bims-medebr 2023-01-29 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒01‒29
twenty-six papers selected by
Regina F. Fernández
Johns Hopkins University

Age and APOE affect L-carnitine system metabolites in the brain in the APOE-TR model.
Understanding FABP7 binding to fatty acid micelles and membranes.
Sex-Dimorphic Glucocorticoid Receptor Regulation of Hypothalamic Primary Astrocyte Glycogen Metabolism: Interaction with Norepinephrine.
Powering the social brain: Mitochondria in social behaviour.
Exploring the Role of Glycolytic Enzymes PFKFB3 and GAPDH in the Modulation of Aβ and Neurodegeneration and Their Potential of Therapeutic Targets in Alzheimer's Disease.
[18F]FDG PET in conditions associated with hyperkinetic movement disorders and ataxia: a systematic review.
Coenzyme Q biochemistry and biosynthesis.
Novel LIAS variants in a patient with epilepsy and profound developmental disabilities.
Case report: Ketogenic diet acutely improves cognitive function in patient with Down syndrome and Alzheimer's disease.
Alterations in ether lipid metabolism and the consequences for the mouse lipidome.
Brain Glucose Sensing and the Problem of Relative Hypoglycemia.
Differences in mitochondrial function between brain and heart of senile rats exposed to acute hypobaric hypoxia. Role of nitric oxide.
Inhibition of Drp1-dependent mitochondrial fission by natural compounds as a therapeutic strategy for organ injuries.
Membrane cholesterol regulates inhibition and substrate transport by the glycine transporter, GlyT2.
Neurological insights on two siblings with GM3 synthase deficiency due to novel compound heterozygous ST3GAL5 variants.
Analysis of the expression and distribution of protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 in the normal adult mouse brain.
PLA2G6-Associated Neurodegeneration: A Rare Case Report of Neurodegeneration with Brain Iron Accumulation in Children.
Identification of the molecular mechanism of insulin-like growth factor-1 (IGF-1): a promising therapeutic target for neurodegenerative diseases associated with metabolic syndrome.
Hacd2 deficiency in mice leads to an early and lethal mitochondrial disease.
Nicotinamide as potential biomarker for Alzheimer's disease: A translational study based on metabolomics.
Inhibition of carnitine palmitoyl-transferase 1 is a potential target in a mouse model of Parkinson's disease.
Determination of endogenous sphingolipid content in stroke rats and HT22 cells subjected to oxygen-glucose deprivation by LC‒MS/MS.
Recurrent sensory-motor neuropathy mimicking CIDP as predominant presentation of PDH deficiency.
Cardiolipin-Mediated Alleviation of Mitochondrial Dysfunction Is a Neuroprotective Effect of Statin in Animal Model of Ischemic Stroke.
Association of sub-acute changes in plasma amino acid levels with long-term brain pathologies in a rat model of moderate-severe traumatic brain injury.
Ketamine administration in idiopathic epileptic and healthy control dogs: Can we detect differences in brain metabolite response with spectroscopy?

Front Aging Neurosci. 2022 ;14 1059017

Age and APOE affect L-carnitine system metabolites in the brain in the APOE-TR model.

Claire J C Huguenard, Adam Cseresznye, Teresa Darcey, Aurore Nkiliza, James E Evans, Stanley L Hazen, Michael Mullan, Fiona Crawford, Laila Abdullah.

  With age the apolipoprotein E (APOE) E4 allele (involved in lipid homeostasis) is associated with perturbation of bioenergetics pathways in Alzheimer's disease (AD). We therefore hypothesized that in aging mice APOE genotype would affect the L-carnitine system (central to lipid bioenergetics), in the brain and in the periphery. Using liquid chromatography-mass spectrometry, levels of L-carnitine and associated metabolites: γ-butyrobetaine (GBB), crotonobetaine, as well as acylcarnitines, were evaluated at 10-, 25-, and 50-weeks, in the brain and the periphery, in a targeted replacement mouse model of human APOE (APOE-TR). Aged APOE-TR mice were also orally administered 125 mg/kg of L-carnitine daily for 7 days followed by evaluation of brain, liver, and plasma L-carnitine system metabolites. Compared to E4-TR, an age-dependent increase among E2- and E3-TR mice was detected for medium- and long-chain acylcarnitines (MCA and LCA, respectively) within the cerebrovasculature and brain parenchyma. While following L-carnitine oral challenge, E4-TR mice had higher increases in the L-carnitine metabolites, GBB and crotonobetaine in the brain and a reduction of plasma to brain total acylcarnitine ratios compared to other genotypes. These studies suggest that with aging, the presence of the E4 allele may contribute to alterations in the L-carnitine bioenergetic system and to the generation of L-carnitine metabolites that could have detrimental effects on the vascular system. Collectively the E4 allele and aging may therefore contribute to AD pathogenesis through aging-related lipid bioenergetics as well as cerebrovascular dysfunctions.

Keywords:  Alzheimer’s disease; apolipoproteins; fatty acid metabolism; lipid oxidation; vascular biology

DOI:  https://doi.org/10.3389/fnagi.2022.1059017
Biophys J. 2023 Jan 24. pii: S0006-3495(23)00039-5. [Epub ahead of print]

Understanding FABP7 binding to fatty acid micelles and membranes.

Stefan Lenz, Iulia Bodnariuc, Margaret Renaud-Young, Tanille M Shandro, Justin L MacCallum.

Fatty acid binding proteins (FABPs) are chaperones that facilitate the transport of long-chain fatty acids within the cell and can provide cargo-dependent localization to specific cellular compartments. Understanding the nature of this transport is important because lipid signaling functions are associated with metabolic pathways impacting disease pathologies including cancer, autism, and schizophrenia. FABPs often associate with cell membranes to acquire and deliver their bound cargo as part of transport. We focus on brain fatty acid binding protein (FABP7), which demonstrates localization to the cytoplasm and nucleus, influencing transcription and fatty acid metabolism. We use a combined biophysical-computational approach to elucidate the interaction between FABP7 and model membranes. Specifically, we use multiple experiments to demonstrate that FABP7 can bind oleic acid (OA) and docosahexaenoic acid (DHA) micelles. Data from NMR and multiscale molecular dynamics simulations reveal that the interaction with micelles is through FABP7's portal region residues. Simulations suggest that binding to membranes occurs through the same residues as micelles. Simulations also capture binding events where fatty acids dissociate from the membrane and enter FABP7's binding pocket. Overall, our data shed light on the interactions between FABP7 and OA or DHA micelles and provide insight into the transport of long-chain fatty acids.

