DOCSLIB.ORG

Translocator Protein 18 Ligand Emapunil Protects Against

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Translocator Protein 18 Ligand Emapunil Protects Against Translocator protein 18 ligand Emapunil protects against neurodegeneration in the MPTP mouse model of Parkinsonism Dissertation for the award of the degree “Doctor rerum naturalium” (Dr.rer.nat) of the Georg-August-Universität Göttingen within the doctoral program in Biology of the Georg-August University School of Science (GAUSS) submitted by Jing Gong from Hubei, China Göttingen, 2019 Members of the Thesis Committee: Prof. Dr. Tiago Fleming Outeiro (Reviewer) Department of Experimental Neurodegeneration, University Medical Center Göttingen Prof. Dr. Gerhard Braus (Reviewer) Department of Microbiology and Genetics, Georg-August-Universität Göttingen Prof. Dr. Anja Schneider Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn German Center for Neurodegenerative Diseases (DZNE), Bonn Members of the Examination Board: Members of the Thesis Committee and Prof. Dr. Markus Zweckstetter Structure determination using NMR, Max Planck Institute for Biophysical Chemistry, Göttingen German Center for Neurodegenerative Diseases (DZNE), Göttingen Prof. Dr. André Fischer Department of Psychiatry and Psychotherapy, University Medical Center Göttingen German Center for Neurodegenerative Diseases (DZNE), Göttingen Prof. Dr. Dr. Hannelore Ehrenreich Department of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen Date of the oral examination 02. 07. 2019 i Affidavit I hereby declare that I have written my doctoral thesis entitled “Translocator protein 18 ligand Emapunil protects against neurodegeneration in the MPTP mouse model of Parkinsonism” independently with no other sources and aids than quoted. Bonn Jing Gong 21. 03. 2019 ii Contents 1 Introduction .......................................................................................................... 1 1.1 Parkinson disease (PD) ............................................................................................................. 1 1.1.1 Milestones of PD research ............................................................................................................. 1 1.1.2 Epidemiology ................................................................................................................................. 2 1.1.3 Neuropathology.............................................................................................................................. 3 1.1.4 Genetic risk factors of PD .............................................................................................................. 4 1.1.5 α-Synuclein pathology in PD ......................................................................................................... 5 1.1.6 Endoplasmic reticulum (ER) stress and response in PD ................................................................ 6 1.2 Neuroinflammation in PD ......................................................................................................... 8 1.2.1 Microglia origins ............................................................................................................................ 8 1.2.2 Resting microglia ........................................................................................................................... 8 1.2.3 Activated Microglia phenotypes .................................................................................................... 9 1.2.3.1 The M1 phenotype ............................................................................................................................. 9 1.2.3.2 M2 phenotypes ................................................................................................................................. 11 1.2.4 Microglia activation in PD ........................................................................................................... 13 1.2.5 Therapeutic manipulation of microglia in PD .............................................................................. 15 1.3 Animal models of Parkinson’s disease ................................................................................... 18 1.3.1 The MPTP mouse model of Parkinsonism .................................................................................. 19 1.3.1.1 Mechanisms of MPTP ...................................................................................................................... 19 1.3.1.2 Acute versus subacute and chronic MPTP models .......................................................................... 20 1.3.1.3 Behavior phenotypes in MPTP models ............................................................................................ 22 1.3.1.4 Advantages and disadvantages of MPTP model .............................................................................. 22 1.4 Translocator protein 18 (TSPO) .............................................................................................. 24 1.4.1 TSPO distribution and function ................................................................................................... 24 1.4.1.1 Role in cholesterol transport ............................................................................................................ 25 1.4.1.2 Other functions of TSPO ................................................................................................................. 26 1.4.2 TSPO structure ............................................................................................................................. 26 1.4.3 TSPO ligands ............................................................................................................................... 28 1.4.3.1 Endogenous ligands of TSPO .......................................................................................................... 28 1.4.3.2 Synthetic ligands of TSPO ............................................................................................................... 30 1.4.4 TSPO radiotracers applied in PD ................................................................................................. 