistic brains, participants with ASD had significantly decreased [18F]BCPP-EF availability specifically in the anterior cingulate cortex compared with typically developed participants. The regional specificity was revealed by a significant interaction between diagnosis and brain regions. Moreover, the lower [18F]BCPP-EF availability in the anterior cingulate cortex was significantly correlated with the more severe ASD core symptom of social communication deficits.
CONCLUSIONS: This study provides direct evidence to link in vivo brain mitochondrial dysfunction with ASD pathophysiology and its communicational deficits. The findings support the possibility that mitochondrial electron transport chain complex I is a novel therapeutic target for ASD core symptoms.

Keywords:  Anterior Cingulate Cortex; Autism Spectrum Disorder; Mitochondrial Electron Transport Chain Complex I; Neurodevelopmental Disorders; Neuroimaging

DOI:  https://doi.org/10.1176/appi.ajp.22010014
Front Oncol. 2022 ;12 968351

Metabolic management of microenvironment acidity in glioblastoma.

Thomas N Seyfried, Gabriel Arismendi-Morillo, Giulio Zuccoli, Derek C Lee, Tomas Duraj, Ahmed M Elsakka, Joseph C Maroon, Purna Mukherjee, Linh Ta, Laura Shelton, Dominic D'Agostino, Michael Kiebish, Christos Chinopoulos.

  Glioblastoma (GBM), similar to most cancers, is dependent on fermentation metabolism for the synthesis of biomass and energy (ATP) regardless of the cellular or genetic heterogeneity seen within the tumor. The transition from respiration to fermentation arises from the documented defects in the number, the structure, and the function of mitochondria and mitochondrial-associated membranes in GBM tissue. Glucose and glutamine are the major fermentable fuels that drive GBM growth. The major waste products of GBM cell fermentation (lactic acid, glutamic acid, and succinic acid) will acidify the microenvironment and are largely responsible for drug resistance, enhanced invasion, immunosuppression, and metastasis. Besides surgical debulking, therapies used for GBM management (radiation, chemotherapy, and steroids) enhance microenvironment acidification and, although often providing a time-limited disease control, will thus favor tumor recurrence and complications. The simultaneous restriction of glucose and glutamine, while elevating non-fermentable, anti-inflammatory ketone bodies, can help restore the pH balance of the microenvironment while, at the same time, providing a non-toxic therapeutic strategy for killing most of the neoplastic cells.

Keywords:  fermentation; glutamate; glutaminolysis; glycolysis; ketogenic diet; ketogenic metabolic therapy; lactate; succinate

DOI:  https://doi.org/10.3389/fonc.2022.968351
Turk J Pediatr. 2022 ;pii: 2480. [Epub ahead of print]64(4): 741-746

Rare cause of ketolysis: Monocarboxylate transporter 1 deficiency.

Ayşe Ergül Bozacı, Aysel Tekmenuray Ünal.

   BACKGROUND: Monocarboxylate transporter 1 (MCT1) deficiency (MIM #616095) is a relatively new identified cause of recurrent ketoacidosis triggered by fasting or infections. MCT1 was first described in 2014 by van Hasselt et al. to result from both homozygous and heterozygous mutations in the SLC16A1 gene. Patients with homozygous mutations are known to have a more severe phenotype with developmental delay and epilepsy. Thirteen patients with MCT1 deficiency with ketoacidosis have been reported in the literature to date.
CASE: We describe a developmentally normal male patient with heterozygous missense variation in the SLC16A1 gene. Our patient who presented with cyclic vomiting and ketoacidosis episodes was found to have a heterozygous c.303T > G (p.Ile101Met) missense mutation.
CONCLUSIONS: It is crucial to take early preventive measures and to minimize the harmful effects of ketoacidotic episodes. MCT1 deficiency should be considered in the differential diagnosis of ketoacidosis in patients with normal SCOT and ACAT1 activities.

Keywords:  MCT1; ketoacidosis; ketone metabolism; vomiting

DOI:  https://doi.org/10.24953/turkjped.2021.4915
Acta Neuropathol Commun. 2022 Sep 08. 10(1): 134

Mitochondrial dysfunction is a key pathological driver of early stage Parkinson's.

