DOCSLIB.ORG

Substance P Antagonists As a Therapeutic Approach to Improving Outcome Following Traumatic Brain Injury

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Substance P Antagonists As a Therapeutic Approach to Improving Outcome Following Traumatic Brain Injury Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Substance P Antagonists as a Therapeutic Approach to Improving Outcome Following Traumatic Brain Injury Robert Vink and Corinna van den Heuvel School of Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia, 5005 Summary: Although a number of secondary injury factors are been implicated in learning and memory, mood and anxiety, known to contribute to the development of morphological in- stress mechanisms, emotion-processing, migraine, emesis, jury and functional deficits following traumatic brain injury, pain, and seizures, all of which may be adversely affected accumulating evidence has suggested that neuropeptides, after brain injury. Inhibition of post-traumatic substance P and in particular substance P, may play a critical role. Sub- activity, either by preventing release or by antagonism of the stance P is released early following acute injury to the CNS neurokinin-1 receptor, has consistently resulted in a pro- as part of a neurogenic inflammatory response. In so doing, found decrease in development of edema and marked im- it facilitates an increase in the permeability of the blood– provements in functional outcome. This review summarizes brain barrier and the development of vasogenic edema. At the current evidence supporting a role for substance P in the cellular level, substance P has been shown to directly acute brain injury. Key Words: Neurotrauma, inflammation, result in neuronal cell death; functionally, substance P has edema, substance P, tachykinins. INTRODUCTION to prevent further injury and improve outcome. Accord- ingly, a significant research effort has been directed at Traumatic brain injury (TBI) is the leading cause of identifying secondary injury factors and then developing death and disability in people under 40 years of age in novel therapies that may attenuate, or even prevent, their developed countries.1 Although the costs for treatment, action. rehabilitation, and care of such individuals is measured in billion of dollars annually, no effective treatment cur- Secondary injury factors identified to date include re- rently exists. Brain injury results in the development of lease of neurotransmitters (such as excitatory amino ac- neurologic deficits through two main mechanisms, com- ids), ion changes, calpain activation, oxidative stress, blood–brain barrier (BBB) disruption, edema, and bioen- prising primary and secondary events. Primary events are 2 made up of the mechanical processes that occur at the ergetic failure. Of these, profound edema has been time of the trauma, including tissue shearing, laceration, clearly associated with mortality following severe TBI, and stretching of nerve fibers.2 Preventive measures such as well as in the development of significant morbidity in 4 as helmets, airbags, and seatbelts are the only interven- up to 50% of surviving TBI patients. It is widely ac- tions that can prevent or attenuate these primary events. cepted that the development of edema has adverse con- In contrast, secondary injury evolves over minutes to sequences on outcome through effects on intracranial 5 days and even months after the initial event and is made pressure (ICP). Current protocols for the management up of delayed biochemical and physiological factors that of elevated ICP include induction of hyperventilation or are initiated by the primary event. These secondary in- hypothermia, pharmacological regimens such as admin- jury factors are thought to account for much of the mor- istration of diuretics or hyperosmotic agents, or surgical bidity following brain injury,3 and their delayed nature procedures such as drainage of CSF and decompressive 6 presents opportunities for interventional pharmacology craniectomy. Unfortunately, these interventions have essentially been inadequate, largely because they target the end-product of edema formation and not the funda- mental issue of what specific mechanisms are associated Address correspondence and reprint requests to: Robert Vink, Ph.D., School of Medical Sciences, The University of Adelaide, SA 5005, with its development. Recent studies have suggested that Australia. E-mail: [email protected]. neuropeptides, and in particular substance P (SP), may 74 Vol. 7, 74–80, January 2010 © The American Society for