32 1.4.5 TSPO ligands have therapeutic effects in neurodegenerative diseases ........................................ 33 2 Materials and Methods ...................................................................................... 35 2.1 Materials .................................................................................................................................. 35 iii 2.1.1 Chemicals and consumables ........................................................................................................ 35 2.1.2 Buffer solutions ............................................................................................................................ 36 2.1.3 Commercial reagents, compounds and consumables ................................................................... 38 2.1.4 Cell culture medium ..................................................................................................................... 39 2.1.4.1 Proliferation medium components ................................................................................................... 39 2.1.4.2 Differentiation medium components................................................................................................ 39 2.1.5 Commercial kits ........................................................................................................................... 39 2.1.6 Primers ......................................................................................................................................... 40 2.1.7 Antibodies .................................................................................................................................... 41 2.1.8 Software ....................................................................................................................................... 42 2.2 Methods ................................................................................................................................... 42 2.2.1 The experimental schedule .......................................................................................................... 42 2.2.1.1 Subacute MPTP treatment ............................................................................................................... 43 2.2.1.2 Emapunil treatment .......................................................................................................................... 43 2.2.1.3 Experimental procedure ................................................................................................................... 43 2.2.2 MPTP metabolism ....................................................................................................................... 44 2.2.3 RT-qPCR ..................................................................................................................................... 44 2.2.3.1 RNA extraction ................................................................................................................................ 44 2.2.3.2 cDNA synthesis ............................................................................................................................... 45 2.2.3.3 RT-qPCR amplification ................................................................................................................... 45 2.2.4 Behavioral tests ............................................................................................................................ 46
Load more

Recommended publications
  • Présentation HJ
    Conflits d’intérêts Astra-Zeneca, Janssen, Abacus international, Laboratoire ETAP, Institut Pasteur. Dr Hervé JAVELOT Pharmacien PH Etablissement Public de Santé Alsace Nord Service Pharmacie 141 avenue de Strasbourg 67 170 BRUMATH Tél. : 03 88 64 61 70 Fax : 03 88 64 61 58 Mail : [email protected] Perspectives dans la psychopharmacologie de l’anxiété et de la dépression Hervé JAVELOT Etablissement Public de Santé Alsace Nord Perspectives dans la psychopharmacologie de l’anxiété et de la dépression Traitements des troubles anxio-dépressifs. Les perspectives. ◦ L’axe GABAergique…éternellement prometteur ? ◦ L’incontournable théorie « monoaminergique »… ◦ Des théories alternatives à suivre … Traitements des troubles anxio-dépressifs. Contexte : ◦ XXI ème siècle : Le « siècle de la dépression » s’installe ? (Hardeveld et al., 2010) L’« ère de l’angoisse » s’affirme ? (Auden, 1947) ◦ Prévalence au cours de la vie : 16 à 17% pour la dépression, 17 à 18% pour les troubles anxieux Co-morbidité des 2 troubles dans 20 à 40% des cas (Antony, 2011 ; Depping et al., 2010 ; Hardeveld et al., 2010 ; Huppert, 2009) Auden WH (1947). The Age of Anxiety: A Baroque Eclogue. Random House: New York. Hardeveld F, Spijker J, De Graaf R, Nolen WA, Beekman AT. Prevalence and predictors of recurrence of major depressive disorder in the adult population. Acta Psychiatr Scand. 2010;122(3):184-91. Antony MM. Recent advances in the treatment of anxiety disorders. Canadian Psychology 2011;52(1), 10-19. Depping AM, Komossa K, Kissling W, Leucht S. Second-generation antipsychotics for anxiety disorders. Cochrane Database Syst Rev. 2010;(12):CD008120. Huppert JD. Anxiety disorders and depression comorbidity.
    [Show full text]
  • WO 2015/072852 Al 21 May 2015 (21.05.2015) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/072852 Al 21 May 2015 (21.05.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 36/84 (2006.01) A61K 31/5513 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/045 (2006.01) A61P 31/22 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/522 (2006.01) A61K 45/06 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, PCT/NL20 14/050780 KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (22) International Filing Date: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 13 November 2014 (13.1 1.2014) PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (25) Filing Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 61/903,430 13 November 2013 (13. 11.2013) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicant: RJG DEVELOPMENTS B.V.
