DOCSLIB.ORG

Investigating the Central Role of Astrocytes in Mediating Postanesthetic Memory Deficits

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Investigating the Central Role of Astrocytes in Mediating Postanesthetic Memory Deficits Investigating the Central Role of Astrocytes in Mediating Postanesthetic Memory Deficits by Kirusanthy Kaneshwaran A thesis submitted in conformity with the requirements for the degree of Master in Science Department of Physiology University of Toronto © Copyright by Kirusanthy Kaneshwaran 2017 Investigating the Central Role of Astrocytes in Mediating Postanesthetic Memory Deficits Kirusanthy Kaneshwaran Master of Science Department of Physiology University of Toronto 2017 Abstract Anesthetics cause postanesthetic memory deficits in animal models, and similar deficits may contribute to postoperative delirium and cognitive dysfunction in patients. We previously showed using a mouse model that etomidate-induced persistent memory deficits result from increased tonic GABAA receptor-mediated inhibitory current in the hippocampus, through an astrocyte-mediated mechanism. However, the underlying mechanisms are uncertain. The aims of this study were to: 1) determine whether widely used anesthetic and sedative agents persistently increase tonic GABAA current; 2) determine whether human astrocytes mediate the increase, and 3) identify the underlying mechanisms. The results show that several GABAergic drugs persistently increase tonic current and human astrocytes release soluble factors that mediate etomidate’s effect on tonic current. Furthermore, etomidate and sevoflurane act through astrocytic GABAA receptors to trigger a pro-inflammatory signaling pathway, which underlies the persistent increase in tonic current. These results increase the mechanistic understanding of postanesthetic memory deficits and delineate treatment targets. ii Acknowledgements During the past two years I have undergone immense growth as a researcher and more importantly, as an individual. I have been privileged enough to be surrounded by wonderful people who have supported me and encouraged me in all my endeavors, research-related and otherwise. I would like to thank my supervisor, Dr. Beverley Orser for your immense support and guidance. You have offered me pearls of wisdom pertaining to not only research, but also life. I strive to be as strong and inspiring a woman as you are in my future. Until then “I will fake it, till I become it”. Thank you for giving me this opportunity to work with amazing individuals and hone my research skills. I also thank the members of my Advisory Committee, Dr. Rob Bonin and Dr. Richard Horner for your time, support, excellent advice (and reference letters upon short notice!). Your advice has really helped me develop my ideas and realize that there is still so much to learn. You have helped me develop a love for learning through example. I would also like to thank Dr. Richard Horner for providing me with an important learning experience as a TA. I would like to convey my sincerest gratitude to the entire Orser Lab. Thank you Dr. Sinziana Avramescu for being my “laboratory mom”: giving me hugs when I needed them most, listening to my worries, sharing my happiness, supporting me even when I was at my worst, and so much more. My gratitude cannot be put in to words. You were everything I needed: a caring friend, an incredible mentor, an inspiring researcher, etc.. Thank you Dr. Dian-Shi Wang, for being one of the best teachers I have had in my life! Your guidance has really helped me improve my critical thinking, organizational, and even technical and math skills! Thank you Dr. Irene Lecker for giving me some of the best advice I have ever received and for supporting me throughout this phase of my life. Thank you Fariya Mostafa for being an incredible friend. I have become a better person through our friendship, and I hope to one day be as kind and caring an individual as you are. I am extremely grateful that you were with me iii through the majority of these past two years: as a fellow laboratory mate to discuss experiments and results, as a friend to share both sad and happy things alike, and as an older sister who gave me incredible advice and support. Thank you Dr. Shelly Au, for being a great friend, listening to my worries and teaching me about life. Thank you Shahin for being my rock, inspiring me to have a love for science and helping me out whenever I needed it. Thank you Nathan Chan for being my ray of sunshine! Thank you Agnes Crnic for being you! Your great humor, Microsoft Word and PowerPoint skills, and friendship have made my life significantly more enjoyable! Also, thank you to everyone who has been a part of the lab: Michael, Alejandro, Dr. Gang Lei, Dr. Junhui Wang, Dr. Yu Feng Xia, Sean Haffey and Dr. Agnes Zurek. I am extremely privileged to have worked with you in the last two years. I would also like to thank all my fellow Physiology graduate students and GASP (Melanie, Ankur, Hanna, Susmita, Farwah, Vivian, Feiya…), who have given me valuable experiences and tolerated my craziness. Last but not least, I would like to thank my family, who has provided me with immense support during the past two years. Thank you for tolerating me when I was at my worst, keeping me humble when I was at my best, and supporting and encouraging me whenever I needed it. Thank you Appa for listening to me talk about science and life during our car rides and giving me your opinion and advice. Thank you Amma for listening to me ramble and vent and supporting me in all that I do. I can never repay you for all that you do for me, and I sincerely value every little thing that you do to make my life better. Thank you Guhaverl and Lokeesan for letting me burrow your stuff and