Experimental NeuroTherapeutics, Inc. SUBSTANCE P ANTAGONISTS 75 play a critical role in edema formation through actions at the level of the BBB.7,8 This alternative mechanistic approach to the management of post-traumatic edema and elevated ICP potentially offers a number of exciting opportunities. KININS AND SUBSTANCE P Substance P is a member of the tachykinin family of kinins. Kinins are a group of peptide mediators that have proinflammatory actions, some of which are mediated via the vasculature where they cause vasodilation and increased vascular permeability. The tachykinins, includ- ing SP, calcitonin gene-related peptide (CGRP), and neu- rokinin A, share specific amino acid sequences that allow them to be sorted into the tachykinin family. This family of compounds represents one of the largest peptide fam- ilies described in animals.9 Substance P was first identi- fied as a crude extract with potent hypotensive and smooth muscle contractile properties isolated from 10 FIG. 1. Schematic of neurogenic inflammation demonstrating equine brain. It was identified in high concentrations in how the release of neuropeptides, and particularly of substance the dorsal root of the spinal cord, leading to the proposal P, is associated with the development of vascular permeability and edema formation. CGRP ϭ calcitonin gene-related peptide; that it is a neuronal sensory transmitter associated with NK ϭ neurokinin receptor; TRPVR ϭ transient receptor potential pain transmission.11 Today, it is accepted that SP is vanilloid receptor. released from both central and peripheral endings of sensory neurons and functions as a neurotransmitter.12 NEUROGENIC INFLAMMATION Its release, along with that of the other tachykinins, pro- Originally described as vasodilation of lower limb duces effects via tachykinin receptors, thereby playing a vessels following stimulation of the dorsal root gan- significant role in the neural component of inflammation glia,20 the concept of neurogenic inflammation (FIG. 1) known as neurogenic inflammation (discussed in the next has evolved to encompass vasodilation, plasma extrava- section). sation, and neuronal hypersensitivity caused by the re- The other distinct family of kinins, the bradykinins, is lease of neuropeptides from sensory neurons.21 Several formed from the cleavage of the plasma globulin kinino- neuropeptides have been implicated in this process, with gen, by plasma and tissue proteases known as kallikreins. CGRP identified as being associated with the vasodila- The active peptides formed by this proteolytic cleavage tion of arterioles and SP being thought to enhance are bradykinin and kallidin (lysyl bradykinin), and these plasma protein extravasation as well as leukocyte adhe- kinins produce their effects through two subtypes of sion to endothelial cells in postcapillary venules.22 Ce- bradykinin receptors, B1 and B2. Bradykinin receptor rebral blood vessels are surrounded by a dense supply of antagonists have been shown to improve neurological sensory neurons, as are virtually all blood vessels of the 13 outcome following TBI, even when administered up body, and these fibers contain both CGRP and SP. Any to 4 h post trauma. This neuroprotection is thought to release of the neuropeptides around the cerebral vascu- be mediated, in part, by attenuating production of lature would initiate neurogenic inflammation, a concept inducible nitric oxide synthase (iNOS) and prostaglan- supported by the fact that neuropeptides are a therapeutic din E2,14 as well as edema formation13 and increases target to reduce vascular permeability in migraine.23 Fol- in ICP.15,16 An anti-inflammatory component has also lowing TBI, both enhanced vascular permeability of the been suggested,17 as well as inhibitory effects on re- BBB and cerebral vasodilation would potentially con- active oxygen species generation.18 There is also ev- tribute to an increase in ICP. idence, however, to suggest that bradykinin itself may Peptide-containing primary sensory neurons are charac- have glial cell-mediated neuroprotective and anti-in- terized by their unique sensitivity to capsaicin, the pungent flammatory effects in the CNS, induced via attenua- ingredient found in capsicum peppers.24 The transient re- tion of cytokine release from activated microglia, as ceptor potential vanilloid receptor-1 (TRPVR1) is the site well as by upregulation of neurotrophic factor produc- of binding by capsaicin,25 and this receptor has been tion in astrocytes.19 identified as a nonselective cation channel whose endog- Neurotherapeutics, Vol. 7, No. 1, 2010 76 VINK AND VAN DEN HEUVEL enous stimulants include heat (Ͼ43°C) and protons (FIG. vestigated the role of classical inflammation in edema 1). Some primary sensory neurons are selectively stim- formation following TBI,32,33 to date few studies have ulated by capsaicin; at higher concentrations, capsaicin examined the role of neurogenic inflammation. Nimmo kills these neurons, blocking the genesis of subsequent et al.7 were among the first to do so, by demonstrating neurogenic inflammatory responses.24 These neurons are that chronic administration of capsaicin prior to TBI defined as capsaicin-sensitive, because of the specific