    [Show full text]
  • Stems for Nonproprietary Drug Names
    USAN STEM LIST STEM DEFINITION EXAMPLES -abine (see -arabine, -citabine) -ac anti-inflammatory agents (acetic acid derivatives) bromfenac dexpemedolac -acetam (see -racetam) -adol or analgesics (mixed opiate receptor agonists/ tazadolene -adol- antagonists) spiradolene levonantradol -adox antibacterials (quinoline dioxide derivatives) carbadox -afenone antiarrhythmics (propafenone derivatives) alprafenone diprafenonex -afil PDE5 inhibitors tadalafil -aj- antiarrhythmics (ajmaline derivatives) lorajmine -aldrate antacid aluminum salts magaldrate -algron alpha1 - and alpha2 - adrenoreceptor agonists dabuzalgron -alol combined alpha and beta blockers labetalol medroxalol -amidis antimyloidotics tafamidis -amivir (see -vir) -ampa ionotropic non-NMDA glutamate receptors (AMPA and/or KA receptors) subgroup: -ampanel antagonists becampanel -ampator modulators forampator -anib angiogenesis inhibitors pegaptanib cediranib 1 subgroup: -siranib siRNA bevasiranib -andr- androgens nandrolone -anserin serotonin 5-HT2 receptor antagonists altanserin tropanserin adatanserin -antel anthelmintics (undefined group) carbantel subgroup: -quantel 2-deoxoparaherquamide A derivatives derquantel -antrone antineoplastics; anthraquinone derivatives pixantrone -apsel P-selectin antagonists torapsel -arabine antineoplastics (arabinofuranosyl derivatives) fazarabine fludarabine aril-, -aril, -aril- antiviral (arildone derivatives) pleconaril arildone fosarilate -arit antirheumatics (lobenzarit type) lobenzarit clobuzarit -arol anticoagulants (dicumarol type) dicumarol
    [Show full text]
  • Translocator Protein (TSPO): the New Story of the Old Protein in Neuroinflammation
    BMB Rep. 2020; 53(1): 20-27 BMB www.bmbreports.org Reports Invited Mini Review Translocator protein (TSPO): the new story of the old protein in neuroinflammation Younghwan Lee1, Youngjin Park1, Hyeri Nam1, Ji-Won Lee1 & Seong-Woon Yu1.2,* 1Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, 2Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea Translocator protein (TSPO), also known as peripheral Mitochondrial membrane proteins are the important regulators benzodiazepine receptor, is a transmembrane protein located of mitochondrial homeostasis, such as ion transport, ATP/ADP on the outer mitochondria membrane (OMM) and mainly transport, and mitochondria fusion/fission. Therefore, defects expressed in glial cells in the brain. Because of the close in these proteins are associated with numerous diseases (4). correlation of its expression level with neuropathology and For this reason, mitochondrial membrane proteins are therapeutic efficacies of several TSPO binding ligands under considered to be promising targets for development of diagnostic many neurological conditions, TSPO has been regarded as tools and therapeutic strategies. TSPO is the mitochondrial both biomarker and therapeutic target, and the biological transmembrane protein that was discovered as the binding site functions of TSPO have been a major research focus. of benzodiazepine in 1977 (5). Studies using TSPO-binding However, recent genetic studies with animal and cellular ligands have revealed that this protein participates in a variety models revealed unexpected results contrary to the anticipated of cellular functions, including cholesterol transport and biological importance of TSPO and cast doubt on the action steroid hormone synthesis, mitochondrial permeability transition modes of the TSPO-binding drugs.
    [Show full text]
  • WO 2015/072853 Al 21 May 2015 (21.05.2015) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/072853 Al 21 May 2015 (21.05.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 45/06 (2006.01) A61K 31/5513 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/045 (2006.01) A61K 31/5517 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/522 (2006.01) A61P 31/22 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/551 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/NL20 14/050781 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 13 November 2014 (13.1 1.2014) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 61/903,433 13 November 2013 (13.
