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Andersen JV. The Glutamate/GABA-Glutamine Cycle: Insights, Updates, and Advances. J Neurochem 2025; 169:e70029. [PMID: 40066661 PMCID: PMC11894596 DOI: 10.1111/jnc.70029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 02/07/2025] [Accepted: 02/17/2025] [Indexed: 03/14/2025]
Abstract
Synaptic homeostasis of the principal neurotransmitters glutamate and GABA is tightly regulated by an intricate metabolic coupling between neurons and astrocytes known as the glutamate/GABA-glutamine cycle. In this cycle, astrocytes take up glutamate and GABA from the synapse and convert these neurotransmitters into glutamine. Astrocytic glutamine is subsequently transferred to neurons, serving as the principal precursor for neuronal glutamate and GABA synthesis. The glutamate/GABA-glutamine cycle integrates multiple cellular processes, including neurotransmitter release, uptake, synthesis, and metabolism. All of these processes are deeply interdependent and closely coupled to cellular energy metabolism. Astrocytes display highly active mitochondrial oxidative metabolism and several unique metabolic features, including glycogen storage and pyruvate carboxylation, which are essential to sustain continuous glutamine release. However, new roles of oligodendrocytes and microglia in neurotransmitter recycling are emerging. Malfunction of the glutamate/GABA-glutamine cycle can lead to severe synaptic disruptions and may be implicated in several brain diseases. Here, I review central aspects and recent advances of the glutamate/GABA-glutamine cycle to highlight how the cycle is functionally connected to critical brain functions and metabolism. First, an overview of glutamate, GABA, and glutamine transport is provided in relation to neurotransmitter recycling. Then, central metabolic aspects of the glutamate/GABA-glutamine cycle are reviewed, with a special emphasis on the critical metabolic roles of glial cells. Finally, I discuss how aberrant neurotransmitter recycling is linked to neurodegeneration and disease, focusing on astrocyte metabolic dysfunction and brain lipid homeostasis as emerging pathological mechanisms. Instead of viewing the glutamate/GABA-glutamine cycle as individual biochemical processes, a more holistic and integrative approach is needed to advance our understanding of how neurotransmitter recycling modulates brain function in both health and disease.
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Affiliation(s)
- Jens V. Andersen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
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2
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Li M, Yuan H, Yang X, Lei Y, Lian J. Glutamine-glutamate centered metabolism as the potential therapeutic target against Japanese encephalitis virus-induced encephalitis. Cell Biosci 2025; 15:6. [PMID: 39844330 PMCID: PMC11755858 DOI: 10.1186/s13578-024-01340-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 12/17/2024] [Indexed: 01/24/2025] Open
Abstract
BACKGROUND Japanese encephalitis (JE) induced by Japanese encephalitis virus (JEV) infection is the most prevalent diagnosed epidemic viral encephalitis globally. The underlying pathological mechanisms remain largely unknown. Given that viruses are obligate intracellular parasites, cellular metabolic reprogramming triggered by viral infection is intricately related to the establishment of infection and progression of disease. Therefore, uncovering and manipulating the metabolic reprogramming that underlies viral infection will help elucidate the pathogenic mechanisms and develop novel therapeutic strategies. METHODS Metabolomics analysis was performed to comprehensively delineate the metabolic profiles in JEV-infected mice brains and neurons. Metabolic flux analysis, quantitative real-time PCR, western blotting and fluorescence immunohistochemistry were utilized to describe detailed glutamine-glutamate metabolic profiles during JEV infection. Exogenous addition of metabolites and associated compounds and RNA interference were employed to manipulate glutamine-glutamate metabolism to clarify its effects on viral replication. The survival rate, severity of neuroinflammation, and levels of viral replication were assessed to determine the efficacy of glutamine supplementation in JEV-challenged mice. RESULTS Here, we have delineated a novel perspective on the pathogenesis of JE by identifying an aberrant low flux in glutamine-glutamate metabolism both in vivo and in vitro, which was critical in the establishment of JEV infection and progression of JE. The perturbed glutamine-glutamate metabolism induced neurotransmitter imbalance and created an immune-inhibitory state with increased gamma-aminobutyric acid/glutamate ratio, thus facilitating efficient viral replication both in JEV-infected neurons and the brain of JEV-infected mice. In addition, viral infection restrained the utilization of glutamine via the glutamate-α-ketoglutaric acid axis in neurons, thus avoiding the adverse effects of glutamine oxidation on viral propagation. As the conversion of glutamine to glutamate was inhibited after JEV infection, the metabolism of glutathione (GSH) was simultaneously impaired, exacerbating oxidative stress in JEV-infected neurons and mice brains and promoting the progression of JE. Importantly, the supplementation of glutamine in vivo alleviated the intracranial inflammation and enhanced the survival of JEV-challenged mice. CONCLUSION Altogether, our study highlights an aberrant glutamine-glutamate metabolism during JEV infection and unveils how this facilitates viral replication and promotes JE progression. Manipulation of these metabolic alterations may potentially be exploited to develop therapeutic approaches for JEV infection.
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Affiliation(s)
- Mengyuan Li
- Department of Infectious Diseases, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China
| | - Hang Yuan
- Pathogenic Biology, Medical College of Yan'an University, Yan'an, 716000, China
| | - Xiaofei Yang
- Department of Infectious Diseases, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China
| | - Yingfeng Lei
- Department of Infectious Diseases, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China.
- Department of Microbiology, School of Basic Medicine, Air Force Medical University, Xi'an, 710032, China.
| | - Jianqi Lian
- Department of Infectious Diseases, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China.
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Küper K, Poschet G, Rossmann J, Garbade SF, Spiegelhalter A, Wen D, Hoffmann GF, Schmitt CP, Opladen T, Peters V. Dipeptides in CSF and plasma: diagnostic and therapeutic potential in neurological diseases. Amino Acids 2024; 57:2. [PMID: 39673003 PMCID: PMC11645304 DOI: 10.1007/s00726-024-03434-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 12/03/2024] [Indexed: 12/15/2024]
Abstract
Dipeptides (DPs), composed of two amino acids (AAs), hold significant therapeutic potential but remain underexplored. Given the crucial role of AAs in central nervous system (CNS) function, this study investigated the presence of DPs in cerebrospinal fluid (CSF) and their correlation with corresponding AAs, potentially indicating their role as AA donors. Plasma and CSF samples were collected from 43 children with neurological or metabolic conditions of unknown origin, including 23 with epilepsy. A panel of 33 DPs was quantified using UPLC-MS/MS. Out of 33 DPs, 18 were detectable in CSF and 20 in plasma, displaying high inter-individual variance. Gly-Asp, Gly-Pro, and Ala-Glu were consistently found in all CSF samples, while only Gly-Asp was universally detectable in plasma. Anserine and carnosine were prominent in CSF and plasma, respectively, with no other histidine-containing DPs observed. Generally, DP concentrations were higher in plasma than in CSF; however, anserine and Gly-Pro had similar concentrations in both fluids. Significant correlations were observed between specific DPs and their corresponding AAs in CSF (Gly-Glu, Gly-Pro and Ser-Gln) and plasma (Glu-Glu and Glu-Ser). Notably, patients with epilepsy had elevated medium anserine concentrations in CSF. This study is the first to demonstrate the presence of numerous DPs in CSF and plasma. Further research is needed to determine if DP patterns can support the diagnosis of neurological diseases and whether DP administration can modulate amino acid availability in the brain, potentially offering new therapeutic options, such as for defects in the amino acid transporter.
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Affiliation(s)
- Katharina Küper
- Division of Pediatric Neurology and Metabolic Medicine, Department I, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Heidelberg University, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany
| | - Gernot Poschet
- Centre for Organismal Studies (COS), Metabolomics Core Technology Platform, Heidelberg University, Heidelberg, Germany
| | - Julia Rossmann
- Division of Pediatric Neurology and Metabolic Medicine, Department I, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Heidelberg University, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany
| | - Sven F Garbade
- Division of Pediatric Neurology and Metabolic Medicine, Department I, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Heidelberg University, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany
| | - Alexander Spiegelhalter
- Centre for Organismal Studies (COS), Metabolomics Core Technology Platform, Heidelberg University, Heidelberg, Germany
| | - Dan Wen
- Division of Pediatric Neurology and Metabolic Medicine, Department I, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Heidelberg University, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany
| | - Georg F Hoffmann
- Division of Pediatric Neurology and Metabolic Medicine, Department I, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Heidelberg University, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany
| | - Claus P Schmitt
- Division of Pediatric Neurology and Metabolic Medicine, Department I, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Heidelberg University, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany
| | - Thomas Opladen
- Division of Pediatric Neurology and Metabolic Medicine, Department I, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Heidelberg University, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany
| | - Verena Peters
- Division of Pediatric Neurology and Metabolic Medicine, Department I, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Heidelberg University, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
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4
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Dos Santos K, Bertho G, Baudin M, Giraud N. Glutamine: A key player in human metabolism as revealed by hyperpolarized magnetic resonance. PROGRESS IN NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY 2024; 144-145:15-39. [PMID: 39645348 DOI: 10.1016/j.pnmrs.2024.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/17/2024] [Accepted: 05/28/2024] [Indexed: 12/09/2024]
Abstract
In recent years, there has been remarkable progress in the field of dissolution dynamic nuclear polarization (D-DNP). This method has shown significant potential for enhancing nuclear polarization by over 10,000 times, resulting in a substantial increase in sensitivity. The unprecedented signal enhancements achieved with D-DNP have opened new possibilities for in vitro analysis. This method enables the monitoring of structural and enzymatic kinetics with excellent time resolution at low concentrations. Furthermore, these advances can be straightforwardly translated to in vivo magnetic resonance imaging and magnetic resonance spectroscopy (MRI and MRS) experiments. D-DNP studies have used a range of 13C labeled molecules to gain deeper insights into the cellular metabolic pathways and disease hallmarks. Over the last 15 years, D-DNP has been used to analyze glutamine, a key player in the cellular metabolism, involved in many diseases including cancer. Glutamine is the most abundant amino acid in blood plasma and the major carrier of nitrogen, and it is converted to glutamate inside the cell, where the latter is the most abundant amino acid. It has been shown that increased glutamine consumption by cells is a hallmark of tumor cancer metabolism. In this review, we first highlight the significance of glutamine in metabolism, providing an in-depth description of its use at the cellular level as well as its specific roles in various organs. Next, we present a comprehensive overview of the principles of D-DNP. Finally, we review the state of the art in D-DNP glutamine analysis and its application in oncology, neurology, and perfusion marker studies.
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Affiliation(s)
- Karen Dos Santos
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques Université Paris Cité, 45 rue des Saints Pères, 75006 Paris, France
| | - Gildas Bertho
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques Université Paris Cité, 45 rue des Saints Pères, 75006 Paris, France
| | - Mathieu Baudin
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques Université Paris Cité, 45 rue des Saints Pères, 75006 Paris, France; Laboratoire des Biomolécules, LBM, Département de chimie, École Normale Supérieure, PSL Université, Sorbonne Université 45 rue d'Ulm, 75005 Paris, France
| | - Nicolas Giraud
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques Université Paris Cité, 45 rue des Saints Pères, 75006 Paris, France.
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Gromadzka G, Czerwińska J, Krzemińska E, Przybyłkowski A, Litwin T. Wilson's Disease-Crossroads of Genetics, Inflammation and Immunity/Autoimmunity: Clinical and Molecular Issues. Int J Mol Sci 2024; 25:9034. [PMID: 39201720 PMCID: PMC11354778 DOI: 10.3390/ijms25169034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 08/11/2024] [Accepted: 08/13/2024] [Indexed: 09/03/2024] Open
Abstract
Wilson's disease (WD) is a rare, autosomal recessive disorder of copper metabolism caused by pathogenic mutations in the ATP7B gene. Cellular copper overload is associated with impaired iron metabolism. Oxidative stress, cuproptosis, and ferroptosis are involved in cell death in WD. The clinical picture of WD is variable. Hepatic/neuropsychiatric/other symptoms may manifest in childhood/adulthood and even old age. It has been shown that phenotypic variability may be determined by the type of ATP7B genetic variants as well as the influence of various genetic/epigenetic, environmental, and lifestyle modifiers. In 1976, immunological abnormalities were first described in patients with WD. These included an increase in IgG and IgM levels and a decrease in the percentage of T lymphocytes, as well as a weakening of their bactericidal effect. Over the following years, it was shown that there is a bidirectional relationship between copper and inflammation. Changes in serum cytokine concentrations and the relationship between cytokine gene variants and the clinical course of the disease have been described in WD patients, as well as in animal models of this disease. Data have also been published on the occurrence of antinuclear antibodies (ANAs), antineutrophil cytoplasmic antibodies (ANCAs), anti-muscle-specific tyrosine kinase antibodies, and anti-acetylcholine receptor antibodies, as well as various autoimmune diseases, including systemic lupus erythematosus (SLE), myasthenic syndrome, ulcerative colitis, multiple sclerosis (MS), polyarthritis, and psoriasis after treatment with d-penicillamine (DPA). The occurrence of autoantibodies was also described, the presence of which was not related to the type of treatment or the form of the disease (hepatic vs. neuropsychiatric). The mechanisms responsible for the occurrence of autoantibodies in patients with WD are not known. It has also not been clarified whether they have clinical significance. In some patients, WD was differentiated or coexisted with an autoimmune disease, including autoimmune hepatitis or multiple sclerosis. Various molecular mechanisms may be responsible for immunological abnormalities and/or the inflammatory processes in WD. Their better understanding may be important for explaining the reasons for the diversity of symptoms and the varied course and response to therapy, as well as for the development of new treatment regimens for WD.