DOI: https://doi.org/10.1016/j.bpj.2023.01.023
Neuroglia. 2022 Dec;3(4): 144-157

Sex-Dimorphic Glucocorticoid Receptor Regulation of Hypothalamic Primary Astrocyte Glycogen Metabolism: Interaction with Norepinephrine.

Prabhat R Napit, Abdulrahman Alhamyani, Khaggeswar Bheemanapally, Paul W Sylvester, Karen P Briski.

  Astrocyte glycogen is a critical metabolic variable that impacts hypothalamic control of glucostasis. Glucocorticoid hormones regulate peripheral glycogen, but their effects on hypothalamic glycogen are not known. A hypothalamic astrocyte primary culture model was used to investigate the premise that glucocorticoids impose sex-dimorphic independent and interactive control of glycogen metabolic enzyme protein expression and glycogen accumulation. The glucocorticoid receptor (GR) agonist dexamethasone (DEX) down-regulated glycogen synthase (GS), glycogen phosphorylase (GP)-brain type (GPbb), and GP-muscle type (GPmm) proteins in glucose-supplied male astrocytes, but enhanced these profiles in female. The catecholamine neurotransmitter norepinephrine (NE) did not alter these proteins, but amplified DEX inhibition of GS and GPbb in male or abolished GR stimulation of GPmm in female. In both sexes, DEX and NE individually increased glycogen content, but DEX attenuated the magnitude of noradrenergic stimulation. Glucoprivation suppressed GS, GPbb, and GPmm in male, but not female astrocytes, and elevated or diminished glycogen in these sexes, respectively. Glucose-deprived astrocytes exhibit GR-dependent induced glycogen accumulation in both sexes, and corresponding loss (male) or attenuation (female) of noradrenergic-dependent glycogen build-up. Current evidence for GR augmentation of hypothalamic astrocyte glycogen content in each sex, yet divergent effects on glycogen enzyme proteins infers that glucocorticoids may elicit opposite adjustments in glycogen turnover in each sex. Results document GR modulation of NE stimulation of glycogen accumulation in the presence (male and female) or absence (female) of glucose. Outcomes provide novel proof that astrocyte energy status influences the magnitude of GR and NE signal effects on glycogen mass.

Keywords:  LC-ESI-MS; dexamethasone; glucoprivation; glycogen; glycogen phosphorylase isoform; norepinephrine

DOI:  https://doi.org/10.3390/neuroglia3040010
Curr Opin Neurobiol. 2023 Jan 23. pii: S0959-4388(22)00169-6. [Epub ahead of print]79 102675

Powering the social brain: Mitochondria in social behaviour.

Doğukan Hazar Ülgen, Silvie Rosalie Ruigrok, Carmen Sandi.

A central role of brain mitochondria in regulating and influencing social behaviour is emerging. In addition to its important roles as the "powerhouses" of the cell, mitochondria possess a plethora of cellular functions, such as regulating ion homeostasis, neurotransmitter levels, and lipid metabolism. Findings in the last decade are revealing an integral role for mitochondria in the regulation of behaviours, including those from the social domain. Here, we discuss recent evidence linking mitochondrial functions and dynamics to social behaviour and deficits, including examples in which social behaviours are modulated by stress in the context of mitochondrial changes, as well as potential therapeutic strategies and outstanding questions in the field.

DOI: https://doi.org/10.1016/j.conb.2022.102675
Appl Biochem Biotechnol. 2023 Jan 24.

Exploring the Role of Glycolytic Enzymes PFKFB3 and GAPDH in the Modulation of Aβ and Neurodegeneration and Their Potential of Therapeutic Targets in Alzheimer's Disease.

Imran Ahmad, Ranjana Singh, Saurabh Pal, Soni Prajapati, Nidhi Sachan, Yusra Laiq, Hadiya Husain.

  Alzheimer's disease (AD) is presently the 6th major cause of mortality across the globe. However, it is expected to rise rapidly, following cancer and heart disease, as a leading cause of death among the elderly peoples. AD is largely characterized by metabolic changes linked to glucose metabolism and age-induced mitochondrial failure. Recent research suggests that the glycolytic pathway is required for a range of neuronal functions in the brain including synaptic transmission, energy production, and redox balance; however, alteration in glycolytic pathways may play a significant role in the development of AD. Moreover, it is hypothesized that targeting the key enzymes involved in glucose metabolism may help to prevent or reduce the risk of neurodegenerative disorders. One of the major pro-glycolytic enzyme is 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3); it is normally absent in neurons but abundant in astrocytes. Similarly, another key of glycolysis is glyceraldehyde-3-phosphate dehydrogenase (GAPDH) which catalyzes the conversion of aldolase and glyceraldehyde 3 phosphates to 1,3 bisphosphoglycerate. GAPDH has been reported to interact with various neurodegenerative disease-associated proteins, including the amyloid-β protein precursor (AβPP). These findings indicate PFKFB3 and GAPDH as a promising therapeutic target to AD. Current review highlight the contributions of PFKFB3 and GAPDH in the modulation of Aβand AD pathogenesis and further explore the potential of PFKFB3 and GAPDH as therapeutic targets in AD.

Keywords:  Alzheimer’s disease; Amyloid-β; GAPDH; PFKFB3; Therapeutic target

DOI:  https://doi.org/10.1007/s12010-023-04340-0
Eur J Nucl Med Mol Imaging. 2023 Jan 27.

[18F]FDG PET in conditions associated with hyperkinetic movement disorders and ataxia: a systematic review.

Elze R Timmers, Marrit R Klamer, Ramesh S Marapin, Adriaan A Lammertsma, Bauke M de Jong, Rudi A J O Dierckx, Marina A J Tijssen.