take up your time. These two years have been the best years of my life thanks to you, and I will cherish my relationship with all of you and the experiences we have had together as precious memories for the rest of my life! iv List of Contributions Kirusanthy Kaneshwaran produced all of the results and content of this thesis except those listed below. The electrophysiological data presented in Figure 4.1 were collected with the help of Ms. Fariya Mostafa, Dr. Sinziana Avramescu, Dr. Irene Lecker, and Dr. Dianshi Wang. They contributed to the recording of tonic current in neurons using different anesthetics. Also, in Chapter 5, Dr. Sinziana Avramescua and Dr. Irene Lecker contributed recordings from neurons for data presented in Figure 5.1C, and Mr. Sean Haffey provided data for Figures 5.3B and 5.4A. This work was completed with the financial support from a Kirk Weber Graduate Award provided by the Department of Anesthesia, Sunnybrook Health Sciences Centre and an Ontario Graduate Scholarship. v Table of Contents Abstract ............................................................................................................................................. ii Acknowledgements .......................................................................................................................... iii List of Contributions .......................................................................................................................... v Table of Contents ............................................................................................................................. vi List of Figures ................................................................................................................................. viii List of Abbreviations ........................................................................................................................ ix Chapter 1. Thesis overview ............................................................................................................... 1 1.1. Rationale ................................................................................................................... 1 1.2. Hypothesis and specific aims .................................................................................... 6 1.3. Thesis structure ......................................................................................................... 9 Chapter 2. General Introduction ..................................................................................................... 11 2.1. Postoperative delirium and cognitive dysfunction ................................................. 11 2.1.1. Defining postoperative delirium and POCD ................................................ 11 2.1.2. Incidence ............................................................................................. 12 2.1.3. Effects on patient outcomes ....................................................................... 14 2.1.4. Risk factors and potential causes of postoperative delirium and POCD in patients ............................................................................................. 15 2.2. Cognitive deficits after anesthesia in animal models ............................................. 19 2.2.1. Evidence in the literature ............................................................................ 19 2.2.2. Proposed mechanisms of postanesthetic cognitive deficits in animals ...... 20 2.3. GABA and GABAA receptors-mediated inhibition ................................................... 24 2.3.1. GABA: synthesis, release, transport and metabolism ................................. 24 2.3.2. Overview of GABA receptors ...................................................................... 26 2.3.3. GABAA receptors mediated inhibition ........................................................ 27 2.3.4. GABAA receptors antagonists (bicuculline) ................................................. 31 2.3.5. Subunit composition
Load more

Recommended publications
  • Immunomodulation: a Broad Perspective for Patients' Survival of COVID-19 Infection
    European Journal ISSN 2449-8955 Review Article of Biological Research DOI: http://dx.doi.org/10.5281/zenodo.3956771 Immunomodulation: a broad perspective for patients’ survival of COVID-19 infection Covenant Femi Adeboboye, Babayemi Olawale Oladejo*, Tinuola Tokunbo Adebolu Department of Microbiology, Federal University of Technology, P.M.B. 704, Akure, Nigeria *Correspondence: Tel: +2349042422526; E-mail: [email protected] Received: 28 May 2020; Revised submission: 15 July 2020; Accepted: 22 July 2020 http://www.journals.tmkarpinski.com/index.php/ejbr Copyright: © The Author(s) 2020. Licensee Joanna Bródka, Poland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/) ABSTRACT: The pathogenesis of the SARS-CoV-2 virus is yet to be well understood. However, patients with the virus show clinical manifestations which are very similar to those of SARS-CoV and MERS-CoV. This and other scientific findings reveal that acute respiratory distress syndrome (ARDS) is the main cause of death in most COVID-19 patients. A vital mechanism for the development of the ARDS is cytokine storm which arises from an aggressive uncontrolled systemic inflammatory response that results from the release of large numbers of pro-inflammatory cytokines. This review seeks to draw the attention of the scientific community to the possibilities of improving the clinical outcome of COVID-19 patients based on the knowledge of altering the development of this hyper-inflammatory process by suggesting drugs that targets the implicated immune cells, receptors, cytokines and inflammatory pathways without having generalized effect on the entire immune system.