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Affiliation(s)
- Grażyna Gromadzka
- Department of Biomedical Sciences, Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University, Wóycickiego Street 1/3, 01-938 Warsaw, Poland
| | - Julia Czerwińska
- Students Scientific Association “Immunis”, Cardinal Stefan Wyszynski University, Dewajtis Street 5, 01-815 Warsaw, Poland
| | - Elżbieta Krzemińska
- Students Scientific Association “Immunis”, Cardinal Stefan Wyszynski University, Dewajtis Street 5, 01-815 Warsaw, Poland
| | - Adam Przybyłkowski
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland;
| | - Tomasz Litwin
- Second Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego Street 9, 02-957 Warsaw, Poland;
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Song Y, Xiao F, Aa J, Wang G. Desorption Electrospray Ionization Mass Spectrometry Imaging Techniques Depict a Reprogramming of Energy and Purine Metabolism in the Core Brain Regions of Chronic Social Defeat Stress Mice. Metabolites 2024; 14:284. [PMID: 38786761 PMCID: PMC11123228 DOI: 10.3390/metabo14050284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 05/06/2024] [Accepted: 05/13/2024] [Indexed: 05/25/2024] Open
Abstract
Depression is associated with pathological changes and metabolic abnormalities in multiple brain regions. The simultaneous comprehensive and in situ detection of endogenous molecules in all brain regions is essential for a comprehensive understanding of depression pathology, which is described in this paper. A method based on desorption electrospray ionization mass spectrometry imaging (DESI-MSI) technology was developed to classify mouse brain regions using characteristic lipid molecules and to detect the metabolites in mouse brain tissue samples simultaneously. The results showed that characteristic lipid molecules can be used to clearly distinguish each subdivision of the mouse brain, and the accuracy of this method is higher than that of the conventional staining method. The cerebellar cortex, medial prefrontal cortex, hippocampus, striatum, nucleus accumbens-core, and nucleus accumbens-shell exhibited the most significant differences in the chronic social defeat stress model. An analysis of metabolic pathways revealed that 13 kinds of molecules related to energy metabolism and purine metabolism exhibited significant changes. A DESI-MSI method was developed for the detection of pathological brain sections. We found, for the first time, that there are characteristic changes in the energy metabolism in the cortex and purine metabolism in the striatum, which is highly important for obtaining a deeper and more comprehensive understanding of the pathology of depression and discovering regulatory targets.
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Affiliation(s)
| | | | - Jiye Aa
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China; (Y.S.); (F.X.)
| | - Guangji Wang
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China; (Y.S.); (F.X.)
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7
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Rothman DL, Behar KL, Dienel GA. Mechanistic stoichiometric relationship between the rates of neurotransmission and neuronal glucose oxidation: Reevaluation of and alternatives to the pseudo-malate-aspartate shuttle model. J Neurochem 2024; 168:555-591. [PMID: 36089566 DOI: 10.1111/jnc.15619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 04/08/2022] [Accepted: 04/15/2022] [Indexed: 11/26/2022]
Abstract
The ~1:1 stoichiometry between the rates of neuronal glucose oxidation (CMRglc-ox-N) and glutamate (Glu)/γ-aminobutyric acid (GABA)-glutamine (Gln) neurotransmitter (NT) cycling between neurons and astrocytes (VNTcycle) has been firmly established. However, the mechanistic basis for this relationship is not fully understood, and this knowledge is critical for the interpretation of metabolic and brain imaging studies in normal and diseased brain. The pseudo-malate-aspartate shuttle (pseudo-MAS) model established the requirement for glycolytic metabolism in cultured glutamatergic neurons to produce NADH that is shuttled into mitochondria to support conversion of extracellular Gln (i.e., astrocyte-derived Gln in vivo) into vesicular neurotransmitter Glu. The evaluation of this model revealed that it could explain half of the 1:1 stoichiometry and it has limitations. Modifications of the pseudo-MAS model were, therefore, devised to address major knowledge gaps, that is, submitochondrial glutaminase location, identities of mitochondrial carriers for Gln and other model components, alternative mechanisms to transaminate α-ketoglutarate to form Glu and shuttle glutamine-derived ammonia while maintaining mass balance. All modified models had a similar 0.5 to 1.0 predicted mechanistic stoichiometry between VNTcycle and the rate of glucose oxidation. Based on studies of brain β-hydroxybutyrate oxidation, about half of CMRglc-ox-N may be linked to glutamatergic neurotransmission and localized in pre-synaptic structures that use pseudo-MAS type mechanisms for Glu-Gln cycling. In contrast, neuronal compartments that do not participate in transmitter cycling may use the MAS to sustain glucose oxidation. The evaluation of subcellular compartmentation of neuronal glucose metabolism in vivo is a critically important topic for future studies to understand glutamatergic and GABAergic neurotransmission.
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Affiliation(s)
- Douglas L Rothman
- Magnetic Resonance Research Center and Departments of Radiology and Biomedical Engineering, Yale University, New Haven, Connecticut, USA
| | - Kevin L Behar
- Magnetic Resonance Research Center and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Gerald A Dienel
- Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
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8
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Sidoryk-Węgrzynowicz M, Adamiak K, Strużyńska L. Astrocyte-Neuron Interaction via the Glutamate-Glutamine Cycle and Its Dysfunction in Tau-Dependent Neurodegeneration. Int J Mol Sci 2024; 25:3050. [PMID: 38474295 DOI: 10.3390/ijms25053050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 02/26/2024] [Accepted: 03/01/2024] [Indexed: 03/14/2024] Open
Abstract
Astroglia constitute the largest group of glial cells and are involved in numerous actions that are critical to neuronal development and functioning, such as maintaining the blood-brain barrier, forming synapses, supporting neurons with nutrients and trophic factors, and protecting them from injury. These properties are deeply affected in the course of many neurodegenerative diseases, including tauopathies, often before the onset of the disease. In this respect, the transfer of essential amino acids such as glutamate and glutamine between neurons and astrocytes in the glutamate-glutamine cycle (GGC) is one example. In this review, we focus on the GGC and the disruption of this cycle in tau-dependent neurodegeneration. A profound understanding of the complex functions of the GGC and, in the broader context, searching for dysfunctions in communication pathways between astrocytes and neurons via GGC in health and disease, is of critical significance for the development of novel mechanism-based therapies for neurodegenerative disorders.
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Affiliation(s)
- Marta Sidoryk-Węgrzynowicz
- Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106 Warsaw, Poland
| | - Kamil Adamiak
- Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106 Warsaw, Poland
| | - Lidia Strużyńska
- Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106 Warsaw, Poland
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9
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Baek JH, Park H, Kang H, Kim R, Kang JS, Kim HJ. The Role of Glutamine Homeostasis in Emotional and Cognitive Functions. Int J Mol Sci 2024; 25:1302. [PMID: 38279303 PMCID: PMC10816396 DOI: 10.3390/ijms25021302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/17/2024] [Accepted: 01/18/2024] [Indexed: 01/28/2024] Open
Abstract
Glutamine (Gln), a non-essential amino acid, is synthesized de novo by glutamine synthetase (GS) in various organs. In the brain, GS is exclusively expressed in astrocytes under normal physiological conditions, producing Gln that takes part in glutamatergic neurotransmission through the glutamate (Glu)-Gln cycle. Because the Glu-Gln cycle and glutamatergic neurotransmission play a pivotal role in normal brain activity, maintaining Gln homeostasis in the brain is crucial. Recent findings indicated that a neuronal Gln deficiency in the medial prefrontal cortex in rodents led to depressive behaviors and mild cognitive impairment along with lower glutamatergic neurotransmission. In addition, exogenous Gln supplementation has been tested for its ability to overcome neuronal Gln deficiency and reverse abnormal behaviors induced by chronic immobilization stress (CIS). Although evidence is accumulating as to how Gln supplementation contributes to normalizing glutamatergic neurotransmission and the Glu-Gln cycle, there are few reviews on this. In this review, we summarize recent evidence demonstrating that Gln supplementation ameliorates CIS-induced deleterious changes, including an imbalance of the Glu-Gln cycle, suggesting that Gln homeostasis is important for emotional and cognitive functions. This is the first review of detailed mechanistic studies on the effects of Gln supplementation on emotional and cognitive functions.
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Affiliation(s)
| | | | | | | | | | - Hyun Joon Kim
- Department of Anatomy and Convergence Medical Sciences, College of Medicine, Institute of Medical Science, Tyrosine Peptide Multiuse Research Group, Anti-Aging Bio Cell Factory Regional Leading Research Center, Gyeongsang National University, 15 Jinju-daero 816 Beongil, Jinju 52727, Gyeongnam, Republic of Korea; (J.H.B.); (H.P.); (H.K.); (R.K.); (J.S.K.)
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10
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Rodríguez JJ, Zallo F, Gardenal E, Cabot J, Busquets X. Prominent and conspicuous astrocyte atrophy in human sporadic and familial Alzheimer's disease. Brain Struct Funct 2023; 228:2103-2113. [PMID: 37730895 PMCID: PMC10587264 DOI: 10.1007/s00429-023-02707-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 08/31/2023] [Indexed: 09/22/2023]
Abstract
Pathophysiology of sporadic Alzheimer's disease (SAD) and familial Alzheimer's disease (FAD) remains poorly known, including the exact role of neuroglia and specifically astroglia, in part because studies of astrocytes in human Alzheimer's disease (AD) brain samples are scarce. As far as we know, this is the first study of a 3-D immunohistochemical and microstructural analysis of glial fibrillary acidic protein (GFAP)- and glutamine synthetase (GS)-positive astrocytes performed in the entorhinal cortex (EC) of human SAD and FAD samples. In this study, we report prominent atrophic changes in GFAP and GS astrocytes in the EC of both SAD and FAD characterised by a decrease in area and volume when compared with non-demented control samples (ND). Furthermore, we did not find neither astrocytic loss nor astrocyte proliferation or hypertrophy (gliosis). In contrast with the astrogliosis classically accepted hypothesis, our results show a highly marked astrocyte atrophy that could have a major relevance in AD pathological processes being fundamental and key for AD mnesic and cognitive alterations equivalent in both SAD and FAD.
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Affiliation(s)
- J J Rodríguez
- Functional Neuroanatomy Group; IKERBASQUE, Basque Foundation for Science, Department of Neurosciences, Medical Faculty, University of the Basque Country (UPV/EHU), 48009/48940, Bilbao/Leioa, Vizcaya, Spain.
| | - F Zallo
- Functional Neuroanatomy Group; IKERBASQUE, Basque Foundation for Science, Department of Neurosciences, Medical Faculty, University of the Basque Country (UPV/EHU), 48009/48940, Bilbao/Leioa, Vizcaya, Spain
| | - E Gardenal
- Functional Neuroanatomy Group; IKERBASQUE, Basque Foundation for Science, Department of Neurosciences, Medical Faculty, University of the Basque Country (UPV/EHU), 48009/48940, Bilbao/Leioa, Vizcaya, Spain
| | - Joan Cabot
- Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, 07122, Palma, Spain
| | - X Busquets
- Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, 07122, Palma, Spain
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11
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Vecera CM, C. Courtes A, Jones G, Soares JC, Machado-Vieira R. Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression. Pharmaceuticals (Basel) 2023; 16:1572. [PMID: 38004437 PMCID: PMC10675154 DOI: 10.3390/ph16111572] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 10/22/2023] [Accepted: 10/25/2023] [Indexed: 11/26/2023] Open
Abstract
Treatment-resistant depression (TRD) is a term used to describe a particular type of major depressive disorder (MDD). There is no consensus about what defines TRD, with various studies describing between 1 and 4 failures of antidepressant therapies, with or without electroconvulsive therapy (ECT). That is why TRD is such a growing concern among clinicians and researchers, and it explains the necessity for investigating novel therapeutic targets beyond conventional monoamine pathways. An imbalance between two primary central nervous system (CNS) neurotransmitters, L-glutamate and γ-aminobutyric acid (GABA), has emerged as having a key role in the pathophysiology of TRD. In this review, we provide an evaluation and comprehensive review of investigational antidepressants targeting these two systems, accessing their levels of available evidence, mechanisms of action, and safety profiles. N-methyl-D-aspartate (NMDA) receptor antagonism has shown the most promise amongst the glutamatergic targets, with ketamine and esketamine (Spravato) robustly generating responses across trials. Two specific NMDA-glycine site modulators, D-cycloserine (DCS) and apimostinel, have also generated promising initial safety and efficacy profiles, warranting further investigation. Combination dextromethorphan-bupropion (AXS-05/Auvelity) displays a unique mechanism of action and demonstrated positive results in particular applicability in subpopulations with cognitive dysfunction. Currently, the most promising GABA modulators appear to be synthetic neurosteroid analogs with positive GABAA receptor modulation (such as brexanolone). Overall, advances in the last decade provide exciting perspectives for those who do not improve with conventional therapies. Of the compounds reviewed here, three are approved by the Food and Drug Administration (FDA): esketamine (Spravato) for TRD, Auvelity (dextromethorphan-bupropion) for major depressive disorder (MDD), and brexanolone (Zulresso) for post-partum depression (PPD). Notably, some concerns have arisen with esketamine and brexanolone, which will be detailed in this study.