  PURPOSE: To give a comprehensive literature overview of alterations in regional cerebral glucose metabolism, measured using [18F]FDG PET, in conditions associated with hyperkinetic movement disorders and ataxia. In addition, correlations between glucose metabolism and clinical variables as well as the effect of treatment on glucose metabolism are discussed.METHODS: A systematic literature search was performed according to PRISMA guidelines. Studies concerning tremors, tics, dystonia, ataxia, chorea, myoclonus, functional movement disorders, or mixed movement disorders due to autoimmune or metabolic aetiologies were eligible for inclusion. A PubMed search was performed up to November 2021.
RESULTS: Of 1240 studies retrieved in the original search, 104 articles were included. Most articles concerned patients with chorea (n = 27), followed by ataxia (n = 25), dystonia (n = 20), tremor (n = 8), metabolic disease (n = 7), myoclonus (n = 6), tics (n = 6), and autoimmune disorders (n = 5). No papers on functional movement disorders were included. Altered glucose metabolism was detected in various brain regions in all movement disorders, with dystonia-related hypermetabolism of the lentiform nuclei and both hyper- and hypometabolism of the cerebellum; pronounced cerebellar hypometabolism in ataxia; and striatal hypometabolism in chorea (dominated by Huntington disease). Correlations between clinical characteristics and glucose metabolism were often described. [18F]FDG PET-showed normalization of metabolic alterations after treatment in tremors, ataxia, and chorea.
CONCLUSION: In all conditions with hyperkinetic movement disorders, hypo- or hypermetabolism was found in multiple, partly overlapping brain regions, and clinical characteristics often correlated with glucose metabolism. For some movement disorders, [18F]FDG PET metabolic changes reflected the effect of treatment.

Keywords:  Hyperkinetic movement disorders; [18F]FDG PET

DOI:  https://doi.org/10.1007/s00259-023-06110-w
Trends Biochem Sci. 2023 Jan 24. pii: S0968-0004(22)00334-6. [Epub ahead of print]

Coenzyme Q biochemistry and biosynthesis.

Rachel M Guerra, David J Pagliarini.

  Coenzyme Q (CoQ) is a remarkably hydrophobic, redox-active lipid that empowers diverse cellular processes. Although most known for shuttling electrons between mitochondrial electron transport chain (ETC) complexes, the roles for CoQ are far more wide-reaching and ever-expanding. CoQ serves as a conduit for electrons from myriad pathways to enter the ETC, acts as a cofactor for biosynthetic and catabolic reactions, detoxifies damaging lipid species, and engages in cellular signaling and oxygen sensing. Many open questions remain regarding the biosynthesis, transport, and metabolism of CoQ, which hinders our ability to treat human CoQ deficiency. Here, we recount progress in filling these knowledge gaps, highlight unanswered questions, and underscore the need for novel tools to enable discoveries and improve the treatment of CoQ-related diseases.

Keywords:  coenzyme Q; complex Q; lipids; mitochondria; oxidative phosphorylation; ubiquinone

DOI:  https://doi.org/10.1016/j.tibs.2022.12.006
Mol Genet Metab. 2023 Jan 07. pii: S1096-7192(23)00003-3. [Epub ahead of print]138(3): 107373

Novel LIAS variants in a patient with epilepsy and profound developmental disabilities.

Parith Wongkittichote, Chanseyha Chhay, Gazelle Zerafati-Jahromi, Judith L Weisenberg, Ali Mian, Laran T Jensen, Dorothy K Grange.

  Multiple mitochondrial enzymes employ lipoic acid as a coenzyme. Pathogenic variants in LIAS, encoding lipoic acid synthase (LIAS), are associated with autosomal recessive LIAS-related disorder (OMIM# 614462). This disorder is characterized by infantile-onset hypotonia, profound psychomotor delay, epileptic encephalopathy, nonketotic hyperglycinemia, and lactic acidosis. We present the case of a 20-year-old female who experienced developmental deficits at the age of 6 months and began to have seizures at 3 years of age. Exome sequencing revealed compound heterozygous novel variants in LIAS, designated c.277delC (p.Leu93Ter) and c.542A > T (p.Asp181Val). The p.Leu93Ter variant is predicted to cause loss of function due to the severe truncation of the encoded protein. To examine the p.Asp181Val variant, functional analysis was performed using Baker's yeast (Saccharomyces cerevisiae) lacking LIP5, the homologue of human LIAS. Wild-type LIAS promoted oxidative growth of the lip5∆ yeast strain. In contrast, lip5∆ yeast expressing p.Asp181Val exhibited poor growth, similar to known pathogenic variants, p.Asp215Glu and p.Met310Thr. Our work has expanded the phenotypic and genotypic spectrum of LIAS-related disorder and established the use of the yeast model as a system for functional study of novel missense variants in LIAS.

Keywords:  Developmental delay; Epilepsy; LIAS-related disorder; Lipoic acid biosynthesis; Mitochondrial disorder; Nonketotic hyperglycinemia

DOI:  https://doi.org/10.1016/j.ymgme.2023.107373
Front Psychiatry. 2022 ;13 1085512

Case report: Ketogenic diet acutely improves cognitive function in patient with Down syndrome and Alzheimer's disease.

Annette Bosworth, Vyvyane Loh, Blackjack N Stranahan, Christopher M Palmer.

  Ketogenic diets have a century-long history as a therapeutic tool to treat intractable epilepsy. Recently, a renewed interest in neuroketotherapeutics has arisen, with ketogenic diets being explored for the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, as well as mental health conditions. Herein, we present a case report of a 47-year-old woman with Down syndrome diagnosed with Alzheimer's disease and absence seizures with accelerated cognitive decline over 6 years. A ketogenic diet restored her cognitive function over 6 weeks, with an increase in Activities of Daily Living Scale score from 34 to 58. A therapeutic ketogenic diet was associated with significant cognitive improvement in this patient with concurrent Down syndrome and dementia.

Keywords:  Alzheimer’s disease; Down syndrome; cognition; episodic memory; executive function; ketogenic; ketone; mild cognitive impairment

DOI:  https://doi.org/10.3389/fpsyt.2022.1085512
Biochim Biophys Acta Mol Cell Biol Lipids. 2023 Jan 20. pii: S1388-1981(23)00009-4. [Epub ahead of print] 159285

Alterations in ether lipid metabolism and the consequences for the mouse lipidome.

Katharina Lackner, Sabrina Sailer, Jan-Bert van Klinken, Eric Wever, Mia L Pras-Raves, Adrie D Dane, Masanori Honsho, Yuichi Abe, Markus A Keller, Georg Golderer, Gabriele Werner-Felmayer, Yukio Fujiki, Frédéric M Vaz, Ernst R Werner, Katrin Watschinger.