Christina E Toomey, Wendy E Heywood, James R Evans, Joanne Lachica, Sarah N Pressey, Sandrine C Foti, Mesfer Al Shahrani, Karishma D'Sa, Iain P Hargreaves, Simon Heales, Michael Orford, Claire Troakes, Johannes Attems, Ellen Gelpi, Miklos Palkovits, Tammaryn Lashley, Steve M Gentleman, Tamas Revesz, Kevin Mills, Sonia Gandhi.

   BACKGROUND: The molecular drivers of early sporadic Parkinson's disease (PD) remain unclear, and the presence of widespread end stage pathology in late disease masks the distinction between primary or causal disease-specific events and late secondary consequences in stressed or dying cells. However, early and mid-stage Parkinson's brains (Braak stages 3 and 4) exhibit alpha-synuclein inclusions and neuronal loss along a regional gradient of severity, from unaffected-mild-moderate-severe. Here, we exploited this spatial pathological gradient to investigate the molecular drivers of sporadic PD.
METHODS: We combined high precision tissue sampling with unbiased large-scale profiling of protein expression across 9 brain regions in Braak stage 3 and 4 PD brains, and controls, and verified these results using targeted proteomic and functional analyses.
RESULTS: We demonstrate that the spatio-temporal pathology gradient in early-mid PD brains is mirrored by a biochemical gradient of a changing proteome. Importantly, we identify two key events that occur early in the disease, prior to the occurrence of alpha-synuclein inclusions and neuronal loss: (i) a metabolic switch in the utilisation of energy substrates and energy production in the brain, and (ii) perturbation of the mitochondrial redox state. These changes may contribute to the regional vulnerability of developing alpha-synuclein pathology. Later in the disease, mitochondrial function is affected more severely, whilst mitochondrial metabolism, fatty acid oxidation, and mitochondrial respiration are affected across all brain regions.
CONCLUSIONS: Our study provides an in-depth regional profile of the proteome at different stages of PD, and highlights that mitochondrial dysfunction is detectable prior to neuronal loss, and alpha-synuclein fibril deposition, suggesting that mitochondrial dysfunction is one of the key drivers of early disease.

Keywords:  Brain; Mitochondria; Neurodegeneration; Parkinson’s; Progression; Proteomics

DOI:  https://doi.org/10.1186/s40478-022-01424-6
Front Pediatr. 2022 ;10 936130

A correlation between Magnetic Resonance Spectroscopy (1-H MRS) and the neurodevelopment of two-year-olds born preterm in an EPIRMEX cohort study.

Catherine Gire, Julie Berbis, Marion Dequin, Stéphane Marret, Jean-Baptiste Muller, Elie Saliba, Barthélémy Tosello.

   Background: Preterm infants are at risk of neurodevelopmental impairments. At present, proton magnetic resonance spectroscopy (1H-MRS) is currently used to evaluate brain metabolites in asphyxiated term infants. The purpose of this study was to identify in the preterm EPIRMEX cohort any correlations between (1H-MRS) metabolites ratio at term equivalent age (TEA) and neurodevelopmental outcomes at 2 years.
Methods: Our study included EPIRMEX eligible patients who were very preterm infants (gestational age at birth ≤32 weeks) and who underwent a brain MRI at TEA and 1H-MRS using a monovoxel technique. The volumes of interest (VOI) were periventricular white matter posterior area and basal ganglia. The ratio of N Acetyl Aspartate (NAA) to Cho (Choline), NAA to Cr (creatine), Cho to Cr, and Lac (Lactate) to Cr were measured. Neurodevelopment was assessed at 24 months TEA with ASQ (Ages and Stages Questionnaire).
Results: A total of 69 very preterm infants had a 1H-MRS at TEA. In white matter there was a significant correlation between a reduction in the NAA/Cho ratio and a total ASQ and/or abnormal communication score, and an increase in the Lac/Cr ratio and an abnormality of fine motor skills. In the gray nuclei there was a trend correlation between the reduction in the NAA/Cho ratio and sociability disorders; and the increase in the Lac/Cr ratio and an anomaly in problem-solving.
Conclusions: Using NAA as a biomarker, the vulnerability of immature oligodendrocytes in preterm children at TEA was correlated to neurodevelopment at 2 years. Similarly, the presence of lactate at TEA was associated with abnormal neurodevelopment at 2 years in the preterm brain.