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Affiliation(s)
- Courtney M. Vecera
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, TX 77054, USA
| | - Alan C. Courtes
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, TX 77054, USA
| | - Gregory Jones
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, TX 77054, USA
| | - Jair C. Soares
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, TX 77054, USA
| | - Rodrigo Machado-Vieira
- John S. Dunn Behavioral Sciences Center at UTHealth Houston, 5615 H.Mark Crosswell Jr St, Houston, TX 77021, USA
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12
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Erickson JD, Kyllo T, Wulff H. Ca 2+-regulated expression of high affinity methylaminoisobutryic acid transport in hippocampal neurons inhibited by riluzole and novel neuroprotective aminothiazoles. Curr Res Physiol 2023; 6:100109. [PMID: 38107787 PMCID: PMC10724208 DOI: 10.1016/j.crphys.2023.100109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 09/13/2023] [Accepted: 09/27/2023] [Indexed: 12/19/2023] Open
Abstract
High affinity methylaminoisobutyric acid(MeAIB)/glutamine(Gln) transport activity regulated by neuronal firing occurs at the plasma membrane in mature rat hippocampal neuron-enriched cultures. Spontaneous Ca2+-regulated transport activity was similarly inhibited by riluzole, a benzothiazole anticonvulsant agent, and by novel naphthalenyl substituted aminothiazole derivatives such as SKA-378. Here, we report that spontaneous transport activity is stimulated by 4-aminopyridine (4-AP) and that phorbol-myristate acetate (PMA) increases high K+ stimulated transport activity that is inhibited by staurosporine. 4-AP-stimulated spontaneous and PMA-stimulated high K+-induced transport is not present at 7 days in vitro (DIV) and is maximal by DIV∼21. The relative affinity for MeAIB is similar for spontaneous and high K+-stimulated transport (Km ∼ 50 μM) suggesting that a single transporter is involved. While riluzole and SKA-378 inhibit spontaneous transport with equal potency (IC50 ∼ 1 μM), they exhibit decreased (∼3-5 X) potency for 4-AP-stimulated spontaneous transport. Interestingly, high K+-stimulated MeAIB transport displays lower and differential sensitivity to the two compounds. SKA-378-related halogenated derivatives of SKA-75 (SKA-219, SKA-377 and SKA-375) preferentially inhibit high K+-induced expression of MeAIB transport activity at the plasma membrane (IC50 < 25 μM), compared to SKA-75 and riluzole (IC50 > 100 μM). Ca2+-dependent spontaneous and high K+-stimulated MeAIB transport activity is blocked by ω-conotoxin MVIIC, ω-agatoxin IVA, ω-agatoxin TK (IC50 ∼ 500 nM) or cadmium ion (IC50 ∼ 20 μM) demonstrating that P/Q-type CaV channels that are required for activity-regulated presynaptic vesicular glutamate (Glu) release are also required for high-affinity MeAIB transport expression at the plasma membrane. We suggest that neural activity driven and Ca2+ dependent trafficking of the high affinity MeAIB transporter to the plasma membrane is a unique target to understand mechanisms of Glu/Gln recycling in synapses and acute neuroprotection against excitotoxic presynaptic Glu induced neural injury.
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Affiliation(s)
- Jeffrey D. Erickson
- Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health-New Orleans, New Orleans, LA, USA
| | - Thomas Kyllo
- Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health-New Orleans, New Orleans, LA, USA
| | - Heike Wulff
- Department of Pharmacology, School of Medicine, University of California-Davis, Davis, CA, USA
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13
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Zhang YM, Qi YB, Gao YN, Chen WG, Zhou T, Zang Y, Li J. Astrocyte metabolism and signaling pathways in the CNS. Front Neurosci 2023; 17:1217451. [PMID: 37732313 PMCID: PMC10507181 DOI: 10.3389/fnins.2023.1217451] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 08/18/2023] [Indexed: 09/22/2023] Open
Abstract
Astrocytes comprise half of the cells in the central nervous system and play a critical role in maintaining metabolic homeostasis. Metabolic dysfunction in astrocytes has been indicated as the primary cause of neurological diseases, such as depression, Alzheimer's disease, and epilepsy. Although the metabolic functionalities of astrocytes are well known, their relationship to neurological disorders is poorly understood. The ways in which astrocytes regulate the metabolism of glucose, amino acids, and lipids have all been implicated in neurological diseases. Metabolism in astrocytes has also exhibited a significant influence on neuron functionality and the brain's neuro-network. In this review, we focused on metabolic processes present in astrocytes, most notably the glucose metabolic pathway, the fatty acid metabolic pathway, and the amino-acid metabolic pathway. For glucose metabolism, we focused on the glycolysis pathway, pentose-phosphate pathway, and oxidative phosphorylation pathway. In fatty acid metabolism, we followed fatty acid oxidation, ketone body metabolism, and sphingolipid metabolism. For amino acid metabolism, we summarized neurotransmitter metabolism and the serine and kynurenine metabolic pathways. This review will provide an overview of functional changes in astrocyte metabolism and provide an overall perspective of current treatment and therapy for neurological disorders.
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Affiliation(s)
- Yong-mei Zhang
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ying-bei Qi
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ya-nan Gao
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Wen-gang Chen
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Ting Zhou
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yi Zang
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jia Li
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
- Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, Jiangsu, China
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14
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Peters TMA, Merx J, Kooijman PC, Noga M, de Boer S, van Gemert LA, Salden G, Engelke UFH, Lefeber DJ, van Outersterp RE, Berden G, Boltje TJ, Artuch R, Pías-Peleteiro L, García-Cazorla Á, Barić I, Thöny B, Oomens J, Martens J, Wevers RA, Verbeek MM, Coene KLM, Willemsen MAAP. Novel cerebrospinal fluid biomarkers of glucose transporter type 1 deficiency syndrome: Implications beyond the brain's energy deficit. J Inherit Metab Dis 2023; 46:66-75. [PMID: 36088537 PMCID: PMC10091941 DOI: 10.1002/jimd.12554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 08/26/2022] [Accepted: 09/07/2022] [Indexed: 01/19/2023]
Abstract
We used next-generation metabolic screening to identify new biomarkers for improved diagnosis and pathophysiological understanding of glucose transporter type 1 deficiency syndrome (GLUT1DS), comparing metabolic cerebrospinal fluid (CSF) profiles from 12 patients to those of 116 controls. This confirmed decreased CSF glucose and lactate levels in patients with GLUT1DS and increased glutamine at group level. We identified three novel biomarkers significantly decreased in patients, namely gluconic + galactonic acid, xylose-α1-3-glucose, and xylose-α1-3-xylose-α1-3-glucose, of which the latter two have not previously been identified in body fluids. CSF concentrations of gluconic + galactonic acid may be reduced as these metabolites could serve as alternative substrates for the pentose phosphate pathway. Xylose-α1-3-glucose and xylose-α1-3-xylose-α1-3-glucose may originate from glycosylated proteins; their decreased levels are hypothetically the consequence of insufficient glucose, one of two substrates for O-glucosylation. Since many proteins are O-glucosylated, this deficiency may affect cellular processes and thus contribute to GLUT1DS pathophysiology. The novel CSF biomarkers have the potential to improve the biochemical diagnosis of GLUT1DS. Our findings imply that brain glucose deficiency in GLUT1DS may cause disruptions at the cellular level that go beyond energy metabolism, underlining the importance of developing treatment strategies that directly target cerebral glucose uptake.
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Affiliation(s)
- Tessa M A Peters
- Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Laboratory Medicine, Translational Metabolic Laboratory (TML), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jona Merx
- Institute for Molecules and Materials, Synthetic Organic Chemistry, Radboud University, Nijmegen, The Netherlands
| | - Pieter C Kooijman
- Institute for Molecules and Materials, FELIX Laboratory, Radboud University, Nijmegen, The Netherlands
| | - Marek Noga
- Department of Laboratory Medicine, Translational Metabolic Laboratory (TML), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Siebolt de Boer
- Department of Laboratory Medicine, Translational Metabolic Laboratory (TML), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Loes A van Gemert
- Amalia Children's Hospital, Department of Pediatric Neurology & Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Guido Salden
- Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Laboratory Medicine, Translational Metabolic Laboratory (TML), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Udo F H Engelke
- Department of Laboratory Medicine, Translational Metabolic Laboratory (TML), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Dirk J Lefeber
- Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Laboratory Medicine, Translational Metabolic Laboratory (TML), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Rianne E van Outersterp
- Institute for Molecules and Materials, FELIX Laboratory, Radboud University, Nijmegen, The Netherlands
| | - Giel Berden
- Institute for Molecules and Materials, FELIX Laboratory, Radboud University, Nijmegen, The Netherlands
| | - Thomas J Boltje
- Institute for Molecules and Materials, Synthetic Organic Chemistry, Radboud University, Nijmegen, The Netherlands
| | - Rafael Artuch
- Clinical Biochemistry Department, Institut de Recerca Sant Joan de Déu, CIBERER and MetabERN Hospital Sant Joan de Déu, Barcelona, Spain
| | - Leticia Pías-Peleteiro
- Clinical Biochemistry Department, Institut de Recerca Sant Joan de Déu, CIBERER and MetabERN Hospital Sant Joan de Déu, Barcelona, Spain
| | - Ángeles García-Cazorla
- Clinical Biochemistry Department, Institut de Recerca Sant Joan de Déu, CIBERER and MetabERN Hospital Sant Joan de Déu, Barcelona, Spain
| | - Ivo Barić
- Department of Pediatrics, University Hospital Center Zagreb & University of Zagreb, School of Medicine, Zagreb, Croatia
| | - Beat Thöny
- Division of Metabolism, University Children's Hospital Zürich, Zürich, Switzerland
| | - Jos Oomens
- Institute for Molecules and Materials, FELIX Laboratory, Radboud University, Nijmegen, The Netherlands
| | - Jonathan Martens
- Institute for Molecules and Materials, FELIX Laboratory, Radboud University, Nijmegen, The Netherlands
| | - Ron A Wevers
- Department of Laboratory Medicine, Translational Metabolic Laboratory (TML), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marcel M Verbeek
- Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Laboratory Medicine, Translational Metabolic Laboratory (TML), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Karlien L M Coene
- Department of Laboratory Medicine, Translational Metabolic Laboratory (TML), Radboud University Medical Center, Nijmegen, The Netherlands
- Laboratory of Clinical Chemistry and Hematology, Elisabeth TweeSteden Hospital, Tilburg, The Netherlands
| | - Michèl A A P Willemsen
- Amalia Children's Hospital, Department of Pediatric Neurology & Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
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15
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Li Y, Xia X, Wang Y, Zheng JC. Mitochondrial dysfunction in microglia: a novel perspective for pathogenesis of Alzheimer's disease. J Neuroinflammation 2022; 19:248. [PMID: 36203194 PMCID: PMC9535890 DOI: 10.1186/s12974-022-02613-9] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 09/28/2022] [Indexed: 11/23/2022] Open
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly globally. Emerging evidence has demonstrated microglia-driven neuroinflammation as a key contributor to the onset and progression of AD, however, the mechanisms that mediate neuroinflammation remain largely unknown. Recent studies have suggested mitochondrial dysfunction including mitochondrial DNA (mtDNA) damage, metabolic defects, and quality control (QC) disorders precedes microglial activation and subsequent neuroinflammation. Therefore, an in-depth understanding of the relationship between mitochondrial dysfunction and microglial activation in AD is important to unveil the pathogenesis of AD and develop effective approaches for early AD diagnosis and treatment. In this review, we summarized current progress in the roles of mtDNA, mitochondrial metabolism, mitochondrial QC changes in microglial activation in AD, and provide comprehensive thoughts for targeting microglial mitochondria as potential therapeutic strategies of AD.
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Affiliation(s)
- Yun Li
- Center for Translational Neurodegeneration and Regenerative Therapy, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200072, China
| | - Xiaohuan Xia
- Center for Translational Neurodegeneration and Regenerative Therapy, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200072, China. .,Shanghai Frontiers Science Center of Nanocatalytic Medicine, Shanghai, 200331, China. .,Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai, 200065, China. .,Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital affiliated to Tongji University School of Medicine, Shanghai, 200434, China.
| | - Yi Wang
- Shanghai Frontiers Science Center of Nanocatalytic Medicine, Shanghai, 200331, China.,Translational Research Center, Shanghai Yangzhi Rehabilitation Hospital Affiliated to Tongji University School of Medicine, Shanghai, 201613, China.,Collaborative Innovation Center for Brain Science, Tongji University, Shanghai, 200092, China
| | - Jialin C Zheng
- Center for Translational Neurodegeneration and Regenerative Therapy, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200072, China. .,Shanghai Frontiers Science Center of Nanocatalytic Medicine, Shanghai, 200331, China. .,Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai, 200065, China. .,Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital affiliated to Tongji University School of Medicine, Shanghai, 200434, China. .,Collaborative Innovation Center for Brain Science, Tongji University, Shanghai, 200092, China.