    [Show full text]
  • 42711 IPEG Programmaboekje
    19 th Biennial Conference 19th Biennial Conference October 26th – 30th 2016 October 26 Nijmegen, the Netherlands th – 30 th 2016 Nijmegen, the Netherlands 2016 Nijmegen, 42711 IPEG programmaboekje omslag.indd 1 06-10-16 17:52 The “International Pharmaco-EEG Society, Association for Electrophysiological Brain Research in Preclinical and Clinical Pharmacology and Related Fields” (IPEG) is a non-profit organization, established in 1980 and composed of scientists and researchers actively involved in electrophysiological brain research in preclinical and clinical pharmacology, neurotoxicology and related areas of interest. my.thesis nl for the design of your Thesis & to show your Thesis 42711 IPEG programmaboekje omslag.indd 2 06-10-16 17:52 IPEG 2016 in Nijmegen | 1 Welcome to Nijmegen, dear attendants of the 19th IPEG meeting. Nijmegen, a 2000 year old city; Nijmegen, a Roman and a medieval city; Nijmegen, the home town of the first catholic university funded by the Faithfull to improve education of a suppressed part of the Netherlands; Nijmegen, the city that heavily suffered in WWII; Nijmegen, the home town of the Donders Institute. Nijmegen, as we hope and trust, your home town for the upcoming IPEG meeting. As you all know, electrophysiological brain research has a long tradition going back as far as 1875 when the first report on the animal electroencephalogram (EEG) was published by Caton. The often forgotten Polish physiologist Adolf Beck was also a EEG pioneer many years before Hans Berger’s initial reports. Beck recorded electrical potentials in several brain areas evoked by peripheral sensory stimuli. Using this technique, Beck localised various centres in the brain of several animal species and described desynchronization in electrical brain potentials.
    [Show full text]
  • 19Th Biennial IPEG Meeting Nijmegen, the Netherlands
    Neuropsychiatric Electrophysiology 2016, 2(Suppl 1):8 DOI 10.1186/s40810-016-0021-4 MEETINGABSTRACTS Open Access 19th biennial IPEG Meeting Nijmegen, The Netherlands. 26-30 October 2016 Published: 29 November 2016 Training course measures. This will be illustrated by means of pertinent examples. These include elucidating the mechanisms of stimulant action re- A1 mediating deficient impulse control and the role of the cannabinoid Thalamocortical sleep oscillations system in human working memory, as well as drug effects on Igor Timofeev1,2 sensory gating and specific aspects of visual-spatial attention. Other 1Department of Psychiatry and Neuroscience, Université Laval, Québec, examples concern the added sensitivity of EEG and ERP measures, Canada; 2Centre de recherche de l’Institut universitaire en santé mentale relative to that of performance measures, in detecting effects of alco- de Québec (CRIUSMQ), Université Laval, Québec, Canada hol, and more generally in monitoring and predicting vigilance and Neuropsychiatric Electrophysiology 2016, 2(Suppl 1):A1 the ability to detect external signals in the immediate future. Rela- tions between brain signals and cognitive competences are revealed In waking and sleeping states, thalamocortical system generates a by either comparing different individuals, or moment-to-moment variety of oscillations ranging from 0.1 Hz to hundreds of Hz. Most of fluctuations within individuals, or differences in state (e.g., drug- them are present during NREM sleep, but slower activities prevail in induced) within individuals. this state of vigilance. Thalamocortical network is organized in a loop in which thalamocortical cells excite reticular thalamic and neocor- tical cells, reticular thalamic cells inhibit thalamocortical cells and A3 corticothalamic cells excite thalamocortical and reticular thalamic EEG and ERP as key techniques for functional brain alterations cells.