Keywords:  2 years follow-up; magnetic resonance spectroscopy; morbidity; neurodevelopmental outcome; very preterm infant

DOI:  https://doi.org/10.3389/fped.2022.936130
Front Oncol. 2022 ;12 932285

Mechanical and metabolic interplay in the brain metastatic microenvironment.

Killian Onwudiwe, Alice A Burchett, Meenal Datta.

  In this Perspective, we provide our insights and opinions about the contribution-and potential co-regulation-of mechanics and metabolism in incurable breast cancer brain metastasis. Altered metabolic activity can affect cancer metastasis as high glucose supply and demand in the brain microenvironment favors aerobic glycolysis. Similarly, the altered mechanical properties of disseminating cancer cells facilitate migration to and metastatic seeding of the brain, where local metabolites support their progression. Cancer cells in the brain and the brain tumor microenvironment often possess opposing mechanical and metabolic properties compared to extracranial cancer cells and their microenvironment, which inhibit the ease of extravasation and metastasis of these cells outside the central nervous system. We posit that the brain provides a metabolic microenvironment that mechanically reinforces the cellular structure of cancer cells and supports their metastatic growth while restricting their spread from the brain to external organs.

Keywords:  brain metastatic microenvironment; cell stiffness; extracellular matrix; fatty acid synthesis; glycolysis; mechanotransduction; tumor mechanics; tumor metabolism

DOI:  https://doi.org/10.3389/fonc.2022.932285
Magn Reson Med. 2022 Sep 05.

Deuterium metabolic imaging of the human brain in vivo at 7 T.

Eulalia Serés Roig, Henk M De Feyter, Terence W Nixon, Loreen Ruhm, Anton V Nikulin, Klaus Scheffler, Nikolai I Avdievich, Anke Henning, Robin A de Graaf.

   PURPOSE: To explore the potential of deuterium metabolic imaging (DMI) in the human brain in vivo at 7 T, using a multi-element deuterium (2 H) RF coil for 3D volume coverage.
METHODS: 1 H-MR images and localized 2 H MR spectra were acquired in vivo in the human brain of 3 healthy subjects to generate DMI maps of 2 H-labeled water, glucose, and glutamate/glutamine (Glx). In addition, non-localized 2 H-MR spectra were acquired both in vivo and in vitro to determine T1 and T2 relaxation times of deuterated metabolites at 7 T. The performance of the 2 H coil was assessed through numeric simulations and experimentally acquired B1 + maps.
RESULTS: 3D DMI maps covering the entire human brain in vivo were obtained from well-resolved deuterated (2 H) metabolite resonances of water, glucose, and Glx. The T1 and T2 relaxation times were consistent with those reported at adjacent field strengths. Experimental B1 + maps were in good agreement with simulations, indicating efficient and homogeneous B1 + transmission and low RF power deposition for 2 H, consistent with a similar array coil design reported at 9.4 T.
CONCLUSION: Here, we have demonstrated the successful implementation of 3D DMI in the human brain in vivo at 7 T. The spatial and temporal nominal resolutions achieved at 7 T (i.e., 2.7 mL in 28 min, respectively) were close to those achieved at 9.4 T and greatly outperformed DMI at lower magnetic fields. DMI at 7 T and beyond has clear potential in applications dealing with small brain lesions.

Keywords:  7 Tesla (7 T); brain energy metabolism; deuterium (2H); deuterium metabolic imaging (DMI); glucose; glutamate/glutamine (Glx); human brain; water

DOI:  https://doi.org/10.1002/mrm.29439
Int J Mol Sci. 2022 Aug 25. pii: 9648. [Epub ahead of print]23(17):

Fatty Acid-Binding Proteins: Their Roles in Ischemic Stroke and Potential as Drug Targets.

