Group I Metabotropic Glutamate Receptor Mediated Dynamic Immune
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Mglur5 Modulation As a Treatment for Parkinson's Disease
mGluR5 modulation as a treatment for Parkinson’s disease Kyle Farmer A thesis submitted to the Faculty of Graduate & Postdoctoral Affairs in partial fulfillment of requirements of the degree of Doctor of Philosophy in Neuroscience Carleton University Ottawa, ON Copyright © 2018 – Kyle Farmer ii Space Abstract Parkinson’s disease is an age related neurodegenerative disease. Current treatments do not reverse the degenerative course; rather they merely manage symptom severity. As such there is an urgent need to develop novel neuroprotective therapeutics. There is an additional need to stimulate and promote inherent neuro-recovery processes. Such processes could maximize the utilization of the existing dopamine neurons, and/or recruit alternate neuronal pathways to promote recovery. This thesis investigates the therapeutic potential of the mGluR5 negative allosteric modulator CTEP in a 6-hydroxydopamine mouse model of Parkinson’s disease. We found that CTEP caused a modest reduction in the parkinsonian phenotype after only 1 week of treatment. When administered for 12 weeks, CTEP was able to completely reverse any parkinsonian behaviours and resulted in full dopaminergic striatal terminal re-innervation. Furthermore, restoration of the striatal terminals resulted in normalization of hyperactive neurons in both the striatum and the motor cortex. The beneficial effects within the striatum iii were associated with an increase in activation of mTOR and p70s6K activity. Accordingly, the beneficial effects of CTEP can be blocked if co-administered with the mTOR complex 1 inhibitor, rapamycin. In contrast, CTEP had differential effects in the motor cortex, promoting ERK1/2 and CaMKIIα instead of mTOR. Together these data suggest that modulating mGluR5 with CTEP may have clinical significance in treating Parkinson’s disease. -
Selective Blockade of the Metabotropic Glutamate Receptor Mglur5 Protects Mouse Livers in in Vitro and Ex Vivo Models of Ischemia Reperfusion Injury
International Journal of Molecular Sciences Article Selective Blockade of the Metabotropic Glutamate Receptor mGluR5 Protects Mouse Livers in In Vitro and Ex Vivo Models of Ischemia Reperfusion Injury Andrea Ferrigno 1,* ID , Clarissa Berardo 1, Laura Giuseppina Di Pasqua 1, Veronica Siciliano 1, Plinio Richelmi 1, Ferdinando Nicoletti 2,3 and Mariapia Vairetti 1 ID 1 Department of Internal Medicine and Therapeutics, Cellular and Molecular Pharmacology and Toxicology Unit, University of Pavia, 27100 Pavia, Italy; [email protected] (C.B.); [email protected] (L.G.D.P.); [email protected] (V.S.); [email protected] (P.R.); [email protected] (M.V.) 2 Department of Physiology and Pharmacology, Sapienza University, 00185 Roma, Italy; [email protected] 3 I.R.C.C.S. Neuromed, 86077 Pozzilli, Italy * Correspondence: [email protected]; Tel.: +39-0382-986451 Received: 20 November 2017; Accepted: 22 January 2018; Published: 23 January 2018 Abstract: 2-Methyl-6-(phenylethynyl)pyridine (MPEP), a negative allosteric modulator of the metabotropic glutamate receptor (mGluR) 5, protects hepatocytes from ischemic injury. In astrocytes and microglia, MPEP depletes ATP. These findings seem to be self-contradictory, since ATP depletion is a fundamental stressor in ischemia. This study attempted to reconstruct the mechanism of MPEP-mediated ATP depletion and the consequences of ATP depletion on protection against ischemic injury. We compared the effects of MPEP and other mGluR5 negative modulators on ATP concentration when measured in rat hepatocytes and acellular solutions. We also evaluated the effects of mGluR5 blockade on viability in rat hepatocytes exposed to hypoxia. Furthermore, we studied the effects of MPEP treatment on mouse livers subjected to cold ischemia and warm ischemia reperfusion. -
Metabotropic Glutamate Receptors