Load more

Recommended publications
  • Vasopressin Release from the Rat Hypothalamo-Neurohypophysial System: Effects of Tachykinin NK–1 and NK–2 Receptors Agonis
    Neuroendocrinology Letters No.4 August Vol.26, 2005 Copyright © 2005 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu Vasopressin release from the rat hypothalamo-neurohy- pophysial system: Effects of tachykinin NK–1 and NK–2 receptors agonists and antagonists ARTICLE ORIGINAL Marlena Juszczak Department of Pathophysiology, Medical University of Lodz, Lodz, Poland. Correspondence to: Marlena Juszczak, Ph.D., D.Sc. Department of Pathophysiology Medical University of Lodz Narutowicza 60 90-136 Lodz, POLAND TEL/FAX: +48 42 6306187 [email protected] Submitted: July 7, 2004 Accepted: October 15, 2004 Key words: tachykinin receptors; substance P; neurokinin A; vasopressin Neuroendocrinol Lett 2005; 26(4):367–372 PMID: 16136007 NEL260405A13 © Neuroendocrinology Letters www.nel.edu Abstract OBJECTIVES: Present experiments were undertaken to study the influence of pep- tide NK–1 and NK–2 receptor agonists and antagonists as well as substance P and neurokinin A (the natural ligands for these tachykinin receptors) on vasopres- sin (AVP) secretion from the rat hypothalamo-neurohypophysial (HN) system in vitro. RESULTS: The results showed that both substance P and highly selective tachykinin 9 11 NK–1 receptor agonist, i.e., [Sar ,Met(O2) ]-Substance P, enhanced significantly AVP secretion, while the NK–1 receptor antagonist (Tyr6,D–Phe7,D–His9)-Sub- stance P (6–11) – sendide – was found to antagonize the substance P–induced hormone release from isolated rat HN system (all peptides at the concentration of 10–7 M/L). The NK–2 receptor selective agonist (β–Ala8)–Neurokinin A (4–10) was essentially inactive in modifying AVP release from the rat HN system in vitro, while neurokinin A (the natural ligand for this tachykinin receptor) was found to stimulate the AVP release; this effect of neurokinin A has been diminished by the 5 6,8,9 10 NK–2 receptor antagonist (Tyr ,D–Trp ,Lys–NH2 )–Neurokinin A (4–10).
    [Show full text]
  • The Significance of NK1 Receptor Ligands and Their Application In
    pharmaceutics Review The Significance of NK1 Receptor Ligands and Their Application in Targeted Radionuclide Tumour Therapy Agnieszka Majkowska-Pilip * , Paweł Krzysztof Halik and Ewa Gniazdowska Centre of Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland * Correspondence: [email protected]; Tel.: +48-22-504-10-11 Received: 7 June 2019; Accepted: 16 August 2019; Published: 1 September 2019 Abstract: To date, our understanding of the Substance P (SP) and neurokinin 1 receptor (NK1R) system shows intricate relations between human physiology and disease occurrence or progression. Within the oncological field, overexpression of NK1R and this SP/NK1R system have been implicated in cancer cell progression and poor overall prognosis. This review focuses on providing an update on the current state of knowledge around the wide spectrum of NK1R ligands and applications of radioligands as radiopharmaceuticals. In this review, data concerning both the chemical and biological aspects of peptide and nonpeptide ligands as agonists or antagonists in classical and nuclear medicine, are presented and discussed. However, the research presented here is primarily focused on NK1R nonpeptide antagonistic ligands and the potential application of SP/NK1R system in targeted radionuclide tumour therapy. Keywords: neurokinin 1 receptor; Substance P; SP analogues; NK1R antagonists; targeted therapy; radioligands; tumour therapy; PET imaging 1. Introduction Neurokinin 1 receptor (NK1R), also known as tachykinin receptor 1 (TACR1), belongs to the tachykinin receptor subfamily of G protein-coupled receptors (GPCRs), also called seven-transmembrane domain receptors (Figure1)[ 1–3]. The human NK1 receptor structure [4] is available in Protein Data Bank (6E59).