    [Show full text]
  • Classification Decisions Taken by the Harmonized System Committee from the 47Th to 60Th Sessions (2011
    CLASSIFICATION DECISIONS TAKEN BY THE HARMONIZED SYSTEM COMMITTEE FROM THE 47TH TO 60TH SESSIONS (2011 - 2018) WORLD CUSTOMS ORGANIZATION Rue du Marché 30 B-1210 Brussels Belgium November 2011 Copyright © 2011 World Customs Organization. All rights reserved. Requests and inquiries concerning translation, reproduction and adaptation rights should be addressed to [email protected]. D/2011/0448/25 The following list contains the classification decisions (other than those subject to a reservation) taken by the Harmonized System Committee ( 47th Session – March 2011) on specific products, together with their related Harmonized System code numbers and, in certain cases, the classification rationale. Advice Parties seeking to import or export merchandise covered by a decision are advised to verify the implementation of the decision by the importing or exporting country, as the case may be. HS codes Classification No Product description Classification considered rationale 1. Preparation, in the form of a powder, consisting of 92 % sugar, 6 % 2106.90 GRIs 1 and 6 black currant powder, anticaking agent, citric acid and black currant flavouring, put up for retail sale in 32-gram sachets, intended to be consumed as a beverage after mixing with hot water. 2. Vanutide cridificar (INN List 100). 3002.20 3. Certain INN products. Chapters 28, 29 (See “INN List 101” at the end of this publication.) and 30 4. Certain INN products. Chapters 13, 29 (See “INN List 102” at the end of this publication.) and 30 5. Certain INN products. Chapters 28, 29, (See “INN List 103” at the end of this publication.) 30, 35 and 39 6. Re-classification of INN products.
    [Show full text]
  • Enhanced Dendritic Inhibition and Impaired NMDAR Activation in a Mouse Model of Down Syndrome
    This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Neurobiology of Disease Enhanced dendritic inhibition and impaired NMDAR activation in a mouse model of Down syndrome Jan M. Schulz1, Frederic Knoflach2, Maria-Clemencia Hernandez2 and Josef Bischofberger1 1Department of Biomedicine, University of Basel, Pestalozzistr. 20, CH-4056 Basel, Switzerland 2Pharma Research and Early Development, Discovery Neuroscience Department, F. Hoffmann-La Roche Ltd, Basel, Switzerland https://doi.org/10.1523/JNEUROSCI.2723-18.2019 Received: 22 October 2018 Revised: 9 April 2019 Accepted: 10 April 2019 Published: 18 April 2019 Author contributions: J.M.S., M.C.H., and J.B. designed research; J.M.S. and F.K. performed research; J.M.S. analyzed data; J.M.S. and J.B. wrote the first draft of the paper; J.M.S. and J.B. wrote the paper; F.K., M.C.H., and J.B. edited the paper. Conflict of Interest: The authors declare no competing financial interests. We would like to thank Tom Otis for helpful comments on the manuscript. We thank Selma Becherer and Martine Schwager for mouse genotyping, histochemical stainings and technical assistance, Marie-Claire Pflimlin for some electrophysiological recordings and Andrew Thomas for RO4938581 supply. This work was supported by a Roche Postdoctoral Fellowship and by the Swiss National Science Foundation (SNSF, Project 31003A_176321). The authors declare no competing financial interests. Correspondence: Dr. Josef Bischofberger, Department of Biomedicine, University of Basel, Pestalozzistr. 20, CH-4046 Basel, Switzerland, Phone: +41-61-2672729, E-mail: [email protected] Cite as: J.