mGluR Metabotropic glutamate receptors mGluR (metabotropic glutamate receptor) is a type of glutamate receptor that are active through an indirect metabotropic process. They are members of thegroup C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatoryneurotransmitter. The mGluRs perform a variety of functions in the central and peripheral nervous systems: mGluRs are involved in learning, memory, anxiety, and the perception of pain. mGluRs are found in pre- and postsynaptic neurons in synapses of the hippocampus, cerebellum, and the cerebral cortex, as well as other parts of the brain and in peripheral tissues. Eight different types of mGluRs, labeled mGluR1 to mGluR8, are divided into groups I, II, and III. Receptor types are grouped based on receptor structure and physiological activity. www.MedChemExpress.com 1 mGluR Agonists, Antagonists, Inhibitors, Modulators & Activators (-)-Camphoric acid (1R,2S)-VU0155041 Cat. No.: HY-122808 Cat. No.: HY-14417A (-)-Camphoric acid is the less active enantiomer (1R,2S)-VU0155041, Cis regioisomer of VU0155041, is of Camphoric acid. Camphoric acid stimulates a partial mGluR4 agonist with an EC50 of 2.35 osteoblast differentiation and induces μM. glutamate receptor expression. Camphoric acid also significantly induced the activation of NF-κB and AP-1. Purity: ≥98.0% Purity: ≥98.0% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10 mM × 1 mL, 100 mg Size: 10 mM × 1 mL, 5 mg, 10 mg, 25 mg (2R,4R)-APDC (R)-ADX-47273 Cat. No.: HY-102091 Cat. No.: HY-13058B (2R,4R)-APDC is a selective group II metabotropic (R)-ADX-47273 is a potent mGluR5 positive glutamate receptors (mGluRs) agonist. -
Dynamic L-Glutamate Signaling in the Prefrontal Cortex and the Effects of Methylphenidate Treatment
University of Kentucky UKnowledge Theses and Dissertations--Neuroscience Neuroscience 2012 DYNAMIC L-GLUTAMATE SIGNALING IN THE PREFRONTAL CORTEX AND THE EFFECTS OF METHYLPHENIDATE TREATMENT Catherine Elizabeth Mattinson University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Mattinson, Catherine Elizabeth, "DYNAMIC L-GLUTAMATE SIGNALING IN THE PREFRONTAL CORTEX AND THE EFFECTS OF METHYLPHENIDATE TREATMENT" (2012). Theses and Dissertations--Neuroscience. 4. https://uknowledge.uky.edu/neurobio_etds/4 This Doctoral Dissertation is brought to you for free and open access by the Neuroscience at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Neuroscience by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained and attached hereto needed written permission statements(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine). I hereby grant to The University of Kentucky and its agents the non-exclusive license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless a preapproved embargo applies. -
Mglur5 Activity Moderates Vulnerability to Chronic Social Stress
Neuropsychopharmacology (2015) 40, 1222–1233 & 2015 American College of Neuropsychopharmacology. All rights reserved 0893-133X/15 www.neuropsychopharmacology.org Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress 1 1 1 1 1 Klaus V Wagner , Jakob Hartmann , Christiana Labermaier , Alexander S Ha¨usl , Gengjing Zhao , 1 1 2 1 1 1 Daniela Harbich , Bianca Schmid , Xiao-Dong Wang , Sara Santarelli , Christine Kohl , Nils C Gassen , 3,4 1 1 1 5 Natalie Matosin , Marcel Schieven , Christian Webhofer , Christoph W Turck , Lothar Lindemann , 6 5 1 1 ,1 Georg Jaschke , Joseph G Wettstein , Theo Rein , Marianne B Mu¨ller and Mathias V Schmidt* 1 2 Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany; Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University 3 School of Medicine, Hangzhou, China; Faculty of Science, Medicine and Health and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia; 4Schizophrenia Research Institute, Sydney NSW, Australia; 5Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology, and Rare Diseases Translational Area (NORD), Basel, Switzerland; 6Roche Pharmaceutical Research and Early Development, Discovery Chemistry, Basel, Switzerland Stress-induced psychiatric disorders, such as depression, have recently been linked to changes in glutamate transmission in the central nervous system. Glutamate signaling is mediated by a range of receptors, including metabotropic glutamate receptors (mGluRs). In particular, mGluR subtype 5 (mGluR5) is highly implicated in stress-induced psychopathology. The major scaffold protein Homer1 critically interacts with mGluR5 and has also been linked to several psychopathologies. -
Aβ Oligomers Induce Sex-Selective Differences in Mglur5 Pharmacology and Pathophysiological Signaling in Alzheimer Mice
bioRxiv preprint doi: https://doi.org/10.1101/803262; this version posted June 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. TITLE: Aβ oligomers induce sex-selective differences in mGluR5 pharmacology and pathophysiological signaling in Alzheimer mice Khaled S. Abd-Elrahman1,2,6,#, Awatif Albaker1,2,7,#, Jessica M. de Souza1,2,8, Fabiola M. Ribeiro8, Michael G. Schlossmacher1,2,3,5, Mario Tiberi1,2,4,5, Alison Hamilton1,2,$ and Stephen S. G. Ferguson1,2,$,* 1University of Ottawa Brain and Mind Institute, 2Departments of Cellular and Molecular Medicine, 3 Medicine, 4Psychiatry, and the 5Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada. 6Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. 7Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 12371, Saudi Arabia 8Department of Biochemistry and Immunology, ICB, Universidade Federalde Minas Gerais, Belo Horizonte, Brazil. #These authors contributed equally $ Co-senior authors ONE-SENTENCE SUMMARY: Aβ/PrPC complex binds to mGluR5 and activates its pathological signaling in male, but not female brain and therefore, mGluR5 does not contribute to the pathology in female Alzheimer’s mice. *Corresponding author Dr. Stephen S. G. Ferguson Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Dr. Ottawa, Ontario, Canada, K1H 8M5. Tel: (613) 562 5800 Ext 8889. [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/803262; this version posted June 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. -
The Effect of Intrahippocampal Injection of Group II and III Metobotropic Glutamate Receptor Agonists on Anxiety; the Role of Neuropeptide Y
Neuropsychopharmacology (2007) 32, 1242–1250 & 2007 Nature Publishing Group All rights reserved 0893-133X/07 $30.00 www.neuropsychopharmacology.org The Effect of Intrahippocampal Injection of Group II and III Metobotropic Glutamate Receptor Agonists on Anxiety; the Role of Neuropeptide Y ´ ,1 1 1 1 Maria Smiałowska* , Joanna M Wieron´ska , Helena Domin and Barbara Zie˛ba 1Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Krako´w, Poland Earlier studies conducted by our group and by other authors indicated that metabotropic glutamatergic receptor (mGluR) ligands might have anxiolytic activity and that amygdalar neuropeptide Y (NPY) neurons were engaged in that effect. Apart from the amygdala, the hippocampus, another limbic structure, also seems to be engaged in regulation of anxiety. It is rich in mGluRs and contains numerous NPY interneurons. In the present study, we investigated the anxiolytic activity of group II and III mGluR agonists after injection into the hippocampus, and attempted to establish whether hippocampal NPY neurons and receptors were engaged in the observed effects. Male Wistar rats were bilaterally microinjected with the group II mGluR agonist (2S,10S,20S)-2-(carboxycyclopropyl)glycine (L-CCG-I), group III mGluR agonist O-Phospho-L-serine (L-SOP), NPY, the Y1 receptor antagonist BIBO 3304, and the Y2 receptor antagonist BIIE 0246 into the CA1 or dentate area (DG). The effect of those compounds on anxiety was tested in the elevated plus-maze. Moreover, the effects of L-CCG-I and L-SOP on the expression of NPYmRNA in the hippocampus were studied using in situ hybridization method. It was found that a significant anxiolytic effect was induced by L-SOP injection into the CA1 region or by L-CCG-I injection into the DG. -
Glutamatergic Regulation of Cognition and Functional Brain Connectivity: Insights from Pharmacological, Genetic and Translational Schizophrenia Research
Title: Glutamatergic regulation of cognition and functional brain connectivity: insights from pharmacological, genetic and translational schizophrenia research Authors: Dr Maria R Dauvermann (1,2) , Dr Graham Lee (2) , Dr Neil Dawson (3) Affiliations: 1. School of Psychology, National University of Ireland, Galway, Galway, Ireland 2. McGovern Institute for Brain Research, Massachusetts Institute of Technology, 77 Massachusetts Ave, Cambridge, MA, 02139, USA 3. Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK Abstract The pharmacological modulation of glutamatergic neurotransmission to improve cognitive function has been a focus of intensive research, particularly in relation to the cognitive deficits seen in schizophrenia. Despite this effort there has been little success in the clinical use of glutamatergic compounds as procognitive drugs. Here we review a selection of the drugs used to modulate glutamatergic signalling and how they impact on cognitive function in rodents and humans. We highlight how glutamatergic dysfunction, and NMDA receptor hypofunction in particular, is a key mechanism contributing to the cognitive deficits observed in schizophrenia, and outline some of the glutamatergic targets that have been tested as putative procognitive targets for the disorder. Using translational research in this area as a leading exemplar, namely models of NMDA receptor hypofunction, we discuss how the study of functional brain network connectivity can provide new insight -
Development of Allosteric Modulators of Gpcrs for Treatment of CNS Disorders Hilary Highfield Nickols A, P