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16
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Andersen JV, Schousboe A, Verkhratsky A. Astrocyte energy and neurotransmitter metabolism in Alzheimer's disease: integration of the glutamate/GABA-glutamine cycle. Prog Neurobiol 2022; 217:102331. [PMID: 35872221 DOI: 10.1016/j.pneurobio.2022.102331] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/14/2022] [Accepted: 07/19/2022] [Indexed: 02/06/2023]
Abstract
Astrocytes contribute to the complex cellular pathology of Alzheimer's disease (AD). Neurons and astrocytes function in close collaboration through neurotransmitter recycling, collectively known as the glutamate/GABA-glutamine cycle, which is essential to sustain neurotransmission. Neurotransmitter recycling is intimately linked to astrocyte energy metabolism. In the course of AD, astrocytes undergo extensive metabolic remodeling, which may profoundly affect the glutamate/GABA-glutamine cycle. The consequences of altered astrocyte function and metabolism in relation to neurotransmitter recycling are yet to be comprehended. Metabolic alterations of astrocytes in AD deprive neurons of metabolic support, thereby contributing to synaptic dysfunction and neurodegeneration. In addition, several astrocyte-specific components of the glutamate/GABA-glutamine cycle, including glutamine synthesis and synaptic neurotransmitter uptake, are perturbed in AD. Integration of the complex astrocyte biology within the context of AD is essential for understanding the fundamental mechanisms of the disease, while restoring astrocyte metabolism may serve as an approach to arrest or even revert clinical progression of AD.
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Affiliation(s)
- Jens V Andersen
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
| | - Arne Schousboe
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Alexei Verkhratsky
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; Achucarro Center for Neuroscience, IKERBASQUE, 48011 Bilbao, Spain; Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, LT-01102 Vilnius, Lithuania.
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17
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Lee MH, Hwang YH, Yun CS, Han BS, Kim DY. Altered small-world property of a dynamic metabolic network in murine left hippocampus after exposure to acute stress. Sci Rep 2022; 12:3885. [PMID: 35273207 PMCID: PMC8913833 DOI: 10.1038/s41598-022-07586-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 02/18/2022] [Indexed: 11/09/2022] Open
Abstract
The acute stress response is a natural and fundamental reaction that balances the physiological conditions of the brain. To maintain homeostasis in the brain, the response is based on changes over time in hormones and neurotransmitters, which are related to resilience and can adapt successfully to acute stress. This increases the need for dynamic analysis over time, and new approaches to examine the relationship between metabolites have emerged. This study investigates whether the constructed metabolic network is a realistic or a random network and is affected by acute stress. While the metabolic network in the control group met the criteria for small-worldness at all time points, the metabolic network in the stress group did not at some time points, and the small-worldness had resilience after the fifth time point. The backbone metabolic network only met the criteria for small-worldness in the control group. Additionally, creatine had lower local efficiency in the stress group than the control group, and for the backbone metabolic network, creatine and glutamate were lower and higher in the stress group than the control group, respectively. These findings provide evidence of metabolic imbalance that may be a pre-stage of alterations to brain structure due to acute stress.
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Affiliation(s)
- Min-Hee Lee
- Institute of Human Genomic Study, College of Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea
| | - Yoon Ho Hwang
- Department of Biomedical Engineering, Yonsei University, Wonju, Republic of Korea
| | - Chang-Soo Yun
- Department of Radiation Convergence Engineering, Yonsei University, Wonju, Republic of Korea
| | - Bong Soo Han
- Department of Radiation Convergence Engineering, Yonsei University, Wonju, Republic of Korea
| | - Dong Youn Kim
- Department of Biomedical Engineering, Yonsei University, Wonju, Republic of Korea.
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18
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Jahani S, Ghiasi M. Platinum complexation with glutamate amino acid: Computational study. MAIN GROUP CHEMISTRY 2021. [DOI: 10.3233/mgc-210071] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
In this research work, complex formation of platinum (Pt) metal particle with the glutamate (Glu) amino acid was investigated by performing density functional theory (DFT) calculations. Such application could be very much important regarding the importance of developing metal based biosensors for biological media. To achieve the purpose of this work, two spin numbers of 0 and 1 were considered for Pt for locating separately towards neutral and anionic forms of Glu for Pt / Glu complexes formations. The obtained results of optimization and QTAIM analyses indicated various configurations for different spin numbers of Pt metal particle towards each of neutral and anionic forms of Glu. Existence of covalent bond was observed for most cases in addition to existence of weak van der Waals interactions for the complexes.
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Affiliation(s)
- Seyedehdelaram Jahani
- Department of Chemistry, Faculty of Physics & Chemistry, Alzahra University, Tehran, Iran
| | - Mina Ghiasi
- Department of Chemistry, Faculty of Physics & Chemistry, Alzahra University, Tehran, Iran
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19
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Dąbrowska K, Skowrońska K, Popek M, Albrecht J, Zielińska M. The Role of Nrf2 Transcription Factor and Sp1-Nrf2 Protein Complex in Glutamine Transporter SN1 Regulation in Mouse Cortical Astrocytes Exposed to Ammonia. Int J Mol Sci 2021; 22:ijms222011233. [PMID: 34681893 PMCID: PMC8538223 DOI: 10.3390/ijms222011233] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/14/2021] [Accepted: 10/15/2021] [Indexed: 11/28/2022] Open
Abstract
Ammonia toxicity in the brain primarily affects astrocytes via a mechanism in which oxidative stress (OS), is coupled to the imbalance between glutamatergic and GABAergic transmission. Ammonia also downregulates the astrocytic N system transporter SN1 that controls glutamine supply from astrocytes to neurons for the replenishment of both neurotransmitters. Here, we tested the hypothesis that activation of Nrf2 is the process that links ammonia-induced OS formation in astrocytes to downregulation and inactivation of SN1 and that it may involve the formation of a complex between Nrf2 and Sp1. Treatment of cultured cortical mouse astrocytes with ammonia (5 mM NH4Cl for 24 h) evoked Nrf2 nuclear translocation, increased its activity in a p38 MAPK pathway-dependent manner, and enhanced Nrf2 binding to Slc38a3 promoter. Nrf2 silencing increased SN1 mRNA and protein level without influencing astrocytic [3H]glutamine transport. Ammonia decreased SN1 expression in Nrf2 siRNA treated astrocytes and reduced [3H]glutamine uptake. In addition, while Nrf2 formed a complex with Sp1 in ammonia-treated astrocytes less efficiently than in control cells, treatment of astrocytes with hybrid-mode inactivated Sp1-Nrf2 complex (Nrf2 silencing + pharmacological inhibition of Sp1) did not affect SN1 protein level in ammonia-treated astrocytes. In summary, the results document that SN1 transporter dysregulation by ammonia in astrocytes involves activation of Nrf2 but does not require the formation of the Sp1-Nrf2 complex.
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20
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Anterior cingulate cortex neurometabolites in bipolar disorder are influenced by mood state and medication: A meta-analysis of 1H-MRS studies. Eur Neuropsychopharmacol 2021; 47:62-73. [PMID: 33581932 DOI: 10.1016/j.euroneuro.2021.01.096] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 01/12/2021] [Accepted: 01/18/2021] [Indexed: 12/13/2022]
Abstract
The anterior cingulate cortex (ACC), a brain region that mediates affect and cognition by connecting the frontal cortex to limbic structures, has been consistently implicated in the neurobiology of Bipolar Disorder (BD). Proton magnetic resonance spectroscopy (1H-MRS) studies have extensively compared in vivo neurometabolite levels of BD patients and healthy controls (HC) in the ACC. However, these studies have not been analyzed in a systematic review or meta-analysis and nor has the influence of mood state and medication on neurometabolites been examined in this cortical region. A systematic review and a meta-analysis of 1H-MRS studies comparing ACC neurometabolite profiles of adult BD patients and HC subjects was conducted, retrieving 27 articles published between 2000 and 2018. Overall increased ACC levels of Glx [glutamine (Gln) + glutamate)/Creatine], Gln, choline (Cho) and Cho/Creatine were found in BD compared to HC. Bipolar depression was associated with higher Cho levels, while euthymia correlated with higher glutamine (Gln) and Cho. Mood stabilizers appeared to affect ACC Glu and Gln metabolites. Increased ACC Cho observed in euthymia, depression and in medication-free groups could be considered a trait marker in BD and attributed to increased cell membrane phospholipid turnover. Overall increased ACC Glx was associated with elevated Gln levels, particularly influenced by euthymia, but no abnormality in Glu was detected. Further 1H-MRS studies, on other voxels, should assess more homogeneous (mood state-specific), larger BD samples and account for medication status using more sensitive 1H-MRS techniques.
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21
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Vieira N, Rito T, Correia-Neves M, Sousa N. Sorting Out Sorting Nexins Functions in the Nervous System in Health and Disease. Mol Neurobiol 2021; 58:4070-4106. [PMID: 33931804 PMCID: PMC8280035 DOI: 10.1007/s12035-021-02388-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 04/05/2021] [Indexed: 12/18/2022]
Abstract
Endocytosis is a fundamental process that controls protein/lipid composition of the plasma membrane, thereby shaping cellular metabolism, sensing, adhesion, signaling, and nutrient uptake. Endocytosis is essential for the cell to adapt to its surrounding environment, and a tight regulation of the endocytic mechanisms is required to maintain cell function and survival. This is particularly significant in the central nervous system (CNS), where composition of neuronal cell surface is crucial for synaptic functioning. In fact, distinct pathologies of the CNS are tightly linked to abnormal endolysosomal function, and several genome wide association analysis (GWAS) and biochemical studies have identified intracellular trafficking regulators as genetic risk factors for such pathologies. The sorting nexins (SNXs) are a family of proteins involved in protein trafficking regulation and signaling. SNXs dysregulation occurs in patients with Alzheimer’s disease (AD), Down’s syndrome (DS), schizophrenia, ataxia and epilepsy, among others, establishing clear roles for this protein family in pathology. Interestingly, restoration of SNXs levels has been shown to trigger synaptic plasticity recovery in a DS mouse model. This review encompasses an historical and evolutionary overview of SNXs protein family, focusing on its organization, phyla conservation, and evolution throughout the development of the nervous system during speciation. We will also survey SNXs molecular interactions and highlight how defects on SNXs underlie distinct pathologies of the CNS. Ultimately, we discuss possible strategies of intervention, surveying how our knowledge about the fundamental processes regulated by SNXs can be applied to the identification of novel therapeutic avenues for SNXs-related disorders.
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Affiliation(s)
- Neide Vieira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057, Braga, Portugal. .,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
| | - Teresa Rito
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Margarida Correia-Neves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Nuno Sousa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
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22
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Duran-Trio L, Fernandes-Pires G, Simicic D, Grosse J, Roux-Petronelli C, Bruce SJ, Binz PA, Sandi C, Cudalbu C, Braissant O. A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism. Sci Rep 2021; 11:1636. [PMID: 33452333 PMCID: PMC7810893 DOI: 10.1038/s41598-020-80824-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 12/28/2020] [Indexed: 11/10/2022] Open
Abstract
Creatine is an organic compound used as fast phosphate energy buffer to recycle ATP, important in tissues with high energy demand such as muscle or brain. Creatine is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Deficit in the endogenous synthesis or in the transport leads to Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain creatine deficiency, intellectual disability with severe speech delay, behavioral troubles such as attention deficits and/or autistic features, and epilepsy. Among CCDS, the X-linked creatine transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different mouse models of CTD were generated by doing long deletions in the Slc6a8 gene showing reduced brain creatine and cognitive deficiencies or impaired motor function. We present a new knock-in (KI) rat model of CTD holding an identical point mutation found in patients with reported lack of transporter activity. KI males showed brain creatine deficiency, increased urinary creatine/creatinine ratio, cognitive deficits and autistic-like traits. The Slc6a8Y389C KI rat fairly enriches the spectrum of CTD models and provides new data about the pathology, being the first animal model of CTD carrying a point mutation.
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Affiliation(s)
- Lara Duran-Trio
- Service of Clinical Chemistry, University of Lausanne and University Hospital of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Gabriella Fernandes-Pires
- Service of Clinical Chemistry, University of Lausanne and University Hospital of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Dunja Simicic
- Centre d'Imagerie Biomedicale (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Jocelyn Grosse
- Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Clothilde Roux-Petronelli
- Service of Clinical Chemistry, University of Lausanne and University Hospital of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Stephen J Bruce
- Service of Clinical Chemistry, University of Lausanne and University Hospital of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Pierre-Alain Binz
- Service of Clinical Chemistry, University of Lausanne and University Hospital of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Carmen Sandi
- Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Cristina Cudalbu
- Centre d'Imagerie Biomedicale (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Olivier Braissant
- Service of Clinical Chemistry, University of Lausanne and University Hospital of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland.