Qingyun Guo, Ichiro Kawahata, An Cheng, Wenbin Jia, Haoyang Wang, Kohji Fukunaga.

  Stroke is among the leading causes of death and disability worldwide. However, despite long-term research yielding numerous candidate neuroprotective drugs, there remains a lack of effective neuroprotective therapies for ischemic stroke patients. Among the factors contributing to this deficiency could be that single-target therapy is insufficient in addressing the complex and extensive mechanistic basis of ischemic brain injury. In this context, lipids serve as an essential component of multiple biological processes and play important roles in the pathogenesis of numerous common neurological diseases. Moreover, in recent years, fatty acid-binding proteins (FABPs), a family of lipid chaperone proteins, have been discovered to be involved in the onset or development of several neurodegenerative diseases, including Alzheimer's and Parkinson's disease. However, comparatively little attention has focused on the roles played by FABPs in ischemic stroke. We have recently demonstrated that neural tissue-associated FABPs are involved in the pathological mechanism of ischemic brain injury in mice. Here, we review the literature published in the past decade that has reported on the associations between FABPs and ischemia and summarize the relevant regulatory mechanisms of FABPs implicated in ischemic injury. We also propose candidate FABPs that could serve as potential therapeutic targets for ischemic stroke.

Keywords:  fatty acid-binding protein; ischemic cascade; ischemic stroke; mitochondria; neurovascular unit

DOI:  https://doi.org/10.3390/ijms23179648
iScience. 2022 Sep 16. 25(9): 104920

Mitochondrial protein synthesis and the bioenergetic cost of neurodevelopment.

Pernille Bülow, Anupam Patgiri, Victor Faundez.

  The human brain consumes five orders of magnitude more energy than the sun by unit of mass and time. This staggering bioenergetic cost serves mostly synaptic transmission and actin cytoskeleton dynamics. The peak of both brain bioenergetic demands and the age of onset for neurodevelopmental disorders is approximately 5 years of age. This correlation suggests that defects in the machinery that provides cellular energy would be causative and/or consequence of neurodevelopmental disorders. We explore this hypothesis from the perspective of the machinery required for the synthesis of the electron transport chain, an ATP-producing and NADH-consuming enzymatic cascade. The electron transport chain is constituted by nuclear- and mitochondrial-genome-encoded subunits. These subunits are synthesized by the 80S and the 55S ribosomes, which are segregated to the cytoplasm and the mitochondrial matrix, correspondingly. Mitochondrial protein synthesis by the 55S ribosome is the rate-limiting step in the synthesis of electron transport chain components, suggesting that mitochondrial protein synthesis is a bottleneck for tissues with high bionergetic demands. We discuss genetic defects in the human nuclear and mitochondrial genomes that affect these protein synthesis machineries and cause a phenotypic spectrum spanning autism spectrum disorders to neurodegeneration during neurodevelopment. We propose that dysregulated mitochondrial protein synthesis is a chief, yet understudied, causative mechanism of neurodevelopmental and behavioral disorders.

Keywords:  Biological Sciences; Cell Biology; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2022.104920
Cells. 2022 Aug 27. pii: 2661. [Epub ahead of print]11(17):

High Fat Diet Multigenerationally Affects Hippocampal Neural Stem Cell Proliferation via Epigenetic Mechanisms.

Francesca Natale, Matteo Spinelli, Saviana Antonella Barbati, Lucia Leone, Salvatore Fusco, Claudio Grassi.

  Early-life metabolic stress has been demonstrated to affect brain development, persistently influence brain plasticity and to exert multigenerational effects on cognitive functions. However, the impact of an ancestor's diet on the adult neurogenesis of their descendants has not yet been investigated. Here, we studied the effects of maternal high fat diet (HFD) on hippocampal adult neurogenesis and the proliferation of neural stem and progenitor cells (NSPCs) derived from the hippocampus of both the second and the third generations of progeny (F2HFD and F3HFD). Maternal HFD caused a multigenerational depletion of neurogenic niche in F2HFD and F3HFD mice. Moreover, NSPCs derived from HFD descendants showed altered expression of genes regulating stem cell proliferation and neurodifferentiation (i.e., Hes1, NeuroD1, Bdnf). Finally, ancestor HFD-related hyper-activation of both STAT3 and STAT5 induced enhancement of their binding on the regulatory sequences of Gfap gene and an epigenetic switch from permissive to repressive chromatin on the promoter of the NeuroD1 gene. Collectively, our data indicate that maternal HFD multigenerationally affects hippocampal adult neurogenesis via an epigenetic derangement of pro-neurogenic gene expression in NSPCs.