    [Show full text]
  • TSPO) Ligands and Benzodiazepines
    Original Paper Phpsy/2014-08-0369/3.2.2015/MPS Enhancing Neurosteroid Synthesis – Relationship to the Pharmacology of Translocator Protein (18 kDa) (TSPO) Ligands and Benzodiazepines Authors L. Wolf1, A. Bauer1, D. Melchner1, H. Hallof-Buestrich1, P. Stoertebecker1, E. Haen1, 2, M. Kreutz3, N. Sarubin1, V. M. Milenkovic1, C. H. Wetzel1, R. Rupprecht1, C. Nothdurfter1 Affiliations 1 Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany 2 Institute of Pharmacy, University of Regensburg, Regensburg, Germany 3 Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany Key words Abstract Results: In BV-2 microglia and C6 glioma cells ●▶ TSPO ligands ▼ all compounds significantly enhanced TSPO ●▶ benzodiazepines Introduction: The treatment of anxiety dis- protein expression. Radioligand binding assays ●▶ pregnenolone orders is still a challenge; novel pharmacologi- revealed the highest binding affinity to TSPO ●▶ neurosteroids cal approaches that combine rapid anxiolytic for XBD173, followed by diazepam and etifox- ●▶ anxiolytic efficacy with fewer side effects are needed. A ine. Pregnenolone synthesis was most potently promising target for such compounds is the mito- enhanced by etifoxine. chondrial translocator protein (18 kDa) (TSPO). Discussion: Etifoxine turned out to be the TSPO plays an important role for the synthesis of most potent enhancer of neurosteroidogenesis, neurosteroids, known to modulate GABAA recep- although its binding affinity to TSPO was lowest. tors, thereby exerting anxiolytic effects. These results indicate that the efficacy of TSPO Methods: We investigated the pharmacological ligands to stimulate neurosteroid synthesis, profile of 2 well established TSPO ligands (XBD173 thereby leading to anxiolytic effects cannot be and etifoxine) compared to the benzodiazepine concluded from their binding affinity to TSPO.
    [Show full text]
  • Download Product Insert (PDF)
    PRODUCT INFORMATION AC-5216 Item No. 18522 CAS Registry No.: 226954-04-7 Formal Name: N-ethyl-7,8-dihydro-7-methyl-8- N oxo-2-phenyl-N-(phenylmethyl)- N 9H-purine-9-acetamide Synonyms: Emapunil, XBD-173 N O N MF: C23H23N5O2 401.5 FW: O Purity: ≥98% Stability: ≥2 years at -20°C N Supplied as: A crystalline solid UV/Vis.: λmax: 292 nm Laboratory Procedures For long term storage, we suggest that AC-5216 be stored as supplied at -20°C. It should be stable for at least two years. AC-5216 is supplied as a crystalline solid. A stock solution may be made by dissolving the AC-5216 in the solvent of choice. AC-5216 is soluble in organic solvents such as DMSO and dimethyl formamide (DMF), which should be purged with an inert gas. The solubility of AC-5216 in these solvents is approximately 5 and 30 mg/ml, respectively. AC-5216 is sparingly soluble in aqueous buffers. For maximum solubility in aqueous buffers, AC-5216 should first be dissolved in DMF and then diluted with the aqueous buffer of choice. AC-5216 has a solubility of approximately 0.05 mg/ml in a 1:20 solution of DMF:PBS (pH 7.2) using this method. We do not recommend storing the aqueous solution for more than one day. Description AC-5216 is a high affinity agonist of the 18 kDa translocator protein (TSPO, previously called the peripheral benzodiazepine receptor) that exhibits a Ki value of 0.297 nM in rat whole brain and IC50 values of 2.73 and 3.04 nM, respectively, against human and rat glial TSPO.1 AC-5216 produces anxiolytic and antidepressant effects in various animal models, without inducing benzodiazepine-like adverse effects.1,2 References 1.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,158,152 B2 Palepu (45) Date of Patent: Apr
    US008158152B2 (12) United States Patent (10) Patent No.: US 8,158,152 B2 Palepu (45) Date of Patent: Apr. 17, 2012 (54) LYOPHILIZATION PROCESS AND 6,884,422 B1 4/2005 Liu et al. PRODUCTS OBTANED THEREBY 6,900, 184 B2 5/2005 Cohen et al. 2002fOO 10357 A1 1/2002 Stogniew etal. 2002/009 1270 A1 7, 2002 Wu et al. (75) Inventor: Nageswara R. Palepu. Mill Creek, WA 2002/0143038 A1 10/2002 Bandyopadhyay et al. (US) 2002fO155097 A1 10, 2002 Te 2003, OO68416 A1 4/2003 Burgess et al. 2003/0077321 A1 4/2003 Kiel et al. (73) Assignee: SciDose LLC, Amherst, MA (US) 2003, OO82236 A1 5/2003 Mathiowitz et al. 2003/0096378 A1 5/2003 Qiu et al. (*) Notice: Subject to any disclaimer, the term of this 2003/OO96797 A1 5/2003 Stogniew et al. patent is extended or adjusted under 35 2003.01.1331.6 A1 6/2003 Kaisheva et al. U.S.C. 154(b) by 1560 days. 2003. O191157 A1 10, 2003 Doen 2003/0202978 A1 10, 2003 Maa et al. 2003/0211042 A1 11/2003 Evans (21) Appl. No.: 11/282,507 2003/0229027 A1 12/2003 Eissens et al. 2004.0005351 A1 1/2004 Kwon (22) Filed: Nov. 18, 2005 2004/0042971 A1 3/2004 Truong-Le et al. 2004/0042972 A1 3/2004 Truong-Le et al. (65) Prior Publication Data 2004.0043042 A1 3/2004 Johnson et al. 2004/OO57927 A1 3/2004 Warne et al. US 2007/O116729 A1 May 24, 2007 2004, OO63792 A1 4/2004 Khera et al.