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23
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Badawy AA, Elghaba R, Soliman M, Hussein AM, AlSadrah SA, Awadalla A, Abulseoud OA. Chronic Valproic Acid Administration Increases Plasma, Liver, and Brain Ammonia Concentration and Suppresses Glutamine Synthetase Activity. Brain Sci 2020; 10:brainsci10100759. [PMID: 33096612 PMCID: PMC7589689 DOI: 10.3390/brainsci10100759] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/07/2020] [Accepted: 10/15/2020] [Indexed: 01/09/2023] Open
Abstract
Asymptomatic valproic acid (VPA)-induced hyperammonemia in the absence of liver impairment is fairly common. However, the underlying mechanisms through which VPA causes elevation in plasma ammonia (NH4) remains under investigation. Male Sprague Dawley rats (n = 72) were randomly allocated to receive VPA 400 mg/kg, 200 mg/kg, or vehicle IP daily for either 8, 14, or 28 consecutive days. The behavioral effects of VPA were assessed. Plasma, liver, and prefrontal cortex (PFC), striatum (Str), and cerebellum (Cere) were collected 1 h post last injection and assayed for NH4 concentration and glutamine synthetase (GS) enzyme activity. Chronic VPA treatment caused attenuation of measured behavioral reflexes (p < 0.0001) and increase in plasma NH4 concentration (p < 0.0001). The liver and brain also showed significant increase in tissue NH4 concentrations (p < 0.0001 each) associated with significant reduction in GS activity (p < 0.0001 and p = 0.0003, respectively). Higher tissue NH4 concentrations correlated with reduced GS activity in the liver (r = −0.447, p = 0.0007) but not in the brain (r = −0.058, p = 0.4). Within the brain, even though NH4 concentrations increased in the PFC (p = 0.001), Str (p < 0.0001), and Cere (p = 0.01), GS activity was reduced only in the PFC (p < 0.001) and not in Str (p = 0.2) or Cere (p = 0.1). These results suggest that VPA-induced elevation in plasma NH4 concentration could be related, at least in part, to the suppression of GS activity in liver and brain tissues. However, even though GS is the primary mechanism in brain NH4 clearance, the suppression of brain GS does not seem to be the main factor in explaining the elevation in brain NH4 concentration. Further research is urgently needed to investigate brain NH4 dynamics under chronic VPA treatment and whether VPA clinical efficacy in treating seizure disorders and bipolar mania is impacted by its effect on GS activity or other NH4 metabolizing enzymes.
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Affiliation(s)
- Abdelnaser A. Badawy
- Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar 73213, Saudi Arabia;
- Department of Biochemistry, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Rasha Elghaba
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt;
| | - Mohamed Soliman
- Department of Microbiology, Faculty of Medicine, Northern Border University, Arar 73213, Saudi Arabia;
| | - Abdelaziz M. Hussein
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt;
- Correspondence: (A.M.H.); (O.A.A.)
| | - Sana A. AlSadrah
- Department of Preventive Medicine, Governmental Hospital Khobar, Health Centers in Khobar, Ministry of Health, Khobar 34446, Saudi Arabia;
| | - Amira Awadalla
- Center of Excellence and Cancer Genome, Mansoura Urology and Nephrology Center, Mansoura 35516, Egypt;
| | - Osama A. Abulseoud
- Neuroimaging Research Branch, IRP, National Institute on Drug Abuse, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224, USA
- Correspondence: (A.M.H.); (O.A.A.)
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24
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Glutamate-glutamine homeostasis is perturbed in neurons and astrocytes derived from patient iPSC models of frontotemporal dementia. Mol Brain 2020; 13:125. [PMID: 32928252 PMCID: PMC7491073 DOI: 10.1186/s13041-020-00658-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 08/21/2020] [Indexed: 02/08/2023] Open
Abstract
Frontotemporal dementia (FTD) is amongst the most prevalent early onset dementias and even though it is clinically, pathologically and genetically heterogeneous, a crucial involvement of metabolic perturbations in FTD pathology is being recognized. However, changes in metabolism at the cellular level, implicated in FTD and in neurodegeneration in general, are still poorly understood. Here we generate induced human pluripotent stem cells (hiPSCs) from patients carrying mutations in CHMP2B (FTD3) and isogenic controls generated via CRISPR/Cas9 gene editing with subsequent neuronal and glial differentiation and characterization. FTD3 neurons show a dysregulation of glutamate-glutamine related metabolic pathways mapped by 13C-labelling coupled to mass spectrometry. FTD3 astrocytes show increased uptake of glutamate whilst glutamate metabolism is largely maintained. Using quantitative proteomics and live-cell metabolic analyses, we elucidate molecular determinants and functional alterations of neuronal and glial energy metabolism in FTD3. Importantly, correction of the mutations rescues such pathological phenotypes. Notably, these findings implicate dysregulation of key enzymes crucial for glutamate-glutamine homeostasis in FTD3 pathogenesis which may underlie vulnerability to neurodegeneration. Neurons derived from human induced pluripotent stem cells (hiPSCs) of patients carrying mutations in CHMP2B (FTD3) display major metabolic alterations compared to CRISPR/Cas9 generated isogenic controls. Using quantitative proteomics, 13C-labelling coupled to mass spectrometry metabolic mapping and seahorse analyses, molecular determinants and functional alterations of neuronal and astrocytic energy metabolism in FTD3 were characterized. Our findings implicate dysregulation of glutamate-glutamine homeostasis in FTD3 pathogenesis. In addition, FTD3 neurons recapitulate glucose hypometabolism observed in FTD patient brains. The impaired mitochondria function found here is concordant with disturbed TCA cycle activity and decreased glycolysis in FTD3 neurons. FTD3 neuronal glutamine hypermetabolism is associated with up-regulation of PAG expression and, possibly, ROS production. Distinct compartments of glutamate metabolism can be suggested for the FTD3 neurons. Endogenous glutamate generated from glutamine via PAG may enter the TCA cycle via AAT (left side of neuron) while exogenous glutamate taken up from the extracellular space may be incorporated into the TCA cycle via GDH (right side of the neuron) FTD3 astrocytic glutamate uptake is upregulated whilst glutamate metabolism is largely maintained. Finally, pharmacological reversal of glutamate hypometabolism manifesting from decreased GDH expression should be explored as a novel therapeutic intervention for treating FTD3.
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25
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Glutamine Supplementation Prevents Chronic Stress-Induced Mild Cognitive Impairment. Nutrients 2020; 12:nu12040910. [PMID: 32224923 PMCID: PMC7230523 DOI: 10.3390/nu12040910] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 03/20/2020] [Accepted: 03/25/2020] [Indexed: 12/26/2022] Open
Abstract
We recently reported that glutamine (Gln) supplementation protected glutamatergic neurotransmission from the harmful effects of chronic stress. Altered glutamatergic neurotransmission is one of the main causes of cognitive disorders. However, the cognitive enhancer function of Gln has not been clearly demonstrated thus far. Here, we evaluated whether and how Gln supplementation actually affects chronic stress-induced cognitive impairment. Using a chronic immobilization stress (CIS) mouse model, we confirmed that chronic stress induced mild cognitive impairment (MCI) and neuronal damage in the hippocampus. In contrast, Gln-supplemented mice did not show evidence of MCI. To investigate possible underlying mechanisms, we confirmed that CIS increased plasma corticosterone levels as well as brain and plasma levels of reactive oxygen/nitrogen species. CIS also increased levels of inducible nitric oxide synthase and NADPH oxidase subunits (p47phox and p67phox) in both the prefrontal cortex and CA1 region of the hippocampus. CIS decreased the number of synaptic puncta in the prefrontal cortex and hippocampus, but these effects were inhibited by Gln supplementation. Taken together, the present results suggest that Gln is an effective agent against chronic stress-induced MCI.
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26
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Maternal cigarette smoke exposure disturbs glutamate/GABA balance in pFRG of neonatal rats. Respir Physiol Neurobiol 2020; 274:103383. [PMID: 31923590 DOI: 10.1016/j.resp.2020.103383] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/21/2019] [Accepted: 01/06/2020] [Indexed: 01/14/2023]
Abstract
We previously found that maternal cigarette smoke (CS) exposure resulted in impairment of central chemoreception and oxidative stress and mitochondrial dysfunction of parafacial respiratory group (pFRG, a critical site for mammalian central chemoreception) in neonatal rats. The present work was carried out to identify if maternal CS exposure could disturb the glutamate (GLU)-ergic and γ-aminobutyric acid (GABA)-ergic balance in pFRG of neonatal rats. We found that maternal CS exposure induced a decrease in GLU content and consequently in GLU/GABA ratio in pFRG of neonatal rats. Maternal CS exposure also decreased glutamine content and glutaminase and glutamine synthetase activity in offspring pFRG. In addition, expression of vesicular glutamate transporter 2 was depressed, and those of glutamate transporter 1 and GABA transporter 3 were elevated by maternal CS exposure. These results indicate that maternal CS exposure leads to a disturbance of GLU/GABA balance in pFRG of the neonatal rats, which might contribute to the suppression of central chemoreception in maternal CS-exposed offspring.
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27
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Wang H, Zhang F, Wen H, Shi W, Huang Q, Huang Y, Xie J, Li P, Chen J, Qin L, Zhou Y. Tumor- and mitochondria-targeted nanoparticles eradicate drug resistant lung cancer through mitochondrial pathway of apoptosis. J Nanobiotechnology 2020; 18:8. [PMID: 31918714 PMCID: PMC6950814 DOI: 10.1186/s12951-019-0562-3] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 12/17/2019] [Indexed: 01/24/2023] Open
Abstract
Chemotherapeutic drugs frequently encounter multidrug resistance. ATP from mitochondria helps overexpression of drug efflux pumps to induce multidrug resistance, so mitochondrial delivery as a means of "repurposing'' chemotherapeutic drugs currently used in the clinic appears to be a worthwhile strategy to pursue for the development of new anti-drug-resistant cancer agents. TPP-Pluronic F127-hyaluronic acid (HA) (TPH), with a mitochondria-targeting triphenylphosphine (TPP) head group, was first synthesized through ester bond formation. Paclitaxel (PTX)-loaded TPH (TPH/PTX) nanomicelles exhibited excellent physical properties and significantly inhibited A549/ADR cells. After TPH/PTX nanomicelles entered acidic lysosomes through macropinocytosis, the positively charged TP/PTX nanomicelles that resulted from degradation of HA by hyaluronidase (HAase) in acidic lysosomes were exposed and completed lysosomal escape at 12 h, finally localizing to mitochondria over a period of 24 h in A549/ADR cells. Subsequently, TPH/PTX caused mitochondrial outer membrane permeabilization (MOMP) by inhibiting antiapoptotic Bcl-2, leading to cytochrome C release and activation of caspase-3 and caspase-9. In an A549/ADR xenograft tumor model and a drug-resistant breast cancer-bearing mouse model with lung metastasis, TPH/PTX nanomicelles exhibited obvious tumor targeting and significant antitumor efficacy. This work presents the potential of a single, nontoxic nanoparticle (NP) platform for mitochondria-targeted delivery of therapeutics for diverse drug-resistant cancers.
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Affiliation(s)
- He Wang
- Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China.,Center of Cancer Research, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Fangke Zhang
- Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Huaying Wen
- Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Wenwen Shi
- Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Qiudi Huang
- Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Yugang Huang
- Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Jiacui Xie
- Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Peiyin Li
- Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Jianhai Chen
- Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Linghao Qin
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China.
| | - Yi Zhou
- Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China.
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28
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Araki T. Regulatory Mechanism of Peripheral Nerve Myelination by Glutamate-Induced Signaling. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1190:23-31. [PMID: 31760635 DOI: 10.1007/978-981-32-9636-7_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/12/2023]
Abstract
Regulation of differentiation and proliferation of Schwann cells is an essential part of the regulation of peripheral nerve development, degeneration, and regeneration. ZNRF1, a ubiquitin ligase, is expressed in undifferentiated/repair Schwann cells, directs glutamine synthetase to proteasomal degradation, and thereby increase glutamate levels in Schwann cell environment. Glutamate elicits subcellular signaling in Schwann cells via mGluR2 to modulate Neuregulin-1/ErbB2/3 signaling and thereby promote undifferentiated phenotype of Schwann cell.
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Affiliation(s)
- Toshiyuki Araki
- Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
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29
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Milewski K, Bogacińska-Karaś M, Hilgier W, Albrecht J, Zielińska M. TNFα increases STAT3-mediated expression of glutaminase isoform KGA in cultured rat astrocytes. Cytokine 2019; 123:154774. [PMID: 31344597 DOI: 10.1016/j.cyto.2019.154774] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 07/05/2019] [Accepted: 07/06/2019] [Indexed: 01/09/2023]
Abstract
Glutamate related excitotoxicity and excess of cerebral levels of tumor necrosis factor alpha (TNFα) are interrelated and well documented abnormalities noticed in many central nervous system diseases. Contribution of kidney type glutaminase (KGA) and shorter alternative splicing form (GAC) to glutamine degradation in astrocytes has been recently a matter of dispute and extensive study but the regulation of the GLS isoforms by inflammatory factors is still not well known. Here we show that treatment of cultured rat cortical astrocytes with pathophysiologically relevant (50 ng/ml) concentration of TNFα specifically increases the expression of KGA but not GAC and increases activity of GLS. No changes in the expression of either of two GLS isoforms were observed following treatment with other tested cytokines IL-1β and IL-6. The TNFα mediated KGA expression was associated with increased phosphorylation of signal transducer and activator of transcription 3 (STAT3). Stimulatory effect of TNF-α on KGA expression was reduced by selective inhibition of (STAT3) but not by inhibition of STAT1 nor nuclear transcription factor kappa. Additionally, the role of miRNA in TNFα-induced expression of KGA in astrocytes was excluded, since the expression of miR-23a/b and miR-200c, potential regulators of KGA expression, was unchanged. This study documents increased KGA expression in the astrocytes under inflammatory stimulation, identifying TNFα as a cytokine mediating this response, and demonstrates the specific and selective involvement of STAT3.