Keywords:  epigenetics; hippocampal adult neurogenesis; maternal HFD; neural stem and progenitor cells

DOI:  https://doi.org/10.3390/cells11172661
IUBMB Life. 2022 Sep 09.

Structural aspects of the glucose and monocarboxylate transporters involved in the Warburg effect.

Xin Jiang, Nieng Yan, Dong Deng, Chuangye Yan.

  Cancer cells shift their glucose catabolism from aerobic respiration to lactic fermentation even in the presence of oxygen, and this is known as the "Warburg effect". To accommodate the high glucose demands and to avoid lactate accumulation, the expression levels of human glucose transporters (GLUTs) and human monocarboxylate transporters (MCTs) are elevated to maintain metabolic homeostasis. Therefore, inhibition of GLUTs and/or MCTs provides potential therapeutic strategies for cancer treatment. Here, we summarize recent advances in the structural characterization of GLUTs and MCTs, providing a comprehensive understanding of their transport and inhibition mechanisms to facilitate further development of anticancer therapies.

Keywords:  Warburg effect; alternating access; glucose transporters; lactate shuttling; monocarboxylate transporters

DOI:  https://doi.org/10.1002/iub.2668
Int J Mol Sci. 2022 Aug 29. pii: 9803. [Epub ahead of print]23(17):

Lipid-Based Molecules on Signaling Pathways in Autism Spectrum Disorder.

Kunio Yui, George Imataka, Shigemi Yoshihara.

  The signaling pathways associated with lipid metabolism contribute to the pathophysiology of autism spectrum disorder (ASD) and provide insights for devising new therapeutic strategies. Prostaglandin E2 is a membrane-derived lipid molecule that contributes to developing ASD associated with canonical Wnt signaling. Cyclooxygenase-2 plays a key role in neuroinflammation and is implicated in the pathogenesis of neurodevelopmental diseases, such as ASD. The endocannabinoid system maintains a balance between inflammatory and redox status and synaptic plasticity and is a potential target for ASD pathophysiology. Redox signaling refers to specific and usually reversible oxidation-reduction reactions, some of which are also involved in pathways accounting for the abnormal behavior observed in ASD. Redox signaling and redox status-sensitive transcription factors contribute to the pathophysiology of ASD. Cannabinoids regulate the redox balance by altering the levels and activity of antioxidant molecules via ROS-producing NADPH oxidase (NOX) and ROS-scavenging superoxide dismutase enzymes. These signaling cascades integrate a broad range of neurodevelopmental processes that may be involved in the pathophysiology of ASD. Based on these pathways, we highlight putative targets that may be used for devising novel therapeutic interventions for ASD.

Keywords:  autism spectrum disorder; cyclooxygenase-2; endocannabinoid system; lipid modified signaling pathway; prostaglandins

DOI:  https://doi.org/10.3390/ijms23179803
Fluids Barriers CNS. 2022 Sep 06. 19(1): 69

Lysophosphatidic acid as a CSF lipid in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1.

Trine L Toft-Bertelsen, Dagne Barbuskaite, Eva Kjer Heerfordt, Sara Diana Lolansen, Søren Norge Andreassen, Nina Rostgaard, Markus Harboe Olsen, Nicolas H Norager, Tenna Capion, Martin Fredensborg Rath, Marianne Juhler, Nanna MacAulay.