    [Show full text]
  • Research Article
    Available Online at http://www.recentscientific.com International Journal of CODEN: IJRSFP (USA) Recent Scientific International Journal of Recent Scientific Research Research Vol. 9, Issue, 6(E), pp. 27560-27565, June, 2018 ISSN: 0976-3031 DOI: 10.24327/IJRSR Research Article BIOSYNTHESIS OF NEUROSTEROID AND PHARMACOLOGYCAL ACTION Vandna Dewangan*., Trilochan Satapthy and Ram Sahu Department of Pharmacology, Columbia Institute of Pharmacy, Tekari, Near Vidhansabha, Raipur-493111(C.G.) India DOI: http://dx.doi.org/10.24327/ijrsr.2018.0906.2285 ARTICLE INFO ABSTRACT Article History: Over the past decade, it has become clear that the brain, like the gonad, adrenal and placenta, is a steroid genic organ. Neurosteroids are synthetized in the central and the peripheral nervous system, Received 20th March, 2018 in glial cells, and also in neurons, from cholesterol or steroidal precursors imported from peripheral Received in revised form 27th sources. However, unlike classic steroid genic tissues, the synthesis of steroids in the nervous April, 2018 system requires the coordinate expression and regulation of the genes encoding the steroid genic Accepted 5th May, 2018 enzymes in several different cell types (neurons and glia) at different locations in the nervous Published online 28th June, 2018 system, and at distances from the cell bodies. The steroids synthesized by the brain and nervous system, given the name neurosteroids Progesterone itself is also a neurosteroid, and a progesterone Key Words: receptor has been detected in peripheral and central glial cells. At different sites in the brain, Neurosteroid, Steroid hormones, neurosteroid concentrations vary according to environmental and behavioural circumstances, such as Progesterone, Glial Cell, Nuclear receptor, stress, sex recognition, or aggressiveness.
    [Show full text]
  • Characterization of Tspo 18 Kda
    CHARACTERIZATION OF TSPO 18 KDA IN NEUROSTEROID SYNTHESIS AND MITOCHONDRIAL METABOLISM CHARAKTERISIERUNG VON TSPO 18 KDA IN DER NEUROSTEROIDSYNTHESE UND DEM MITOCHONDRIALEN STOFFWECHSEL DISSERTATION ZUR ERLANGUNG DES DOKTORGRADES DER NATURWISSENSCHAFTEN (DR. RER. NAT.) DER NATURWISSENSCHAFTLICHEN FAKULTÄT IV CHEMIE UND PHARMAZIE DER UNIVERSITÄT REGENSBURG vorgelegt von Luisa Scheck, geb. Wolf aus Schmalkalden im Februar 2017 Promotionsgesuch eingereicht am: 24. Februar 2017 Die Arbeit wurde angeleitet von: Prof. Dr. med. Dr. rer. nat. Ekkehard Haen Table of contents ACKNOWLEDGEMENTS .................................................................................................. 1 ABSTRACT ................................................................................................................... 2 TRANSLATION OF THE ABSTRACT (GERMAN) .................................................................. 4 1 TSPO 18KDA - A CONTROVERSIAL PROTEIN OF THE OMM ....................................... 6 1.1 Expression of TSPO ...................................................................................... 6 1.2 TSPO structure and resulting functions ......................................................... 7 1.3 Recent TSPO structure ................................................................................. 8 1.4 TSPO ligands ................................................................................................ 9 2 NEW PERSPECTIVES FOR TSPO ..........................................................................