  Alkylglycerol monooxygenase (AGMO) and plasmanylethanolamine desaturase (PEDS1) are enzymes involved in ether lipid metabolism. While AGMO degrades plasmanyl lipids by oxidative cleavage of the ether bond, PEDS1 exclusively synthesizes a specific subclass of ether lipids, the plasmalogens, by introducing a vinyl ether double bond into plasmanylethanolamine phospholipids. Ether lipids are characterized by an ether linkage at the sn-1 position of the glycerol backbone and they are found in membranes of different cell types. Decreased plasmalogen levels have been associated with neurological diseases like Alzheimer's disease. Agmo-deficient mice do not present an obvious phenotype under unchallenged conditions. In contrast, Peds1 knockout mice display a growth phenotype. To investigate the molecular consequences of Agmo and Peds1 deficiency on the mouse lipidome, five tissues from each mouse model were isolated and subjected to high resolution mass spectrometry allowing the characterization of up to 2013 lipid species from 42 lipid subclasses. Agmo knockout mice moderately accumulated plasmanyl and plasmenyl lipid species. Peds1-deficient mice manifested striking changes characterized by a strong reduction of plasmenyl lipids and a concomitant massive accumulation of plasmanyl lipids resulting in increased total ether lipid levels in the analyzed tissues except for the class of phosphatidylethanolamines where total levels remained remarkably constant also in Peds1 knockout mice. The rate-limiting enzyme in ether lipid metabolism, FAR1, was not upregulated in Peds1-deficient mice, indicating that the selective loss of plasmalogens is not sufficient to activate the feedback mechanism observed in total ether lipid deficiency.

Keywords:  Glycerolipids; Glycerophospholipids; Knockout mouse models; Lipidomics; Phospholipids; Plasmalogens

DOI:  https://doi.org/10.1016/j.bbalip.2023.159285
Diabetes Care. 2023 Feb 01. 46(2): 237-244

Brain Glucose Sensing and the Problem of Relative Hypoglycemia.

Michael W Schwartz, James S Krinsley, Chelsea L Faber, Irl B Hirsch, Michael Brownlee.

"Relative hypoglycemia" is an often-overlooked complication of diabetes characterized by an increase in the glycemic threshold for detecting and responding to hypoglycemia. The clinical relevance of this problem is linked to growing evidence that among patients with critical illness, higher blood glucose in the intensive care unit is associated with higher mortality among patients without diabetes but lower mortality in patients with preexisting diabetes and an elevated prehospitalization HbA1c. Although additional studies are needed, the cardiovascular stress associated with hypoglycemia perception, which can occur at normal or even elevated glucose levels in patients with diabetes, offers a plausible explanation for this difference in outcomes. Little is known, however, regarding how hypoglycemia is normally detected by the brain, much less how relative hypoglycemia develops in patients with diabetes. In this article, we explore the role in hypoglycemia detection played by glucose-responsive sensory neurons supplying peripheral vascular beds and/or circumventricular organs. These observations support a model wherein relative hypoglycemia results from diabetes-associated impairment of this neuronal glucose-sensing process. By raising the glycemic threshold for hypoglycemia perception, this impairment may contribute to the increased mortality risk associated with standard glycemic management of critically ill patients with diabetes.

DOI: https://doi.org/10.2337/dc22-1445
Exp Gerontol. 2023 Jan 20. pii: S0531-5565(23)00021-9. [Epub ahead of print]173 112100

Differences in mitochondrial function between brain and heart of senile rats exposed to acute hypobaric hypoxia. Role of nitric oxide.

P La Padula, L E Costa, A Karadayian, S Lores-Arnaiz, A Czerniczyniec.

  Rat brain and heart display different endogenous protective responses against hypobaric hypoxia in an age-dependent way. The aim of the present work was to evaluate the effects of acute hypobaric hypoxia (HH, 48 h) on brain and heart mitochondrial function as well as the participation of nitric oxide (NO) in old rats (22-month old). Cortical mitochondria from rats exposed to HH decreased respiratory rates (37 %, state 3) and membrane potential (20 %), but NO and H2O2 production increased by 48 %, and 23 %, respectively. Hippocampal mitochondria preserved O2 consumption and H2O2 production, decreased membrane potential (18 %) and increased NO production (46 %). By contrast, HH decreased NO production (53 %) in mitochondria from left heart ventricles associated with increased cytochrome oxidase activity (39 %) and decreased NADPH oxidase activity (31 %). Also, a tendency to increase complex I-III (24 %) and complex II-III (65 %) activity was observed. In conclusion, after HH hippocampal and cortical mitochondria showed mild uncoupling and increased NO production. However, only the hippocampus preserved O2 consumption and H2O2 levels. Interestingly, heart mitochondria showed a decreased ROS production through increased cytochrome oxidase activity associated with a decrease in NO production. This may be interpreted as a self-protective mechanism against hypoxia.

Keywords:  Aging; Brain; Heart; Hypobaric hypoxia; Mitochondria; Nitric oxide

DOI:  https://doi.org/10.1016/j.exger.2023.112100
Pharmacol Res. 2023 Jan 20. pii: S1043-6618(23)00028-2. [Epub ahead of print]188 106672

Inhibition of Drp1-dependent mitochondrial fission by natural compounds as a therapeutic strategy for organ injuries.

Sohrab Rahmani, Ali Roohbakhsh, Gholamreza Karimi.

  Mitochondria are morphologically dynamic organelles frequently undergoing fission and fusion processes that regulate mitochondrial integrity and bioenergetics. These processes are considered critical for cell survival. The mitochondrial fission process regulates mitochondrial biogenesis and mitophagy. It is associated with apoptosis, while mitochondrial fusion controls the accurate distribution of mitochondrial DNA and metabolic substances across the mitochondria. Excessive mitochondrial fission results in mitochondrial structural changes, dysfunction, and cell damage. Accumulating evidence demonstrates that mitochondrial dynamics affect neurodegenerative and cardiovascular diseases along with several other diseases. Biological molecules regulating the process of mitochondrial fission are potential targets for developing therapeutic agents. Many natural products target the dynamin-related protein 1 (Drp1)-dependent mitochondrial fission pathway, and their inhibitory effects ameliorate mitochondrial fragmentation. In this article, we reviewed the research literature that describes Drp1-dependent inhibition as a mechanism for the protective effects of natural compounds.

Keywords:  Apoptosis; Dynamin-related protein 1; Fission inhibitors; Free radical production; Herbal medicine; Mitochondrial fission; Mitochondrial fusion; Natural compound

DOI:  https://doi.org/10.1016/j.phrs.2023.106672
Life Sci Alliance. 2023 Apr;pii: e202201708. [Epub ahead of print]6(4):

Membrane cholesterol regulates inhibition and substrate transport by the glycine transporter, GlyT2.