   BACKGROUND: A range of neurological pathologies may lead to secondary hydrocephalus. Treatment has largely been limited to surgical cerebrospinal fluid (CSF) diversion, as specific and efficient pharmacological options are lacking, partly due to the elusive molecular nature of the CSF secretion apparatus and its regulatory properties in physiology and pathophysiology.
METHODS: CSF obtained from patients with subarachnoid hemorrhage (SAH) and rats with experimentally inflicted intraventricular hemorrhage (IVH) was analyzed for lysophosphatidic acid (LPA) by alpha-LISA. We employed the in vivo rat model to determine the effect of LPA on ventricular size and brain water content, and to reveal the effect of activation and inhibition of the transient receptor potential vanilloid 4 (TRPV4) ion channel on intracranial pressure and CSF secretion rate. LPA-mediated modulation of TRPV4 was determined with electrophysiology and an ex vivo radio-isotope assay was employed to determine the effect of these modulators on choroid plexus transport.
RESULTS: Elevated levels of LPA were observed in CSF obtained from patients with subarachnoid hemorrhage (SAH) and from rats with experimentally-inflicted intraventricular hemorrhage (IVH). Intraventricular administration of LPA caused elevated brain water content and ventriculomegaly in experimental rats, via its action as an agonist of the choroidal transient receptor potential vanilloid 4 (TRPV4) channel. TRPV4 was revealed as a novel regulator of ICP in experimental rats via its ability to modulate the CSF secretion rate through its direct activation of the Na+/K+/2Cl- cotransporter (NKCC1) implicated in CSF secretion.
CONCLUSIONS: Together, our data reveal that a serum lipid present in brain pathologies with hemorrhagic events promotes CSF hypersecretion and ensuing brain water accumulation via its direct action on TRPV4 and its downstream regulation of NKCC1. TRPV4 may therefore be a promising future pharmacological target for pathologies involving brain water accumulation.

Keywords:  Brain water; Cerebrospinal fluid; Choroid plexus; IVH; Intraventricular hemorrhage; LPA; Membrane transport; SAH; Subarachnoid hemorrhage; Transient receptor potential vanilloid 4

DOI:  https://doi.org/10.1186/s12987-022-00361-9
Exp Mol Med. 2022 Sep 08.

Tracing the lactate shuttle to the mitochondrial reticulum.

George A Brooks, Casey C Curl, Robert G Leija, Adam D Osmond, Justin J Duong, Jose A Arevalo.

Isotope tracer infusion studies employing lactate, glucose, glycerol, and fatty acid isotope tracers were central to the deduction and demonstration of the Lactate Shuttle at the whole-body level. In concert with the ability to perform tissue metabolite concentration measurements, as well as determinations of unidirectional and net metabolite exchanges by means of arterial-venous difference (a-v) and blood flow measurements across tissue beds including skeletal muscle, the heart and the brain, lactate shuttling within organs and tissues was made evident. From an extensive body of work on men and women, resting or exercising, before or after endurance training, at sea level or high altitude, we now know that Organ-Organ, Cell-Cell, and Intracellular Lactate Shuttles operate continuously. By means of lactate shuttling, fuel-energy substrates can be exchanged between producer (driver) cells, such as those in skeletal muscle, and consumer (recipient) cells, such as those in the brain, heart, muscle, liver and kidneys. Within tissues, lactate can be exchanged between white and red fibers within a muscle bed and between astrocytes and neurons in the brain. Within cells, lactate can be exchanged between the cytosol and mitochondria and between the cytosol and peroxisomes. Lactate shuttling between driver and recipient cells depends on concentration gradients created by the mitochondrial respiratory apparatus in recipient cells for oxidative disposal of lactate.

DOI: https://doi.org/10.1038/s12276-022-00802-3
Turk J Pediatr. 2022 ;pii: 2481. [Epub ahead of print]64(4): 747-753

A rare case of hypomyelinating leukodystrophy-14 benefiting from ketogenic diet therapy.

Aycan Ünalp, Melis Köse, Pakize Karaoğlu, Yiğithan Güzin, Ünsal Yılmaz.