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Affiliation(s)
- Krzysztof Milewski
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
| | - Małgorzata Bogacińska-Karaś
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - Wojciech Hilgier
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - Jan Albrecht
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - Magdalena Zielińska
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
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30
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Matés JM, Di Paola FJ, Campos-Sandoval JA, Mazurek S, Márquez J. Therapeutic targeting of glutaminolysis as an essential strategy to combat cancer. Semin Cell Dev Biol 2019; 98:34-43. [PMID: 31100352 DOI: 10.1016/j.semcdb.2019.05.012] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 05/11/2019] [Accepted: 05/13/2019] [Indexed: 01/08/2023]
Abstract
Metabolic reprogramming in cancer targets glutamine metabolism as a key mechanism to provide energy, biosynthetic precursors and redox requirements to allow the massive proliferation of tumor cells. Glutamine is also a signaling molecule involved in essential pathways regulated by oncogenes and tumor suppressor factors. Glutaminase isoenzymes are critical proteins to control glutaminolysis, a key metabolic pathway for cell proliferation and survival that directs neoplasms' fate. Adaptive glutamine metabolism can be altered by different metabolic therapies, including the use of specific allosteric inhibitors of glutaminase that can evoke synergistic effects for the therapy of cancer patients. We also review other clinical applications of in vivo assessment of glutaminolysis by metabolomic approaches, including diagnosis and monitoring of cancer.
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Affiliation(s)
- José M Matés
- Instituto de Investigación Biomédica de Málaga (IBIMA), Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Málaga, E-29071 Málaga, Spain
| | - Floriana J Di Paola
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University of Giessen, D-35392 Giessen, Germany
| | - José A Campos-Sandoval
- Instituto de Investigación Biomédica de Málaga (IBIMA), Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Málaga, E-29071 Málaga, Spain
| | - Sybille Mazurek
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University of Giessen, D-35392 Giessen, Germany
| | - Javier Márquez
- Instituto de Investigación Biomédica de Málaga (IBIMA), Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Málaga, E-29071 Málaga, Spain.
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31
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Exchange-mode glutamine transport across CNS cell membranes. Neuropharmacology 2019; 161:107560. [PMID: 30853601 DOI: 10.1016/j.neuropharm.2019.03.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 02/28/2019] [Accepted: 03/02/2019] [Indexed: 12/18/2022]
Abstract
CNS cell membranes possess four transporters capable of exchanging Lglutamine (Gln) for other amino acids: the large neutral amino acid (LNAA) transporters LAT1 and LAT2, the hybrid basic amino acid (L-arginine (Arg), L-leucine (Leu)/LNAA transporter y+LAT2, and the L-alanine/L-serine/L-cysteine transporter 2 (ASCT2). LAT1/LAT2 and y+LAT2 are present in astrocytes, neurons and the blood brain barrier (BBB) - forming cerebral vascular endothelial cells (CVEC), while the location of ASCT2 in the individual cell types is a matter of debate. In the healthy brain, contribution of the exchangers to Gln shuttling from astrocytes to neurons and thus their role in controlling the conversion of Gln to the amino acid neurotransmitters l-glutamate (Glu) and γ-aminobutyric acid (GABA) and Gln flux across the BBB appears negligible as compared to the system A and system N uniporters. Insofar, except for the contribution of LAT1 to the maintenance of Gln homeostasis in the interstitial fluid (ISF), no well-defined CNS-specific function has been established for either of the three transporters in the healthy brain. The Gln-accepting amino acid exchangers appear to gain significance under conditions of excessive brain Gln load (glutaminosis). Excess Gln efflux across the BBB enhances influx into the brain of L-tryptophan (Trp). Excess of Trp is responsible for overloading the brain with neuroactive compounds: serotonin, kynurenic acid, quinolinic acid and/or oxindole, which contribute to neurotransmission imbalance accompanying hyperammonemia. In turn, alterations of y+LAT2-mediated Gln/Arg exchange and Arg uptake in astrocyte, modulate astrocytic nitric oxide synthesis and oxidative/nitrosative stress in ammonia-overexposed brain. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.
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Cabrera-Pastor A, Arenas YM, Taoro-Gonzalez L, Montoliu C, Felipo V. Chronic hyperammonemia alters extracellular glutamate, glutamine and GABA and membrane expression of their transporters in rat cerebellum. Modulation by extracellular cGMP. Neuropharmacology 2019; 161:107496. [PMID: 30641078 DOI: 10.1016/j.neuropharm.2019.01.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 12/15/2018] [Accepted: 01/10/2019] [Indexed: 12/14/2022]
Abstract
Trafficking of glutamate, glutamine and GABA between astrocytes and neurons is essential to maintain proper neurotransmission. Chronic hyperammonemia alters neurotransmission and cognitive function. The aims of this work were to analyze in cerebellum of rats the effects of chronic hyperammonemia on: a) extracellular glutamate, glutamine and GABA concentrations; b) membrane expression of glutamate, glutamine and GABA transporters; c) how they are modulated by extracellular cGMP. Hyperammonemic rats show increased levels of extracellular glutamate, glutamine, GABA and citrulline in cerebellum in vivo. Hyperammonemic rats show: a) increased membrane expression of the astrocytic glutamine transporter SNAT3 and reduced membrane expression of the neuronal transporter SNAT1; b) reduced membrane expression of the neuronal GABA transporter GAT1 and increased membrane expression of the astrocytic GAT3 transporter; c) reduced membrane expression of the astrocytic glutamate transporters GLAST and GLT-1 and of the neuronal transporter EAAC1. Increasing extracellular cGMP normalizes membrane expression of SNAT3, GAT3, GAT1 and GLAST and extracellular glutamate, glutamine, GABA and citrulline hyperammonemic rats. Extracellular cGMP also modulates membrane expression of most transporters in control rats, reducing membrane expression of SNAT1, GLT-1 and EAAC1 and increasing that of GAT1 and GAT3. Modulation of SNAT3, SNAT1, GLT-1 and EAAC1 by extracellular cGMP would be mediated by inhibition of glycine receptors. These data suggest that, in pathological situations such as hyperammonemia, hepatic encephalopathy or Alzheimer's disease, reduced levels of extracellular cGMP contribute to alterations in membrane expression of glutamine, glutamate and GABA transporters, in the extracellular levels of glutamine, glutamate and GABA and in neurotransmission. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.
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Affiliation(s)
- Andrea Cabrera-Pastor
- Laboratory of Neurobiology, Centro de Investigación Principe Felipe, Valencia, Spain; Fundacion Investigacion Hospital Clinico Valencia, Instituto de Investigacion Sanitaria INCLIVA, Valencia, Spain
| | - Yaiza M Arenas
- Laboratory of Neurobiology, Centro de Investigación Principe Felipe, Valencia, Spain
| | - Lucas Taoro-Gonzalez
- Laboratory of Neurobiology, Centro de Investigación Principe Felipe, Valencia, Spain
| | - Carmina Montoliu
- Fundacion Investigacion Hospital Clinico Valencia, Instituto de Investigacion Sanitaria INCLIVA, Valencia, Spain
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Principe Felipe, Valencia, Spain.
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Silencing of Transcription Factor Sp1 Promotes SN1 Transporter Regulation by Ammonia in Mouse Cortical Astrocytes. Int J Mol Sci 2019; 20:ijms20020234. [PMID: 30634395 PMCID: PMC6359076 DOI: 10.3390/ijms20020234] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 12/27/2018] [Accepted: 12/27/2018] [Indexed: 12/15/2022] Open
Abstract
The involvement of the astrocytic SN1 (SNAT3) transporter in ammonia-induced l-glutamine retention was recently documented in mouse-cultured astrocytes. Here we investigated the involvement of specificity protein 1 (Sp1) transcription factor in SN1 regulation in ammonium chloride (“ammonia”)-treated astrocytes. Sp1 expression and its cellular localization were determined using real-time qPCR, Western blot, and confocal microscopy. Sp1 binding to Snat3 promoter was analyzed by chromatin immunoprecipitation. The role of Sp1 in SN1 expression and SN1-mediated [3H]glutamine uptake in ammonia-treated astrocytes was verified using siRNA and mithramycin A. The involvement of protein kinase C (PKC) isoforms in Sp1 level/phosphorylation status was verified using siRNA technology. Sp1 translocation to the nuclei and its enhanced binding to the Snat3 promoter, along with Sp1 dependence of system N-mediated [3H]glutamine uptake, were observed in astrocytes upon ammonia exposure. Ammonia decreased the level of phosphorylated Sp1, and the effect was reinforced by long-term incubation with PKC modulator, phorbol 12-myristate 13-acetate, which is a treatment likely to dephosphorylate Sp1. Furthermore, silencing of the PKCδ isoform appears to enhance the ammonia effect on the Sp1 level. Collectively, the results demonstrate the regulatory role of Sp1 in regulation of SN1 expression and activity in ammonia-treated astrocytes and implicate altered Sp1 phosphorylation status in this capacity.
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Canfield CA, Bradshaw PC. Amino acids in the regulation of aging and aging-related diseases. TRANSLATIONAL MEDICINE OF AGING 2019. [DOI: 10.1016/j.tma.2019.09.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Shimamoto A, Rappeneau V, Munjal H, Farris T, Davis C, Wilson A, Edwards M, Moore C, Reynolds C, Meshul CK. Glutamate-Glutamine Transfer and Chronic Stress-Induced Sex Differences in Cocaine Responses. Neuroscience 2018; 391:104-119. [DOI: 10.1016/j.neuroscience.2018.09.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 09/05/2018] [Accepted: 09/06/2018] [Indexed: 01/16/2023]
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Dąbrowska K, Albrecht J, Zielińska M. Protein kinase C-mediated impairment of glutamine outward transport and SN1 transporter distribution by ammonia in mouse cortical astrocytes. Neurochem Int 2018; 118:225-232. [DOI: 10.1016/j.neuint.2018.07.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 06/19/2018] [Accepted: 07/03/2018] [Indexed: 01/07/2023]
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Chen Q, Kirk K, Shurubor YI, Zhao D, Arreguin AJ, Shahi I, Valsecchi F, Primiano G, Calder EL, Carelli V, Denton TT, Beal MF, Gross SS, Manfredi G, D'Aurelio M. Rewiring of Glutamine Metabolism Is a Bioenergetic Adaptation of Human Cells with Mitochondrial DNA Mutations. Cell Metab 2018; 27:1007-1025.e5. [PMID: 29657030 PMCID: PMC5932217 DOI: 10.1016/j.cmet.2018.03.002] [Citation(s) in RCA: 123] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 01/03/2018] [Accepted: 03/12/2018] [Indexed: 01/05/2023]
Abstract
Using molecular, biochemical, and untargeted stable isotope tracing approaches, we identify a previously unappreciated glutamine-derived α-ketoglutarate (αKG) energy-generating anaplerotic flux to be critical in mitochondrial DNA (mtDNA) mutant cells that harbor human disease-associated oxidative phosphorylation defects. Stimulating this flux with αKG supplementation enables the survival of diverse mtDNA mutant cells under otherwise lethal obligatory oxidative conditions. Strikingly, we demonstrate that when residual mitochondrial respiration in mtDNA mutant cells exceeds 45% of control levels, αKG oxidative flux prevails over reductive carboxylation. Furthermore, in a mouse model of mitochondrial myopathy, we show that increased oxidative αKG flux in muscle arises from enhanced alanine synthesis and release into blood, concomitant with accelerated amino acid catabolism from protein breakdown. Importantly, in this mouse model of mitochondriopathy, muscle amino acid imbalance is normalized by αKG supplementation. Taken together, our findings provide a rationale for αKG supplementation as a therapeutic strategy for mitochondrial myopathies.
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Affiliation(s)
- Qiuying Chen
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Kathryne Kirk
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA
| | - Yevgeniya I Shurubor
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA
| | - Dazhi Zhao
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA
| | - Andrea J Arreguin
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA
| | - Ifrah Shahi
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA
| | - Federica Valsecchi
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA
| | - Guido Primiano
- Institute of Neurology, Catholic University of the Sacred Heart, Rome, Italy
| | - Elizabeth L Calder
- Center for Stem Cell Biology and Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA
| | - Valerio Carelli
- IRCCS, Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy; Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
| | - Travis T Denton
- Department of Pharmaceutical Sciences, Washington State University, College of Pharmacy, Spokane, WA 99210, USA
| | - M Flint Beal
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA
| | - Steven S Gross
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Giovanni Manfredi
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA.
| | - Marilena D'Aurelio
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA.