    [Show full text]
  • The Agonistic TSPO Ligand XBD173 Attenuates the Glial Response
    Mages et al. Journal of Neuroinflammation (2019) 16:43 https://doi.org/10.1186/s12974-019-1424-5 RESEARCH Open Access The agonistic TSPO ligand XBD173 attenuates the glial response thereby protecting inner retinal neurons in a murine model of retinal ischemia Kristin Mages1, Felix Grassmann1,2, Herbert Jägle3, Rainer Rupprecht4, Bernhard H. F. Weber1, Stefanie M. Hauck5 and Antje Grosche1,6* Abstract Background: Ligand-driven modulation of the mitochondrial translocator protein 18 kDa (TSPO) was recently described to dampen the neuroinflammatory response of microglia in a retinal light damage model resulting in protective effects on photoreceptors. We characterized the effects of the TSPO ligand XBD173 in the postischemic retina focusing on changes in the response pattern of the major glial cell types of the retina—microglia and Müller cells. Methods: Retinal ischemia was induced by increasing the intraocular pressure for 60 min followed by reperfusion of the tissue in mice. On retinal cell types enriched via immunomagnetic separation expression analysis of TSPO, its ligand diazepam-binding inhibitor (DBI) and markers of glial activation were performed at transcript and protein level using RNA sequencing, qRT-PCR, lipid chromatography-mass spectrometry, and immunofluorescent labeling. Data on cell morphology and numbers were assessed in retinal slice and flatmount preparations. The retinal functional integrity was determined by electroretinogram recordings. Results: We demonstrate that TSPO is expressed by Müller cells, microglia, vascular cells, retinal pigment epithelium (RPE) of the healthy and postischemic retina, but only at low levels in retinal neurons. While an alleviated neurodegeneration upon XBD173 treatment was found in postischemic retinae as compared to vehicle controls, this neuroprotective effect of XBD173 is mediated putatively by its action on retinal glia.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,980,887 B2 Yang Et Al
    US00898O887B2 (12) United States Patent (10) Patent No.: US 8,980,887 B2 Yang et al. (45) Date of Patent: Mar. 17, 2015 (54) 2-ARYL Trapanietal, J. Med. Chem. 2005, 48,292-305.* IMIDAZO 1.2-APYRIDINE-3-ACETAMIDE Supplementary European Search Report dated Oct. 23, 2013 PCT/ DERIVATIVES, PREPARATION METHODS CN2011075500 in corresponding application. AND USES THEREOF S. Paul, et al., "Zinc Medicated Friedel-Crafts Acylation in Solvent Free Conditions Under Microwave Irradiation' Synthesis 2003, No. 18, pp. 2877-2881. (75) Inventors: Rifang Yang, Beijing (CN); Yunfeng Li, G. Trapani, et al., Structure-Activity Relationships and Effects on Beijing (CN); Yongzhen Li, Beijing Neuroactive Steroid Synthesis in a Series of 2-Phenylimidazo[1,2-C. (CN); Nan Zhao, Beijing (CN); Pyridineacetamide Peripheral Benzodiazepine Receptors Ligands, Liuhong Yun, Beijing (CN), Juanjuan Journal of Medicinal Chemistry, 2005, vol. 48, No. 1. Published Dec. Qin, Beijing (CN); Zhongyao Feng, 13, 2004, pp. 292-305. Beijing (CN); Youzhi Zhang, Beijing Papadopoulos V. et al., “Translocator protein (18kDa): new nomen (CN) clature for the peripheral-type benzodiazepine receptor based on its structure and molecular function.” Trends in Pharmacological Sci (73) Assignees: Institute of Pharmacology, Beijing ence, vol. 27, No. 8, p. 402-409 (2006). (CN); Toxicology Academy of Military Scarf A.M. et al., “The translocator protein (18 kDa): central nervous Medical Sciences P.L.A., China, system disease and drug design.” Journal of Medicinal Chemistry, Beijing (CN) vol. 52, No. 3, p. 581-592 (2009). Li Y. et al., Synthesis and anxiolytic effects of 2-aryl imidazo[1,2-a (*) Notice: Subject to any disclaimer, the term of this pyridine-3-acetamide derivatives, Journal of International Pharma patent is extended or adjusted under 35 ceutical Research, vol.
    [Show full text]