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2011/0224301 A1 ZAMORA Et Al
    US 20110224301A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0224301 A1 ZAMORA et al. (43) Pub. Date: Sep. 15, 2011 (54) HMGB1 EXPRESSION AND PROTECTIVE Publication Classification ROLE OF SEMAPMOD IN NEC (51) Int. Cl. (75) Inventors: Ruben ZAMORA, Pittsburgh, PA st iOS CR (US); Henri R. FORD, La Canada, (2006.01) CA (US); Thais A6IP3L/2 (2006.01) SIELECK-DZURDZ, Kennett A6IP33/6 (2006.01) Square, PA (US); Vidal F. DE LA CRUZ, Phoenixville, PA (US) (52) U.S. Cl. ........................................................ S14/615 (73) Assignee: CYTOKINE PHARMASCIENCES, INC., King (57) ABSTRACT of Prussia, PA (US) Methods are described, which include the administration of (21) Appl. No.: 12/879,144 semapimod or guanylhydraZone containing compounds, salt thereof, or a combination of the compound and a salt thereof 22) Filed1C Sep.ep. 10,1U, 2010 forOr the 1inhibiti 1t1on, treatment, and/ord/ prevention off any o f NEC, a condition associated with the release of HMGB1, a Related U.S. Application Data condition associated with the release of iNOS protein, a con dition associated with the release of Bax protein, a condition (63) sity pig, S. 21,666 filed on associated with the release of Bad protein, a condition asso • us s • L vs - s -- a-- s- u. I • ciated with the release of COX-2 protein, or a condition (60) Provisional application No. 60/685,875, filed on Jun. associated with the release of RAGE, or a combination 1, 2005. thereof to a subject in need thereof. Patent Application Publication Sep. 15, 2011 Sheet 1 of 12 US 2011/0224301 A1 Fig.
    [Show full text]
  • Lääkeaineiden Yleisnimet (INN-Nimet) 21.6.2021
    Lääkealan turvallisuus- ja kehittämiskeskus Säkerhets- och utvecklingscentret för läkemedelsområdet Finnish Medicines Agency Lääkeaineiden yleisnimet (INN-nimet) 21.6.
    [Show full text]
  • World of Cognitive Enhancers
    ORIGINAL RESEARCH published: 11 September 2020 doi: 10.3389/fpsyt.2020.546796 The Psychonauts’ World of Cognitive Enhancers Flavia Napoletano 1,2, Fabrizio Schifano 2*, John Martin Corkery 2, Amira Guirguis 2,3, Davide Arillotta 2,4, Caroline Zangani 2,5 and Alessandro Vento 6,7,8 1 Department of Mental Health, Homerton University Hospital, East London Foundation Trust, London, United Kingdom, 2 Psychopharmacology, Drug Misuse, and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom, 3 Swansea University Medical School, Institute of Life Sciences 2, Swansea University, Swansea, United Kingdom, 4 Psychiatry Unit, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy, 5 Department of Health Sciences, University of Milan, Milan, Italy, 6 Department of Mental Health, Addictions’ Observatory (ODDPSS), Rome, Italy, 7 Department of Mental Health, Guglielmo Marconi” University, Rome, Italy, 8 Department of Mental Health, ASL Roma 2, Rome, Italy Background: There is growing availability of novel psychoactive substances (NPS), including cognitive enhancers (CEs) which can be used in the treatment of certain mental health disorders. While treating cognitive deficit symptoms in neuropsychiatric or neurodegenerative disorders using CEs might have significant benefits for patients, the increasing recreational use of these substances by healthy individuals raises many clinical, medico-legal, and ethical issues. Moreover, it has become very challenging for clinicians to Edited by: keep up-to-date with CEs currently available as comprehensive official lists do not exist. Simona Pichini, Methods: Using a web crawler (NPSfinder®), the present study aimed at assessing National Institute of Health (ISS), Italy Reviewed by: psychonaut fora/platforms to better understand the online situation regarding CEs.
    [Show full text]
  • Comparing the Effects of Α5gabaa Receptor Negative Allosteric Modulators on Inhibitory Currents in Hippocampal Neurons
    Comparing the Effects of α5GABAA Receptor Negative Allosteric Modulators on Inhibitory Currents in Hippocampal Neurons by Marc Anthony Manzo A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Physiology University of Toronto © Copyright by Marc Anthony Manzo 2020 Comparing the effects of α5GABAA receptor negative allosteric modulators on inhibitory currents in hippocampal neurons Marc Anthony Manzo Master of Science Department of Physiology University of Toronto 2020 Abstract Overactivity of α5 subunit-containing GABAA (α5GABAA) receptors contributes to cognitive deficits in many neurological disorders. Negative allosteric modulators that preferentially inhibit α5GABAA receptors (α5-NAMs) have been developed to treat such deficits. α5-NAMs have been primarily studied using recombinant GABAA receptors expressed in non-neuronal cells. Surprisingly, although the native neuronal environment influences GABAA receptor pharmacology, no study has directly compared α5-NAM effects on GABAA receptors expressed in primary neurons. This comparison would aid in the development and selection of more effective compounds for clinical trials. Thus, the current study was undertaken to compare the effects of five α5-NAMs on the function of GABAA receptors in cultured mouse hippocampal neurons, using whole-cell voltage- clamp recordings. While α5-NAMs similarly inhibited GABAA receptor-mediated currents; the most efficacious concentrations varied 100-fold. Given that maximal efficacy is similar ii among α5-NAMs, factors such as potency, selectivity, and toxicity should be emphasized in the development and selection of α5-NAMs for clinical trials. iii Acknowledgments Over the last two years, I have grown tremendously as both a person and scientist. This growth was a consequence of the talented people I worked with and learned from on a daily basis.