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Nagy AM, Fekete R, Horvath G, Koncsos G, Kriston C, Sebestyen A, Giricz Z, Kornyei Z, Madarasz E, Tretter L. Versatility of microglial bioenergetic machinery under starving conditions. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2017; 1859:201-214. [PMID: 29273412 DOI: 10.1016/j.bbabio.2017.12.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 12/11/2017] [Accepted: 12/16/2017] [Indexed: 11/18/2022]
Abstract
Microglia are highly dynamic cells in the brain. Their functional diversity and phenotypic versatility brought microglial energy metabolism into the focus of research. Although it is known that microenvironmental cues shape microglial phenotype, their bioenergetic response to local nutrient availability remains unclear. In the present study effects of energy substrates on the oxidative and glycolytic metabolism of primary - and BV-2 microglial cells were investigated. Cellular oxygen consumption, glycolytic activity, the levels of intracellular ATP/ADP, autophagy, mTOR phosphorylation, apoptosis and cell viability were measured in the absence of nutrients or in the presence of physiological energy substrates: glutamine, glucose, lactate, pyruvate or ketone bodies. All of the oxidative energy metabolites increased the rate of basal and maximal respiration. However, the addition of glucose decreased microglial oxidative metabolism and glycolytic activity was enhanced. Increased ATP/ADP ratio and cell viability, activation of the mTOR and reduction of autophagic activity were observed in glutamine-supplemented media. Moreover, moderate and transient oxidation of ketone bodies was highly enhanced by glutamine, suggesting that anaplerosis of the TCA-cycle could stimulate ketone body oxidation. It is concluded that microglia show high metabolic plasticity and utilize a wide range of substrates. Among them glutamine is the most efficient metabolite. To our knowledge these data provide the first account of microglial direct metabolic response to nutrients under short-term starvation and demonstrate that microglia exhibit versatile metabolic machinery. Our finding that microglia have a distinct bioenergetic profile provides a critical foundation for specifying microglial contributions to brain energy metabolism.
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Affiliation(s)
- Adam M Nagy
- Department of Medical Biochemistry, MTA-SE Laboratory for Neurobiochemistry, Semmelweis University, 1094 Tuzolto st. 37-47, Budapest, Hungary
| | - Rebeka Fekete
- Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Szigony st. 43, Budapest, Hungary
| | - Gergo Horvath
- Department of Medical Biochemistry, MTA-SE Laboratory for Neurobiochemistry, Semmelweis University, 1094 Tuzolto st. 37-47, Budapest, Hungary
| | - Gabor Koncsos
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Nagyvarad square 4, Budapest, Hungary
| | - Csilla Kriston
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Ulloi st. 26, Budapest, Hungary
| | - Anna Sebestyen
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Ulloi st. 26, Budapest, Hungary
| | - Zoltan Giricz
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Nagyvarad square 4, Budapest, Hungary
| | - Zsuzsanna Kornyei
- Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Szigony st. 43, Budapest, Hungary
| | - Emilia Madarasz
- Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Szigony st. 43, Budapest, Hungary
| | - Laszlo Tretter
- Department of Medical Biochemistry, MTA-SE Laboratory for Neurobiochemistry, Semmelweis University, 1094 Tuzolto st. 37-47, Budapest, Hungary.
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Guo Y, Zhang Y, Jia P, Wang W, Zhou Q, Sun L, Zhao A, Zhang X, Wang X, Li Y, Zhang J, Jiang W. Preoperative Serum Metabolites Are Associated With Postoperative Delirium in Elderly Hip-Fracture Patients. J Gerontol A Biol Sci Med Sci 2017; 72:1689-1696. [PMID: 28180239 DOI: 10.1093/gerona/glx001] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 01/25/2017] [Indexed: 12/18/2022] Open
Abstract
Background Hypotheses on the development of postoperative delirium (PD) include "neuroinflammatory," "neuronal aging," "oxidative stress," "neurotransmitter deficiency," and "neuroendocrine." Here, we employed metabolomics to determine the serum metabolites in the baseline associated with an increased risk of PD. Methods Two hundred and nine elderly hip-fracture patients who had undergone hemiarthroplasty and had completed our assessments were selected. Fasting venous blood was collected at 7:00 on the morning of surgery and a serum sample bank was created for analysis. On the first 3 postoperative days, the patients were assessed twice daily using the Confusion Assessment Method - Chinese Revision. Ultimately, 43 patients were diagnosed with PD, who comprised the PD group. Meanwhile, 43 matched non-PD patients were selected based on age, sex, and body mass index. Serum samples from the two groups were analyzed by gas chromatography-time-of-flight mass spectrometry and Acquity ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Results The demographic characteristics of the groups were matched. Four metabolites associated with an increased risk of PD were identified, including S-methylcysteine, linolenic acid, eicosapentaenoic acid, and linoleic acid. Conclusions Multiple metabolic pathways in the PD group altered before surgery, including deficiency of ω3 and ω6 fatty acids, energy metabolism and oxidative stress with interactions between hypoxia and mitochondrial dysfunction, in addition to glutamate-glutamine cycle dysfunction. These metabolic abnormalities could possibly increase the fragility of the brain and then contribute to PD.
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Affiliation(s)
- Yong Guo
- Department of Anesthesiology and Critical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, China.,Department of Anesthesiology and Critical Care Medicine, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, China
| | - Yinan Zhang
- Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, China
| | - Peiyu Jia
- Department of Anesthesiology and Critical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, China
| | - Wenying Wang
- Department of Anesthesiology and Critical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, China
| | - Quanhong Zhou
- Department of Anesthesiology and Critical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, China
| | - Lulu Sun
- Department of Anesthesiology and Critical Care Medicine, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, China
| | - Aihua Zhao
- Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, China
| | - Xin Zhang
- Department of Anesthesiology and Critical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, China
| | - Xuemin Wang
- Department of Anesthesiology and Critical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, China
| | - Yingchuan Li
- Department of Anesthesiology and Critical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, China
| | - Junfeng Zhang
- Department of Anesthesiology and Critical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, China
| | - Wei Jiang
- Department of Anesthesiology and Critical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, China
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Effects of Aging and Tocotrienol-Rich Fraction Supplementation on Brain Arginine Metabolism in Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:6019796. [PMID: 29348790 PMCID: PMC5733770 DOI: 10.1155/2017/6019796] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 10/04/2017] [Accepted: 10/09/2017] [Indexed: 12/31/2022]
Abstract
Accumulating evidence suggests that altered arginine metabolism is involved in the aging and neurodegenerative processes. This study sought to determine the effects of age and vitamin E supplementation in the form of tocotrienol-rich fraction (TRF) on brain arginine metabolism. Male Wistar rats at ages of 3 and 21 months were supplemented with TRF orally for 3 months prior to the dissection of tissue from five brain regions. The tissue concentrations of L-arginine and its nine downstream metabolites were quantified using high-performance liquid chromatography and liquid chromatography tandem mass spectrometry. We found age-related alterations in L-arginine metabolites in the chemical- and region-specific manners. Moreover, TRF supplementation reversed age-associated changes in arginine metabolites in the entorhinal cortex and cerebellum. Multiple regression analysis revealed a number of significant neurochemical-behavioral correlations, indicating the beneficial effects of TRF supplementation on memory and motor function.
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Liu Z, Huang Y, Liu L, Zhang L. Inhibitions of PKC and CaMK-II synergistically rescue ischemia-induced astrocytic dysfunction. Neurosci Lett 2017; 657:199-203. [DOI: 10.1016/j.neulet.2017.08.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 08/02/2017] [Accepted: 08/07/2017] [Indexed: 01/29/2023]
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Ortega-Ibarra J, López-Pérez S, Morales-Villagrán A. An electrochemiluminescent method for glutamate measurement in small microdialysate samples in asphyxiated young rats. LUMINESCENCE 2017; 33:47-53. [PMID: 28718955 DOI: 10.1002/bio.3371] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 05/16/2017] [Accepted: 05/28/2017] [Indexed: 11/08/2022]
Abstract
Glutamate (Glu) quantification has been performed by a combination of intracerebral microdialysis through which the samples are obtained and analyzed by high performance liquid chromatography (HPLC); its measurement requires a large expenditure of time (15-30 min per sample) and special training. Therefore, an alternative method is presented here, based on the electrochemiluminescence produced by the use of an enzymatic reactor, containing glutamate-oxidase, mixed and incubated with microdialysate from dorsal striatum (DS) and prefrontal cortex (PFC) of young rats asphyxiated during the neonatal period, under a global asphyxia model in order to test this method. Using this approach, we found high extracellular Glu concentration in the DS of asphyxiated animals, but only during K+ stimulation, while in the PFC, only a delay in the rise of Glu after K+ stimulation was observed, without any difference in extracellular Glu content when compared with controls. This new method permitted a fast measurement of Glu in brain dialysate samples, it significantly reduces the cost of the analysis per sample, since only a single device and pump are needed without using columns and high pressure inside the system or complex hardware and software to control pumps, detector, fraction collector or any other peripheral used in HPLC.
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Affiliation(s)
- Jorge Ortega-Ibarra
- Laboratory of Neurophysiology and Neurochemistry, Department of Cellular and Molecular Biology, CUCBA, University of Guadalajara, Jalisco, Mexico
| | - Silvia López-Pérez
- Laboratory of Neurophysiology and Neurochemistry, Department of Cellular and Molecular Biology, CUCBA, University of Guadalajara, Jalisco, Mexico
| | - Alberto Morales-Villagrán
- Laboratory of Neurophysiology and Neurochemistry, Department of Cellular and Molecular Biology, CUCBA, University of Guadalajara, Jalisco, Mexico
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Abulseoud OA, Zuccoli ML, Zhang L, Barnes A, Huestis MA, Lin DT. The acute effect of cannabis on plasma, liver and brain ammonia dynamics, a translational study. Eur Neuropsychopharmacol 2017; 27:679-690. [PMID: 28456476 PMCID: PMC6091863 DOI: 10.1016/j.euroneuro.2017.03.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Revised: 02/22/2017] [Accepted: 03/18/2017] [Indexed: 01/08/2023]
Abstract
Recent reports of ammonia released during cannabis smoking raise concerns about putative neurotoxic effects. Cannabis (54mg) was administered in a double-blind, placebo-controlled design to healthy cannabis users (n=15) either orally, or through smoking (6.9%THC cigarette) or inhalation of vaporized cannabis (Volcano®). Serial assay of plasma ammonia concentrations at 0, 2, 4, 6, 8, 10, 15, 30, and 90min from onset of cannabis administration showed significant time (P=0.016), and treatment (P=0.0004) effects with robust differences between placebo and edible at 30 (P=0.002), and 90min (P=0.007) and between placebo and vaporized (P=0.02) and smoking routes (P=0.01) at 90min. Furthermore, plasma ammonia positively correlated with blood THC concentrations (P=0.03). To test the hypothesis that this delayed increase in plasma ammonia originates from the brain we administered THC (3 and 10mg/kg) to mice and measured plasma, liver, and brain ammonia concentrations at 1, 3, 5 and 30min post-injection. Administration of THC to mice did not cause significant change in plasma ammonia concentrations within the first 5min, but significantly reduced striatal glutamine-synthetase (GS) activity (P=0.046) and increased striatal ammonia concentration (P=0.016). Furthermore, plasma THC correlated positively with striatal ammonia concentration (P<0.001) and negatively with striatal GS activity (P=0.030). At 30min, we found marked increase in striatal ammonia (P<0.0001) associated with significant increase in plasma ammonia (P=0.042) concentration. In conclusion, the results of these studies demonstrate that cannabis intake caused time and route-dependent increases in plasma ammonia concentrations in human cannabis users and reduced brain GS activity and increased brain and plasma ammonia concentrations in mice.
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Affiliation(s)
- Osama A Abulseoud
- Chemistry and Drug Metabolism Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
| | - Maria Laura Zuccoli
- Chemistry and Drug Metabolism Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA; Department of Internal Medicine, Pharmacology and Toxicology Unit, University of Genoa, Italy
| | - Lifeng Zhang
- Neural Engineering Unit, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA
| | - Allan Barnes
- Chemistry and Drug Metabolism Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA
| | - Marilyn A Huestis
- Chemistry and Drug Metabolism Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA
| | - Da-Ting Lin
- Neural Engineering Unit, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
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Erickson JD. Functional identification of activity-regulated, high-affinity glutamine transport in hippocampal neurons inhibited by riluzole. J Neurochem 2017; 142:29-40. [PMID: 28423185 DOI: 10.1111/jnc.14046] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 03/17/2017] [Accepted: 04/05/2017] [Indexed: 12/23/2022]
Abstract
Glutamine (Gln) is considered the preferred precursor for the neurotransmitter pool of glutamate (Glu), the major excitatory transmitter in the mammalian CNS. Here, an activity-regulated, high-affinity Gln transport system is described in developing and mature neuron-enriched hippocampal cultures that is potently inhibited by riluzole (IC50 1.3 ± 0.5 μM), an anti-glutamatergic drug, and is blocked by low concentrations of 2-(methylamino)isobutyrate (MeAIB), a system A transport inhibitor. K+ -stimulated MeAIB transport displays an affinity (Km ) for MeAIB of 37 ± 1.2 μM, saturates at ~ 200 μM, is dependent on extracellular Ca2+ , and is blocked by inhibition of voltage-gated Ca2+ channels. Spontaneous MeAIB transport is also dependent on extracellullar Ca2+ and voltage-gated calcium channels, but is also blocked by the Na+ channel blocker tetrodotoxin, by Glu receptor antagonists, and by GABA indicating its dependence on intact neural circuits driven by endogenous glutamatergic activity. The transport of MeAIB itself does not rely on Ca2+ , but on Na+ ions, and is pH sensitive. Activity-regulated, riluzole-sensitive spontaneous and K+ -stimulated transport is minimal at 7-8 days in vitro, coordinately induced during the next 2 weeks and is maximally expressed by days in vitro > 20; the known period for maturation of the Glu/Gln cycle and regulated pre-synaptic Glu release. Competition analyses with various amino acids indicate that Gln is the most likely physiological substrate. Activity-regulated Gln/MeAIB transport is not observed in astrocytes. The functional identification of activity-regulated, high-affinity, riluzole-sensitive Gln/MeAIB transport in hippocampal neurons may have important ramifications in the neurobiology of activity-stimulated pre-synaptic Glu release, the Glu/Gln cycle between astrocytes and neurons, and neuronal Glu-induced excitotoxicity. Cover Image for this issue: doi: 10.1111/jnc.13805.