Zachary J Frangos, Katie A Wilson, Heather M Aitken, Ryan Cantwell Chater, Robert J Vandenberg, Megan L O'Mara.

Membrane cholesterol binds to and modulates the function of various SLC6 neurotransmitter transporters, including stabilizing the outward-facing conformation of the dopamine and serotonin transporters. Here, we investigate how cholesterol binds to GlyT2 (SLC6A5), modulates glycine transport rate, and influences bioactive lipid inhibition of GlyT2. Bioactive lipid inhibitors are analgesics that bind to an allosteric site accessible from the extracellular solution when GlyT2 adopts an outward-facing conformation. Using molecular dynamics simulations, mutagenesis, and cholesterol depletion experiments, we show that bioactive lipid inhibition of glycine transport is modulated by the recruitment of membrane cholesterol to a binding site formed by transmembrane helices 1, 5, and 7. Recruitment involves cholesterol flipping from its membrane orientation, and insertion of the 3' hydroxyl group into the cholesterol binding cavity, close to the allosteric site. The synergy between cholesterol and allosteric inhibitors provides a novel mechanism of inhibition and a potential avenue for the development of potent GlyT2 inhibitors as alternative therapeutics for the treatment of neuropathic pain and therapeutics that target other SLC6 transporters.

DOI: https://doi.org/10.26508/lsa.202201708
Brain Dev. 2023 Jan 21. pii: S0387-7604(23)00002-5. [Epub ahead of print]

Neurological insights on two siblings with GM3 synthase deficiency due to novel compound heterozygous ST3GAL5 variants.

Shiena Watanabe, Ming Lei, Eiji Nakagawa, Eri Takeshita, Kei-Ichiro Inamori, Fumi Shishido, Masayuki Sasaki, Satomi Mitsuhashi, Naomichi Matsumoto, Yuiko Kimura, Masaki Iwasaki, Yuji Takahashi, Hidehiro Mizusawa, Ohsuke Migita, Isao Ohno, Jin-Ichi Inokuchi.

  BACKGROUND: ST3GAL5 encodes GM3 synthase (ST3 beta-galactoside alpha-2,3-sialyltransferase 5; ST3GAL5), which synthesizes GM3 by transferring sialic acid to lactosylceramide. GM3, a sialic acid-containing glycosphingolipid known as ganglioside, is a precursor to the biosynthesis of various more complex gangliosides that are active in the brain. Biallelic variants in ST3GAL5 cause GM3 synthase deficiency (GM3SD), a rare congenital disorder of glycosylation. GM3SD was first identified in the Amish population in 2004.CASE: We report two siblings diagnosed with GM3SD due to novel compound heterozygous ST3GAL5 variants. The novel ST3GAL5 variants, detected by whole-exome sequencing in the patients, were confirmed to be pathogenic by GM3 synthase assay. The clinical courses of these patients, which began in infancy with irritability and growth failure, followed by developmental delay and hearing loss, were consistent with previous case reports of GM3SD. The older sibling underwent deep brain stimulation for severe involuntary movements at the age of 9 years. The younger sibling suffered from acute encephalopathy at the age of 9 months and subsequently developed refractory epilepsy.
DISCUSSION: Reports of GM3SD outside the Amish population are rare, and whole-exome sequencing may be required to diagnose GM3SD in non-Amish patients. Since an effective treatment for GM3SD has not yet been established, we might select deep brain stimulation as a symptomatic treatment for involuntary movements in GM3SD.

Keywords:  Deep brain stimulation; Developmental delay; Epilepsy; GM3 synthase deficiency; Ganglioside; Involuntary movement; ST3GAL5

DOI:  https://doi.org/10.1016/j.braindev.2023.01.002
Front Neuroanat. 2022 ;16 1043924

Analysis of the expression and distribution of protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 in the normal adult mouse brain.

Hanxiao Jiang, Yuxue Feng, Guiqiong He, Yuanjie Liu, Xiaofeng Li.

  Introduction: Protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) is crucial for the elongation of O-mannosyl glycans. Mutations in POMGNT1 cause muscle-eye-brain (MEB) disease, one of the main features of which is anatomical aberrations in the brain. A growing number of studies have shown that defects in POMGNT1 affect neuronal migration and distribution, disrupt basement membranes, and misalign Cajal-Retzius cells. Several studies have examined the distribution and expression of POMGNT1 in the fetal or neonatal brain for neurodevelopmental studies in the mouse or human brain. However, little is known about the neuroanatomical distribution and expression of POMGNT1 in the normal adult mouse brain.Methods: We analyzed the expression of POMGNT1 mRNA and protein in the brains of various neuroanatomical regions and spinal cords by western blotting and RT-qPCR. We also detected the distribution profile of POMGnT1 in normal adult mouse brains by immunohistochemistry and double-immunofluorescence.
Results: In the present study, we found that POMGNT1-positive cells were widely distributed in various regions of the brain, with high levels of expression in the cerebral cortex and hippocampus. In terms of cell type, POMGNT1 was predominantly expressed in neurons and was mainly enriched in glutamatergic neurons; to a lesser extent, it was expressed in glial cells. At the subcellular level, POMGNT1 was mainly co-localized with the Golgi apparatus, but expression in the endoplasmic reticulum and mitochondria could not be excluded.
Discussion: The present study suggests that POMGNT1, although widely expressed in various brain regions, may has some regional and cellular specificity, and the outcomes of this study provide a new laboratory basis for revealing the possible involvement of POMGNT1 in normal physiological functions of the brain from a morphological perspective.

Keywords:  Golgi; O-mannosylation; POMGNT1; adult mouse; brain distribution; neurons

DOI:  https://doi.org/10.3389/fnana.2022.1043924
Pak J Med Sci. 2023 Jan-Feb;39(1):39(1): 310-313

PLA2G6-Associated Neurodegeneration: A Rare Case Report of Neurodegeneration with Brain Iron Accumulation in Children.

Nurani Widianti, Meta Herdiana Hanindita, Nur Aisiyah Widjaja, Roedi Irawan.