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Neurobiology of Disease 61 (2014) 55–71 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi Review Development of allosteric modulators of GPCRs for treatment of CNS disorders Hilary Highfield Nickols a, P. Jeffrey Conn b,⁎ a Division of Neuropathology, Department of Pathology, Microbiology and Immunology, Vanderbilt University, USA b Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA article info abstract Article history: The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy Received 25 July 2013 with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Tradition- Revised 13 September 2013 al drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind en- Accepted 17 September 2013 dogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor Available online 27 September 2013 function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than Keywords: Allosteric modulator orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological CNS modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with pos- Drug discovery itive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as “bitopic” ligands that GPCR interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug Metabotropic glutamate receptor selectivity and potentially decreased adverse side effects. -
Acamprosate in the Treatment of Binge Eating Disorder: a Placebo-Controlled Trial
CE ACTIVITY Acamprosate in the Treatment of Binge Eating Disorder: A Placebo-Controlled Trial Susan L. McElroy, MD1* ABSTRACT obsessive-compulsiveness of binge eat- 1 Objective: To assess preliminarily the ing, food craving, and quality of life. Anna I. Guerdjikova, PhD effectiveness of acamprosate in binge Among completers, weight and BMI 1 Erin L. Winstanley, PhD eating disorder (BED). decreased slightly in the acamprosate 1 group but increased in the placebo Anne M. O’Melia, MD Method: In this 10-week, randomized, 1 group. Nicole Mori, CNP placebo-controlled, flexible dose trial, 40 1 Jessica McCoy, BA outpatients with BED received acampro- Discussion: Although acamprosate did Paul E. Keck Jr., MD1 sate (N 5 20) or placebo (N 5 20). The not separate from placebo on any out- James I. Hudson, MD, ScD2 primary outcome measure was binge eat- come variable in the longitudinal analy- ing episode frequency. sis, results of the endpoint and completer analyses suggest the drug may have Results: While acamprosate was not some utility in BED. VC 2010 by Wiley associated with a significantly greater Periodicals, Inc. rate of reduction in binge eating episode frequency or any other measure in the Keywords: acamprosate; binge eating primary longitudinal analysis, in the end- disorder; obesity; glutamate point analysis it was associated with stat- istically significant improvements in binge day frequency and measures of (Int J Eat Disord 2011; 44:81–90) Introduction The treatment of BED remains a challenge.5 Cogni- tive behavioral and interpersonal therapies and selec- Binge eating disorder (BED), characterized by recur- tive serotonin-reuptake inhibitor (SSRI) antidepres- rent binge-eating episodes without inappropriate sants are effective for reducing binge eating, but usu- 1 compensatory weight loss behaviors, is an impor- ally are not associated with clinically significant tant public health problem. -
GPCR/G Protein
Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com GPCR/G Protein G Protein Coupled Receptors (GPCRs) perceive many extracellular signals and transduce them to heterotrimeric G proteins, which further transduce these signals intracellular to appropriate downstream effectors and thereby play an important role in various signaling pathways. G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). In unstimulated cells, the state of G alpha is defined by its interaction with GDP, G beta-gamma, and a GPCR. Upon receptor stimulation by a ligand, G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell. These effects include activating the MAPK and PI3K pathways, as well as inhibition of the Na+/H+ exchanger in the plasma membrane, and the lowering of intracellular Ca2+ levels. Most human GPCRs can be grouped into five main families named; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secretin, forming the GRAFS classification system. A series of studies showed that aberrant GPCR Signaling including those for GPCR-PCa, PSGR2, CaSR, GPR30, and GPR39 are associated with tumorigenesis or metastasis, thus interfering with these receptors and their downstream targets might provide an opportunity for the development of new strategies for cancer diagnosis, prevention and treatment. At present, modulators of GPCRs form a key area for the pharmaceutical industry, representing approximately 27% of all FDA-approved drugs. References: [1] Moreira IS. Biochim Biophys Acta. 2014 Jan;1840(1):16-33. -
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