   BACKGROUND: Hypomyelinating leukodystrophy-14 (HLD14) is a rarely seen neurodevelopmental disease caused by homozygous pathogenic ubiquitin-fold modifier 1 gene variants. The disease has an autosomal recessive inheritance. All patients with this condition reported to date have drug-resistant epilepsy. The posttranslational modification of proteins with ubiquitin fold modifier 1 is defective in these patients and is thought to be responsible for severe neurodevelopmental problems. There is no previous report on the effectiveness of the ketogenic diet in the treatment of drug-resistant epileptic seizures in this disease. Therefore, we present a pediatric case diagnosed with HLD14 and whose drug-resistant epileptic seizures were controlled by ketogenic diet therapy.
CASE: The patient was a three-year-old male with drug-resistant epilepsy and developmental delay. His brain magnetic resonance imaging revealed cerebellar atrophy, periventricular white matter hypomyelination, and ventricular enlargement. Whole-exome sequencing analysis identified a homozygous pathogenic variant in the ubiquitin-fold modifier 1 gene on chromosome 13q13. Ketogenic diet therapy was initiated for his drug-resistant seizures and subsequently reduced seizure frequency by more than 75%. The patient is still on ketogenic diet therapy.
CONCLUSIONS: Ketogenic diet therapy may be beneficial for seizure control in HLD14 patients with drug-resistant seizures.

Keywords:  children; drug-resistant epilepsy; hypomyelinating leukodystrophy-14; ketogenic diet therapy

DOI:  https://doi.org/10.24953/turkjped.2021.1662
J Pediatr Endocrinol Metab. 2022 Sep 08.

Newborn screening and genetic variation of medium chain acyl-CoA dehydrogenase deficiency in the Chinese population.

Yu-Yu Li, Jia Xu, Xue-Cheng Sun, Hong-Yu Li, Kai Mu.

   OBJECTIVES: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder of the fatty acid oxidative metabolism. This study aimed to investigate the epidemiological characteristics, the spectrum of variation, clinical phenotype, and prognosis of MCADD in Chinese newborns.
METHODS: We retrospectively analysed newborn screening (NBS) data in the Zibo area from January 2016 to March 2022 and summarized 42 cases recently reported in Chinese neonates. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and next-generation sequencing (NGS) were used to detect the concentrations of carnitine in the blood spots and for diagnosis.
RESULTS: A total of 183,082 newborns were detected, and six patients were diagnosed with MCADD (1/3,0514). The primary octanoylcarnitine (C8) and the octanoylcarnitine/decanoylcarnitine ratio (C8/C10) were elevated in all patients. Gene analysis revealed four known and four novel variants of the ACADM gene. Five patients were asymptomatic and developed normally under dietary guidance. One child died of vaccination-induced MCADD, presenting with hypoglycemia and elevated acylcarnitines.
CONCLUSIONS: The incidence of MCADD in Chinese newborns varies geographically from 1/222,903 to 1/30,514, and the most common pathogenic variant is c.449_452 del CTGA (p. T150Rfs∗4) in ACADM gene with a frequency of 27.7%. HPLC-MS/MS and genetic analysis are beneficial for early prevention and good prognosis of MCADD.

Keywords:  ACADM gene; acylcarnitine; inherited metabolic diseases; medium-chain acyl-CoA dehydrogenase deficiency; newborn screening

DOI:  https://doi.org/10.1515/jpem-2022-0394
Front Pharmacol. 2022 ;13 983920

Dexmedetomidine alleviates olfactory cognitive dysfunction by promoting neurogenesis in the subventricular zone of hypoxic-ischemic neonatal rats.

Andi Chen, Xiaohui Chen, Jianhui Deng, Jianjie Wei, Haitao Qian, Yongxin Huang, Shuyan Wu, Fei Gao, Cansheng Gong, Yanling Liao, Xiaochun Zheng.