  This report aimed to describe and review the clinical features, neuroimaging findings, and PLA2G6 mutations identified in a 34-month-old girl with regression of developmental milestones. A 34 months old girl came to Dr.Soetomo Hospital's outpatient clinic, Surabaya, with a developmental regression for six months, and got worse until she could not do any activity and was followed by recurrent seizures. She had a sibling who had similar problems and symptoms and then died at five years of age. The head MRI revealed brain atrophy, the possibility of an early sign of metabolic disorder, and a white matter lesion at the globuspallidus bilateral that supports the encephalopathy metabolic view. The genetic test revealed a positive homozygous such as a pathogenic variant in the PLA2G6 gene, which confirmed the diagnosis. PLA2G6-Associated with Neurodegeneration (PLAN) should be considered as a diagnosis in children with developmental regression.

Keywords:  Developmental regression; Inherited metabolic diseases; NBIA; PLAN

DOI:  https://doi.org/10.12669/pjms.39.1.6801
Cell Biosci. 2023 Jan 23. 13(1): 16

Identification of the molecular mechanism of insulin-like growth factor-1 (IGF-1): a promising therapeutic target for neurodegenerative diseases associated with metabolic syndrome.

Archana Arjunan, Dhiraj Kumar Sah, Minna Woo, Juhyun Song.

  Neurodegenerative disorders are accompanied by neuronal degeneration and glial dysfunction, resulting in cognitive, psychomotor, and behavioral impairment. Multiple factors including genetic, environmental, metabolic, and oxidant overload contribute to disease progression. Recent evidences suggest that metabolic syndrome is linked to various neurodegenerative diseases. Metabolic syndrome (MetS) is known to be accompanied by symptoms such as hyperglycemia, abdominal obesity, hypertriglyceridemia, and hypertension. Despite advances in knowledge about the pathogenesis of neurodegenerative disorders, effective treatments to combat neurodegenerative disorders caused by MetS have not been developed to date. Insulin growth factor-1 (IGF-1) deficiency has been associated with MetS-related pathologies both in-vivo and in-vitro. IGF-1 is essential for embryonic and adult neurogenesis, neuronal plasticity, neurotropism, angiogenesis, metabolic function, and protein clearance in the brain. Here, we review the evidence for the potential therapeutic effects of IGF-1 in the neurodegeneration related to metabolic syndrome. We elucidate how IGF-1 may be involved in molecular signaling defects that occurs in MetS-related neurodegenerative disorders and highlight the importance of IGF-1 as a potential therapeutic target in MetS-related neurological diseases.

Keywords:  Alzheimer’s disease (AD); Insulin-like growth factor-1 (IGF-1); Metabolic syndrome (MetS); Neurodegeneration; Neuroprotection

DOI:  https://doi.org/10.1186/s13578-023-00966-z
Mol Metab. 2023 Jan 21. pii: S2212-8778(23)00011-X. [Epub ahead of print] 101677

Hacd2 deficiency in mice leads to an early and lethal mitochondrial disease.

Nahed Khadhraoui, Alexandre Prola, Aymeline Vandestienne, Jordan Blondelle, Laurent Guillaud, Guillaume Courtin, Maxime Bodak, Bastien Prost, Hélène Huet, Mélody Wintrebert, Christine Péchoux, Audrey Solgadi, Frédéric Relaix, Laurent Tiret, Fanny Pilot-Storck.

  OBJECTIVE: Mitochondria fuel most animal cells with ATP, ensuring proper energetic metabolism of organs. Early and extensive mitochondrial dysfunction often leads to severe disorders through multiorgan failure. Hacd2 gene encodes an enzyme involved in very long chain fatty acid (C ≥ 18) synthesis, yet its roles in vivo remain poorly understood. Since mitochondria function relies on specific properties of their membranes conferred by a particular phospholipid composition, we investigated if Hacd2 gene participates to mitochondrial integrity.METHODS: We generated two mouse models, the first one leading to a partial knockdown of Hacd2 expression and the second one, to a complete knockout of Hacd2 expression. We performed an in-depth analysis of the associated phenotypes, from whole organism to molecular scale.
RESULTS: Thanks to these models, we show that Hacd2 displays an early and broad expression, and that its deficiency in mice is lethal. Specifically, partial knockdown of Hacd2 expression leads to death within one to four weeks after birth, from a sudden growth arrest followed by cachexia and lethargy. The total knockout of Hacd2 is even more severe, characterized by embryonic lethality around E9.5 following developmental arrest and pronounced cardiovascular malformations. In-depth mechanistic analysis revealed that Hacd2 deficiency causes altered mitochondrial efficiency and ultrastructure, as well as accumulation of oxidized cardiolipin.
CONCLUSIONS: Altogether, these data indicate that the Hacd2 gene is essential for energetic metabolism during embryonic and postnatal development, acting through the control of proper mitochondrial organization and function.

Keywords:  ELOVL; Fatty acid; Heart development; OXPHOS coupling; Phospholipid; VLCFA

DOI:  https://doi.org/10.1016/j.molmet.2023.101677
Front Mol Biosci. 2022 ;9 1067296

Nicotinamide as potential biomarker for Alzheimer's disease: A translational study based on metabolomics.

María C Dalmasso, Martín Arán, Pablo Galeano, Silvina Perin, Patrick Giavalisco, Pamela V Martino Adami, Gisela V Novack, Eduardo M Castaño, A Claudio Cuello, Martin Scherer, Wolfgang Maier, Michael Wagner, Steffi Riedel-Heller, Alfredo Ramirez, Laura Morelli.

  Introduction: The metabolic routes altered in Alzheimer's disease (AD) brain are poorly understood. As the metabolic pathways are evolutionarily conserved, the metabolic profiles carried out in animal models of AD could be directly translated into human studies. Methods: We performed untargeted Nuclear Magnetic Resonance metabolomics in hippocampus of McGill-R-Thy1-APP transgenic (Tg) rats, a model of AD-like cerebral amyloidosis and the translational potential of these findings was assessed by targeted Gas Chromatography-Electron Impact-Mass Spectrometry in plasma of participants in the German longitudinal cohort AgeCoDe. Results: In rat hippocampus 26 metabolites were identified. Of these 26 metabolites, nine showed differences between rat genotypes that were nominally significant. Two of them presented partial least square-discriminant analysis (PLS-DA) loadings with the larger absolute weights and the highest Variable Importance in Projection (VIP) scores and were specifically assigned to nicotinamide adenine dinucleotide (NAD) and nicotinamide (Nam). NAD levels were significantly decreased in Tg rat brains as compared to controls. In agreement with these results, plasma of AD patients showed significantly reduced levels of Nam in respect to cognitively normal participants. In addition, high plasma levels of Nam showed a 27% risk reduction of progressing to AD dementia within the following 2.5 years, this hazard ratio is lost afterwards. Discussion: To our knowledge, this is the first report showing that a decrease of Nam plasma levels is observed couple of years before conversion to AD, thereby suggesting its potential use as biomarker for AD progression.