    [Show full text]
  • Semapimod Sensitizes Glioblastoma Tumors to Ionizing Radiation by Targeting Microglia
    Semapimod Sensitizes Glioblastoma Tumors to Ionizing Radiation by Targeting Microglia Ian S. Miller1¤a, Sebastien Didier1, David W. Murray1¤a, Tia H. Turner1, Magimairajan Issaivanan1¤b, Rosamaria Ruggieri1, Yousef Al-Abed2, Marc Symons1* 1 Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, New York, United States of America, 2 Center for Molecular Innovation, The Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, New York, United States of America Abstract Glioblastoma is the most malignant and lethal form of astrocytoma, with patients having a median survival time of approximately 15 months with current therapeutic modalities. It is therefore important to identify novel therapeutics. There is mounting evidence that microglia (specialized brain-resident macrophages) play a significant role in the development and progression of glioblastoma tumors. In this paper we show that microglia, in addition to stimulating glioblastoma cell invasion, also promote glioblastoma cell proliferation and resistance to ionizing radiation in vitro. We found that semapimod, a drug that selectively interferes with the function of macrophages and microglia, potently inhibits microglia- stimulated GL261 invasion, without affecting serum-stimulated glioblastoma cell invasion. Semapimod also inhibits microglia-stimulated resistance of glioblastoma cells to radiation, but has no significant effect on microglia-stimulated glioblastoma cell proliferation. We also found that intracranially administered semapimod strongly increases the survival of GL261 tumor-bearing animals in combination with radiation, but has no significant benefit in the absence of radiation. In conclusion, our observations indicate that semapimod sensitizes glioblastoma tumors to ionizing radiation by targeting microglia and/or infiltrating macrophages.
    [Show full text]
  • Paving the Way for Therapy
    Paving the Way for Therapy 2nd International Conference of the Trisomy 21 Research Society June 7-11, 2017 Feinberg Conference Center, Northwestern Memorial Hospital Chicago, IL USA Founding Sponsors of T21RS 1 Paving the Way for Therapy 2nd International Conference of the Trisomy 21 Research Society June 7-11, 2017 Feinberg Conference Center, Northwestern Memorial Hospital Chicago, IL USA Conference Organizers Roger Reeves, PhD Mara Dierssen, MD, PhD Johns Hopkins University School of CRG – Center for Genomic Medicine Regulation Jean Delabar, PhD John O’Bryan, PhD CNRS-ICM University of Illinois Chicago Scientific Program Committee Mara Dierssen, MD, PhD - Chair Anita Bhattacharyya, PhD CRG-Center for Genomic Regulation University of Wisconsin-Madison Cynthia Lemere, PhD Jean Delabar, PhD Harvard Medical School CNRS-ICM Dean Nizetic, MD, PhD Jorge Busciglio, PhD Nanyang Technological University University of California-Irvine Singapore Nicole Schupf, PhD, DrPH Pablo Caviedes, MD, PhD Columbia University Medical Center University of Chile Deny Menghini, PhD Bambino Gesu Children's Hospital 2 3 Annette Karmiloff-Smith Thesis Award Program COMPETITION FOR OUTSTANDING PH.D. THESIS Application Deadline: June 30, 2018 Prizes will be awarded for up to 2 outstanding doctoral dissertations. Each recipient will receive an honorarium of 1,000 Euros. The topic of the dissertation must be in the field of Down syndrome Eligibility Participation in the 2017 competition is limited to candidates who obtained the Ph.D. title during the period January 1, 2016-December 31, 2017. Applicants must be members of T21RS (www.t21rs.org/register). Required Documentation Documentation accompanying the application must be submitted exclusively in an email to [email protected] in PDF format and must be written in English.
    [Show full text]