  Background: Hypoxic-ischemic brain damage (HIBD) is the main cause of neurological dysfunction in neonates. Olfactory cognitive function is important for feeding, the ability to detect hazardous situations and social relationships. However, only a few studies have investigated olfactory cognitive dysfunction in neonates with HIBD; furthermore, the specific mechanisms involved are yet to be elucidated. It has been reported that neurogenesis in the subventricular zone (SVZ) is linked to olfactory cognitive function. Recently, dexmedetomidine (DEX) has been shown to provide neuroprotection in neonates following HIBD. In the present study, we investigated whether DEX could improve olfactory cognitive dysfunction in neonatal rats following HIBD and attempted to determine the underlying mechanisms. Methods: We induced HIBD in rats using the Rice-Vannucci model, and DEX (25 μg/kg, i.p.) was administered immediately after the induction of HIBD. Next, we used triphenyl tetrazolium chloride (TTC) staining and the Zea-longa score to assess the success of modelling. The levels of BDNF, TNF-α, IL-1β and IL-6 were determined by western blotting. Immunofluorescence staining was used to detect microglial activation and microglial M1/M2 polarization as well as to evaluate the extent of neurogenesis in the SVZ. To evaluate the olfactory cognitive function, the rats in each group were raised until post-natal days 28-35; then, we performed the buried food test and the olfactory memory test. Results: Analysis showed that HIBD induced significant brain infarction, neurological deficits, and olfactory cognitive dysfunction. Furthermore, we found that DEX treatment significantly improved olfactory cognitive dysfunction in rat pups with HIBD. DEX treatment also increased the number of newly formed neuroblasts (BrdU/DCX) and neurons (BrdU/NeuN) in the SVZ by increasing the expression of BDNF in rat pups with HIBD. Furthermore, analysis showed that the neurogenic effects of DEX were possibly related to the inhibition of inflammation and the promotion of M1 to M2 conversion in the microglia. Conclusion: Based on the present findings, DEX treatment could improve olfactory cognitive dysfunction in neonatal rats with HIBD by promoting neurogenesis in the SVZ and enhancing the expression of BDNF in the microglia. It was possible associated that DEX inhibited neuroinflammation and promoted M1 to M2 conversion in the microglia.

Keywords:  BDNF; dexmedetomidine; hypoxic-ischemic; neonate; neurogenesis; subventricular zone

DOI:  https://doi.org/10.3389/fphar.2022.983920
PLoS One. 2022 ;17(9): e0268590

A potent and selective inhibitor for the modulation of MAGL activity in the neurovasculature.

Alicia M Kemble, Benoit Hornsperger, Iris Ruf, Hans Richter, Jörg Benz, Bernd Kuhn, Dominik Heer, Matthias Wittwer, Britta Engelhardt, Uwe Grether, Ludovic Collin.

Chronic inflammation and blood-brain barrier dysfunction are key pathological hallmarks of neurological disorders such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. Major drivers of these pathologies include pro-inflammatory stimuli such as prostaglandins, which are produced in the central nervous system by the oxidation of arachidonic acid in a reaction catalyzed by the cyclooxygenases COX1 and COX2. Monoacylglycerol lipase hydrolyzes the endocannabinoid signaling lipid 2-arachidonyl glycerol, enhancing local pools of arachidonic acid in the brain and leading to cyclooxygenase-mediated prostaglandin production and neuroinflammation. Monoacylglycerol lipase inhibitors were recently shown to act as effective anti-inflammatory modulators, increasing 2-arachidonyl glycerol levels while reducing levels of arachidonic acid and prostaglandins, including PGE2 and PGD2. In this study, we characterized a novel, highly selective, potent and reversible monoacylglycerol lipase inhibitor (MAGLi 432) in a mouse model of lipopolysaccharide-induced blood-brain barrier permeability and in both human and mouse cells of the neurovascular unit: brain microvascular endothelial cells, pericytes and astrocytes. We confirmed the expression of monoacylglycerol lipase in specific neurovascular unit cells in vitro, with pericytes showing the highest expression level and activity. However, MAGLi 432 did not ameliorate lipopolysaccharide-induced blood-brain barrier permeability in vivo or reduce the production of pro-inflammatory cytokines in the brain. Our data confirm monoacylglycerol lipase expression in mouse and human cells of the neurovascular unit and provide the basis for further cell-specific analysis of MAGLi 432 in the context of blood-brain barrier dysfunction caused by inflammatory insults.

DOI: https://doi.org/10.1371/journal.pone.0268590