Keywords:  NAD salvage pathway; alzheimer’s disease; biomarkers, brain alterations; case-control analysis; nicotinamide (NAM); transgenic rats; vit B3

DOI:  https://doi.org/10.3389/fmolb.2022.1067296
NPJ Parkinsons Dis. 2023 Jan 21. 9(1): 6

Inhibition of carnitine palmitoyl-transferase 1 is a potential target in a mouse model of Parkinson's disease.

Michael Sloth Trabjerg, Dennis Christian Andersen, Pam Huntjens, Kasper Mørk, Nikolaj Warming, Ulla Bismark Kullab, Marie-Louise Nibelius Skjønnemand, Michal Krystian Oklinski, Kirsten Egelund Oklinski, Luise Bolther, Lona J Kroese, Colin E J Pritchard, Ivo J Huijbers, Angelique Corthals, Mads Toft Søndergaard, Henrik Bech Kjeldal, Cecilie Fjord Morre Pedersen, John Dirk Vestergaard Nieland.

Glucose metabolism is dysregulated in Parkinson's disease (PD) causing a shift toward the metabolism of lipids. Carnitine palmitoyl-transferase 1A (CPT1A) regulates the key step in the metabolism of long-chain fatty acids. The aim of this study is to evaluate the effect of downregulating CPT1, either genetically with a Cpt1a P479L mutation or medicinally on PD using chronic rotenone mouse models using C57Bl/6J and Park2 knockout mice. We show that Cpt1a P479L mutant mice are resistant to rotenone-induced PD, and that inhibition of CPT1 is capable of restoring neurological function, normal glucose metabolism, and alleviate markers of PD in the midbrain. Furthermore, we show that downregulation of lipid metabolism via CPT1 alleviates pathological motor and non-motor behavior, oxidative stress, and disrupted glucose homeostasis in Park2 knockout mice. Finally, we confirm that rotenone induces gut dysbiosis in C57Bl/6J and, for the first time, in Park2 knockout mice. We show that this dysbiosis is alleviated by the downregulation of the lipid metabolism via CPT1.

DOI: https://doi.org/10.1038/s41531-023-00450-y
Lipids Health Dis. 2023 Jan 25. 22(1): 13

Determination of endogenous sphingolipid content in stroke rats and HT22 cells subjected to oxygen-glucose deprivation by LC‒MS/MS.

Keqi Zeng, Xin Zhou, Wanyi Liu, Cong Nie, Yingfeng Zhang.

  BACKGROUND: Stroke is the leading cause of death in humans worldwide, and its incidence increases every year. It is well documented that lipids are closely related to stroke. Analyzing the changes in lipid content in the stroke model after absolute quantification and investigating whether changes in lipid content can predict stroke severity provides a basis for the combination of clinical stroke and quantitative lipid indicators.METHODS: This paper establishes a rapid, sensitive, and reliable LC‒MS/MS analytical method for the detection of endogenous sphingolipids in rat serum and brain tissue and HT22 cells and quantifies the changes in sphingolipid content in the serum and brain tissue of rats from the normal and pMCAO groups and in cells from the normal and OGD/R groups. Using sphingosine (d17:1) as the internal standard, a chloroform: methanol (9:1) mixed system was used for protein precipitation and lipid extraction, followed by analysis by reversed-phase liquid chromatography coupled to triple quadrupole mass spectrometry.
RESULTS: Based on absolute quantitative analysis of lipids in multiple biological samples, our results show that compared with those in the normal group, the contents of sphinganine (d16:0), sphinganine (d18:0), and phytosphingosine were significantly increased in the model group, except sphingosine-1-phosphate, which was decreased in various biological samples. The levels of each sphingolipid component in serum fluctuate with time.
CONCLUSION: This isotope-free and derivatization-free LC‒MS/MS method can achieve absolute quantification of sphingolipids in biological samples, which may also help identify lipid biomarkers of cerebral ischemia.

Keywords:  Content determination; Endogenous; Ischemic stroke; Liquid chromatography; Mass spectrometry; OGD/R-Induced; Sphingolipids

DOI:  https://doi.org/10.1186/s12944-022-01762-3
Neuropediatrics. 2023 Jan 24.

Recurrent sensory-motor neuropathy mimicking CIDP as predominant presentation of PDH deficiency.

Carolina Croci, Matteo Cataldi, Serena Baratto, Claudio Bruno, Federica Trucco, Stefano Doccini, Alessandro Romano, Claudia Nesti, Filippo Maria Santorelli, Chiara Fiorillo.

INTRODUCTION: PDH deficiency (OMIM # 312170) is a relatively common mitochondrial disorder, caused by mutations in the X-linked PDHA1 gene and presenting with a variable phenotypic spectrum, ranging from severe infantile encephalopathy to milder chronic neurological disorders. Isolated peripheral neuropathy as predominant clinical presentation is uncommon.RESULTS: We report on a patient, now 21 years old, presenting at the age of 2 years with recurrent symmetric weakness as first symptom of a PDH deficiency. Neurophysiological evaluation proving a sensory-motor polyneuropathy with conduction blocks and presence of elevated CSF proteins, suggested a chronic inflammatory polyneuropathy (CIDP). The evidence of high serum lactate and the alterations in oxidative metabolism in muscle biopsy pointed toward the final diagnosis. After starting nutritional supplements, no further episodes occurred. A hemizygous mutation in PDHA1 (p.Arg88Cys) was identified. This mutation has been previously described in 5 patients with a similar phenotype. A 3D-reconstruction demonstrated that mutations affecting this Arg88 destabilize the interactions between the subunits of the E1 complex.
CONCLUSION: We summarize the clinical and genetic characteristics of one patient with PDH deficiency presenting isolated peripheral nervous system involvement. This study highlights that the diagnosis of PDH deficiency should be considered in children with unexplained peripheral neuropathy, even with features suggestive of acquired forms, especially in case of early onset and limited response to treatment. A simple analysis of lactic acid could help to target the diagnosis. In addition, we suggest that the residue Arg88 is the most frequently involved in this specific phenotype of PDH deficiency.

DOI: https://doi.org/10.1055/a-2018-4845
ACS Chem Neurosci. 2023 Jan 27.