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Affiliation(s)
- Jeffrey D Erickson
- Neuroscience Center of Excellence, School of Medicine, Lousiania State University Health New Orleans, New Orleans, Louisiana, USA
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Yudkoff M. Interactions in the Metabolism of Glutamate and the Branched-Chain Amino Acids and Ketoacids in the CNS. Neurochem Res 2017; 42:10-18. [PMID: 27696119 PMCID: PMC5285401 DOI: 10.1007/s11064-016-2057-z] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 08/29/2016] [Accepted: 09/01/2016] [Indexed: 01/17/2023]
Abstract
Glutamatergic neurotransmission entails a tonic loss of glutamate from nerve endings into the synapse. Replacement of neuronal glutamate is essential in order to avoid depletion of the internal pool. In brain this occurs primarily via the glutamate-glutamine cycle, which invokes astrocytic synthesis of glutamine and hydrolysis of this amino acid via neuronal phosphate-dependent glutaminase. This cycle maintains constancy of internal pools, but it does not provide a mechanism for inevitable losses of glutamate N from brain. Import of glutamine or glutamate from blood does not occur to any appreciable extent. However, the branched-chain amino acids (BCAA) cross the blood-brain barrier swiftly. The brain possesses abundant branched-chain amino acid transaminase activity which replenishes brain glutamate and also generates branched-chain ketoacids. It seems probable that the branched-chain amino acids and ketoacids participate in a "glutamate-BCAA cycle" which involves shuttling of branched-chain amino acids and ketoacids between astrocytes and neurons. This mechanism not only supports the synthesis of glutamate, it also may constitute a mechanism by which high (and potentially toxic) concentrations of glutamate can be avoided by the re-amination of branched-chain ketoacids.
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Affiliation(s)
- Marc Yudkoff
- Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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Rappeneau V, Blaker A, Petro JR, Yamamoto BK, Shimamoto A. Disruption of the Glutamate-Glutamine Cycle Involving Astrocytes in an Animal Model of Depression for Males and Females. Front Behav Neurosci 2016; 10:231. [PMID: 28018190 PMCID: PMC5147055 DOI: 10.3389/fnbeh.2016.00231] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 11/22/2016] [Indexed: 12/13/2022] Open
Abstract
Background: Women are twice as likely as men to develop major depression. The brain mechanisms underlying this sex disparity are not clear. Disruption of the glutamate–glutamine cycle has been implicated in psychiatric disturbances. This study identifies sex-based impairments in the glutamate–glutamine cycle involving astrocytes using an animal model of depression. Methods: Male and female adult Long-Evans rats were exposed to chronic social defeat stress (CSDS) for 21 days, using a modified resident-intruder paradigm. Territorial aggression was used for males and maternal aggression was used for females to induce depressive-like deficits for intruders. The depressive-like phenotype was assessed with intake for saccharin solution, weight gain, estrous cycle, and corticosterone (CORT). Behaviors displayed by the intruders during daily encounters with residents were characterized. Rats with daily handling were used as controls for each sex. Ten days after the last encounter, both the intruders and controls were subjected to a no-net-flux in vivo microdialysis to assess glutamate accumulation and extracellular glutamine in the nucleus accumbens (NAc). The contralateral hemispheres were used for determining changes in astrocytic markers, including glial fibrillary acidic protein (GFAP) and glutamate transporter-1 (GLT-1). Results: Both male and female intruders reduced saccharin intake over the course of CSDS, compared to their pre-stress period and to their respective controls. Male intruders exhibited submissive/defensive behaviors to territorial aggression by receiving sideways threats and bites. These males showed reductions in striatal GLT-1 and spontaneous glutamine in the NAc, compared to controls. Female intruders exhibited isolated behaviors to maternal aggression, including immobility, rearing, and selfgrooming. Their non-reproductive days were extended. Also, they showed reductions in prefrontal and accumbal GFAP+ cells and prefrontal GLT-1, compared to controls. When 10 μM of glutamate was infused, these females showed a significant accumulation of glutamate compared to controls. Infusions of glutamate reduced extracellular glutamine for both male and female intruders compared to their respective controls. Conclusion: Twenty-one days of territorial or maternal aggression produced a depressive-like phenotype and impaired astrocytes in both male and female intruders. Disruption of the glutamate–glutamine cycle in the PFC-striatal network may be linked to depressive-like deficits more in females than in males.
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Affiliation(s)
- Virginie Rappeneau
- Department of Neuroscience and Pharmacology, Meharry Medical College School of Medicine Nashville, TN, USA
| | - Amanda Blaker
- Department of Pharmacology and Toxicology, Indiana University School of Medicine Indianapolis, IN, USA
| | - Jeff R Petro
- Department of Neuroscience and Pharmacology, Meharry Medical College School of Medicine Nashville, TN, USA
| | - Bryan K Yamamoto
- Department of Pharmacology and Toxicology, Indiana University School of Medicine Indianapolis, IN, USA
| | - Akiko Shimamoto
- Department of Neuroscience and Pharmacology, Meharry Medical College School of Medicine Nashville, TN, USA
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Zielińska M, Dąbrowska K, Hadera MG, Sonnewald U, Albrecht J. System N transporters are critical for glutamine release and modulate metabolic fluxes of glucose and acetate in cultured cortical astrocytes: changes induced by ammonia. J Neurochem 2015; 136:329-38. [DOI: 10.1111/jnc.13376] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Revised: 08/25/2015] [Accepted: 09/14/2015] [Indexed: 12/28/2022]
Affiliation(s)
- Magdalena Zielińska
- Department of Neurotoxicology; Mossakowski Medical Research Centre; Polish Academy of Sciences; Warsaw Poland
| | - Katarzyna Dąbrowska
- Department of Neurotoxicology; Mossakowski Medical Research Centre; Polish Academy of Sciences; Warsaw Poland
| | - Mussie Ghezu Hadera
- Department of Neuroscience; Faculty of Medicine; Norwegian University of Science and Technology (NTNU); Trondheim Norway
| | - Ursula Sonnewald
- Department of Neuroscience; Faculty of Medicine; Norwegian University of Science and Technology (NTNU); Trondheim Norway
- Department of Drug Design and Pharmacology; Faculty of Health and Medical Sciences; University of Copenhagen; Copenhagen Denmark
| | - Jan Albrecht
- Department of Neurotoxicology; Mossakowski Medical Research Centre; Polish Academy of Sciences; Warsaw Poland
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Targeted Gene Resequencing (Astrochip) to Explore the Tripartite Synapse in Autism-Epilepsy Phenotype with Macrocephaly. Neuromolecular Med 2015; 18:69-80. [PMID: 26537360 DOI: 10.1007/s12017-015-8378-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 10/27/2015] [Indexed: 12/26/2022]
Abstract
The frequent co-occurrence of autism spectrum disorders (ASD) and epilepsy, or paroxysmal EEG abnormalities, defines a condition termed autism-epilepsy phenotype (AEP). This condition results, in some cases , from dysfunctions of glial inwardly rectifying potassium channels (Kir), which are mainly expressed in astrocytes where they mediate neuron-glia communication. Macrocephaly is also often comorbid with autism-epilepsy (autism-epilepsy phenotype with macrocephaly, MAEP), and it is tempting to hypothesize that shared pathogenic mechanisms might explain concurrence of these conditions. In the present study, we assessed whether protein pathways involved, along with Kir channels, in astrocyte-neuron interaction at the tripartite synapse play a role in the etiopathogenesis of MAEP. Using a targeted resequencing methodology, we investigated the coding regions of 35 genes in 61 patients and correlated genetic results with clinical features. Variants were subdivided into 12 classes and clustered into four groups. We detected rare or previously unknown predicted deleterious missense changes in GJA1, SLC12A2, SNTA1, EFNA3, CNTNAP2, EPHA4, and STXBP1 in seven patients and two high-frequency variants in DLG1 in six individuals. We also found that a group of variants (predicted deleterious and non-coding), segregating with the comorbid MAEP/AEP subgroups, belong to proteins specifically involved in glutamate transport and metabolism (namely, SLC17A6, GRM8, and GLUL), as well as in potassium conductance (KCNN3). This "endophenotype-oriented" study, performed using a targeted strategy, helped to further delineate part of the complex genetic background of ASD, particularly in the presence of coexisting macrocephaly and/or epilepsy/paroxysmal EEG, and suggests that use of stringent clinical clustering might be an approach worth adopting in order to unravel the complex genomic data in neurodevelopmental disorders.
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Pun H, Awamleh L, Lee JC, Avivi-Arber L. Decreased face primary motor cortex (face-M1) excitability induced by noxious stimulation of the rat molar tooth pulp is dependent on the functional integrity of medullary astrocytes. Exp Brain Res 2015; 234:645-57. [DOI: 10.1007/s00221-015-4448-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 09/18/2015] [Indexed: 02/03/2023]
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Xu R, Pi HC, Xiong ZY, Liao JL, Hao L, Liu GL, Ren YP, Wang Q, Zheng ZX, Duan LP, Dong J. Hyponatremia and Cognitive Impairment in Patients Treated with Peritoneal Dialysis. Clin J Am Soc Nephrol 2015; 10:1806-13. [PMID: 26231192 PMCID: PMC4594065 DOI: 10.2215/cjn.02240215] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 07/11/2015] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES Hyponatremia has been identified as a relevant factor for cognitive impairment but has not been investigated in patients receiving peritoneal dialysis (PD). This study investigated the relationship between hyponatremia and cognitive functions in PD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 476 clinically stable patients from five PD units who were older than 18 years of age and had undergone PD for at least 3 months between March 2013 and March 2014 were enrolled in this multicenter cross-sectional study. Global cognitive function was measured using the Modified Mini-Mental State Examination (3MS); executive function, by trail making tests A (trails A) and B (trails B); and immediate memory, delayed memory, and language ability, by subtests of Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Hyponatremia was defined as serum sodium level ≤135 mmol/L, which was calculated as the mean of measurements taken over the preceding 3 months. RESULTS Fifty patients (10.5%) had hyponatremia; these patients tended to be older and less educated, to have less inflammation, and to have the higher prevalence of cognitive impairment. They also had lower scores on RBANS subtests. After adjustment for demographic and clinical confounders, hyponatremia was independently associated with lower 3MS score (coefficient, -5.28; 95% confidence interval [CI], -8.44 to -2.13) and longer completion time of trials A (coefficient, 22.68; 95% CI, 3.44 to 41.92) and B (coefficient, 45.56; 95% CI, 1.30 to 89.81). After additional adjustment for laboratory measures, hyponatremia was still associated with 3MS score and completion time of trails A. Hyponatremia was independently associated with CI (odds ratio, 2.17; 95% CI, 1.02 to 4.94) and executive dysfunction (odds ratio, 2.43; 95% CI, 1.01 to 5.87) using multivariate logistic regression analysis. Sensitivity analyses with multivariable models that included propensity score still supported the association between hyponatremia and cognitive impairment. CONCLUSIONS Hyponatremia was associated with global and specific cognitive impairment in PD patients.
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Affiliation(s)
- Rong Xu
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China; Institute of Nephrology, Peking University, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health, Beijing, China; Key Laboratory of Renal Disease, Ministry of Education, Beijing, China
| | - Hai-chen Pi
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China; Institute of Nephrology, Peking University, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health, Beijing, China; Key Laboratory of Renal Disease, Ministry of Education, Beijing, China
| | - Zu-ying Xiong
- Renal Division, Peking University Shenzhen Hospital, Shenzhen, China
| | - Jin-lan Liao
- Renal Division, Peking University Shenzhen Hospital, Shenzhen, China
| | - Li Hao
- Renal Division, Second Hospital of Anhui Medical University, Anhui, China
| | - Gui-ling Liu
- Renal Division, Second Hospital of Anhui Medical University, Anhui, China
| | - Ye-Ping Ren
- Renal Division, Second Affiliated Hospital of Harbin Medical University, Heilongjiang, China; and
| | - Qin Wang
- Renal Division, Second Affiliated Hospital of Harbin Medical University, Heilongjiang, China; and
| | | | - Li-ping Duan
- Renal Division, Handan Central Hospital, Hebei, China
| | - Jie Dong
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China; Institute of Nephrology, Peking University, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health, Beijing, China; Key Laboratory of Renal Disease, Ministry of Education, Beijing, China;
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