Cardiolipin-Mediated Alleviation of Mitochondrial Dysfunction Is a Neuroprotective Effect of Statin in Animal Model of Ischemic Stroke.

Deepaneeta Sarmah, Abhishek Sarkar, Aishika Datta, Bijoyani Ghosh, Nikita Rana, Shubhrakanta Sahu, Vishal Gupta, Vrushali Thongire, Antra Chaudhary, Namrata Vadak, Harpreet Kaur, Swapnil Raut, Upasna Singh, Anupom Borah, Pallab Bhattacharya.

  In clinical settings, the benefit of statin for stroke is debatable as regular statin users may suffer from myalgia, statin-associated myopathy (SAM), and rarely rhabdomyolysis. Studies suggest that patients on statin therapy show lesser vulnerability toward ischemic stroke and post-stroke frailty. Both pre- and post-treatment benefits of statin have been reported as evident by its neuroprotective effects in both cases. As mitochondrial dysfunction following stroke is the fulcrum for neuronal death, we hereby explore the role of statin in alleviating mitochondrial dysfunction by regulating the mitochondrial dynamics. In the present study, we intend to evaluate the role of statin in modulating cardiolipin-mediated mitochondrial functionality and further providing a therapeutic rationale for repurposing statins either as preventive or an adjunctive therapy for stroke.

Keywords:  cardiolipin; ischemic stroke; mitochondria; neuroprotection; pleiotropic effect; simvastatin

DOI:  https://doi.org/10.1021/acschemneuro.2c00645
Front Neurosci. 2022 ;16 1014081

Association of sub-acute changes in plasma amino acid levels with long-term brain pathologies in a rat model of moderate-severe traumatic brain injury.

Xuan Vinh To, Abdalla Z Mohamed, Paul Cumming, Fatima A Nasrallah.

  Introduction: Traumatic brain injury (TBI) induces a cascade of cellular alterations that are responsible for evolving secondary brain injuries. Changes in brain structure and function after TBI may occur in concert with dysbiosis and altered amino acid fermentation in the gut. Therefore, we hypothesized that subacute plasma amino acid levels could predict long-term microstructural outcomes as quantified using neurite orientation dispersion and density imaging (NODDI).Methods: Fourteen 8-10-week-old male rats were randomly assigned either to sham (n = 6) or a single moderate-severe TBI (n = 8) procedure targeting the primary somatosensory cortex. Venous blood samples were collected at days one, three, seven, and 60 post-procedure and NODDI imaging were carried out at day 60. Principal Component Regression analysis was used to identify time dependent plasma amino acid concentrations after in the subacute phase post-injury that predicted NODDI metric outcomes at day 60.
Results: The TBI group had significantly increased plasma levels of glutamine, arginine, alanine, proline, tyrosine, valine, isoleucine, leucine, and phenylalanine at days three-seven post-injury. Higher levels of several neuroprotective amino acids, especially the branched-chain amino acids (valine, isoleucine, leucine) and phenylalanine, as well as serine, arginine, and asparagine at days three-seven post-injury were also associated with lower isotropic diffusion volume fraction measures in the ventricles and thus lesser ventricular dilation at day 60.
Discussion: In the first such study, we examined the relationship between the long-term post-TBI microstructural outcomes across whole brain and the subacute changes in plasma amino acid concentrations. At days three to seven post-injury, we observed that increased plasma levels of several amino acids, particularly the branched-chain amino acids and phenylalanine, were associated with lesser degrees of ventriculomegaly and hydrocephalus TBI neuropathology at day 60 post-injury. The results imply that altered amino acid fermentation in the gut may mediate neuroprotection in the aftermath of TBI.

Keywords:  amino acids; brain microstructure; diffusion magnetic resonance imaging; neurite orientation dispersion and density imaging (NODDI); traumatic brain injury

DOI:  https://doi.org/10.3389/fnins.2022.1014081
Front Vet Sci. 2022 ;9 1093267

Ketamine administration in idiopathic epileptic and healthy control dogs: Can we detect differences in brain metabolite response with spectroscopy?

Manuela Wieser, Katrin Melanie Beckmann, Annette P N Kutter, Nico Mauri, Henning Richter, Niklaus Zölch, Rima Nadine Bektas.

  Introduction: In recent years ketamine has increasingly become the focus of multimodal emergency management for epileptic seizures. However, little is known about the effect of ketamine on brain metabolites in epileptic patients. Magnetic resonance spectroscopy (MRS) is a non-invasive technique to estimate brain metabolites in vivo. Our aim was to measure the effect of ketamine on thalamic metabolites in idiopathic epileptic (IE) dogs using 3 Tesla MRS. We hypothesized that ketamine would increase the glutamine-glutamate (GLX)/creatine ratio in epileptic dogs with and without antiseizure drug treatment, but not in control dogs. Furthermore, we hypothesized that no different responses after ketamine administration in other measured brain metabolite ratios between the different groups would be detected.Methods: In this controlled prospective experimental trial IE dogs with or without antiseizure drug treatment and healthy client-owned relatives of the breeds Border Collie and Greater Swiss Mountain Dog, were included. After sedation with butorphanol, induction with propofol and maintenance with sevoflurane in oxygen and air, a single voxel MRS at the level of the thalamus was performed before and 2 min after intravenous administration of 1 mg/kg ketamine. An automated data processing spectral fitting linear combination model algorithm was used to estimate all commonly measured metabolite ratios. A mixed ANOVA with the independent variables ketamine administration and group allocation was performed for all measured metabolites. A p < 0.05 was considered statistically significant.
Results: Twelve healthy control dogs, 10 untreated IE and 12 treated IE dogs were included. No significant effects for GLX/creatine were found. However, increased glucose/creatine ratios were found (p < 0.001) with no effect of group allocation. Furthermore, increases in the GABA/creatine ratio were found in IEU dogs.
Discussion: MRS was able to detect changes in metabolite/creatine ratios after intravenous administration of 1 mg/kg ketamine in dogs and no evidence was found that excitatory effects are induced in the thalamus. Although it is beyond the scope of this study to investigate the antiseizure potential of ketamine in dogs, results of this research suggest that the effect of ketamine on the brain metabolites could be dependent on the concentrations of brain metabolites before administration.

Keywords:  GABA; GLX; MRS; glucose; glutamate; seizures; spectroscopy; thalamus

DOI:  https://doi.org/10.3389/fvets.2022.1093267