    [Show full text]
  • G Protein‐Coupled Receptors
    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: G protein-coupled receptors. British Journal of Pharmacology (2019) 176, S21–S141 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors Stephen PH Alexander1 , Arthur Christopoulos2 , Anthony P Davenport3 , Eamonn Kelly4, Alistair Mathie5 , John A Peters6 , Emma L Veale5 ,JaneFArmstrong7 , Elena Faccenda7 ,SimonDHarding7 ,AdamJPawson7 , Joanna L Sharman7 , Christopher Southan7 , Jamie A Davies7 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia 3Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK 4School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 5Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 6Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 7Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website.
    [Show full text]
  • Neuropeptide-Induced Modulation of Carcinogenesis in a Metastatic Breast Cancer Cell Line (MDA-MB-231LUC+)
    Gutierrez and Boada Cancer Cell Int (2018) 18:216 https://doi.org/10.1186/s12935-018-0707-8 Cancer Cell International PRIMARY RESEARCH Open Access Neuropeptide‑induced modulation of carcinogenesis in a metastatic breast cancer LUC cell line (MDA‑MB‑231 +) Silvia Gutierrez and M. Danilo Boada* Abstract Background: Metastatic cancer to bone is well-known to produce extreme pain. It has been suggested that the magnitude of this perceived pain is associated with disease progression and poor prognosis. These data suggest a potential cross-talk between cancer cells and nociceptors that contribute not only to pain, but also to cancer aggres- siveness although the underlying mechanisms are yet to be stablished. Methods: The in vitro dose dependent efect of neuropeptides (NPs) (substance P [SP], calcitonin gene-related LUC peptide and neurokinin A [NKA]) and/or its combination, on the migration and invasion of MDA-MB-231 + were assessed by wound healing and collagen-based cell invasion assays, respectively. The efect of NPs on the expression of its receptors (SP [NK1] and neurokinin A receptors [NK2], CALCRL and RAMP1) and kininogen (high-molecular- LUC weight kininogen) release to the cell culture supernatant of MDA-MB-231 +, were measured using western-blot analysis and an ELISA assay, respectively. Statistical signifcance was tested using one-way ANOVA, repeated measures ANOVA, or the paired t-test. Post-hoc testing was performed with correction for multiple comparisons as appropriate. Results: Our data show that NPs strongly modify the chemokinetic capabilities of a cellular line commonly used as a LUC model of metastatic cancer to bone (MDA-MB-231 +) and increased the expression of their receptors (NK1R, NK2R, RAMP1, and CALCRL) on these cells.
    [Show full text]
  • 798.Full.Pdf
    The Journal of Neuroscience, February 1, 2001, 21(3):798–811 Adaptive Plasticity in Tachykinin and Tachykinin Receptor Expression after Focal Cerebral Ischemia Is Differentially Linked to GABAergic and Glutamatergic Cerebrocortical Circuits and Cerebrovenular Endothelium Ralf K. Stumm,1 Carsten Culmsee,2 Martin K.-H. Scha¨ fer,1 Josef Krieglstein,2 and Eberhard Weihe1 1Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Clinics of Philipps University Marburg, 35033 Marburg, Germany, and 2Institute of Pharmacology and Toxicology, Philipps University Marburg, 35037 Marburg, Germany To test the hypothesis of an involvement of tachykinins in activity at 2 and 7 d after MCAO were confined to GABAergic destabilization and hyperexcitation of neuronal circuits, gliosis, interneurons. In parallel, the expression of NK3 was markedly and neuroinflammation during cerebral ischemia, we investi- downregulated in pyramidal neurons. MCAO caused transient gated cell-specific expressional changes of the genes encoding NK1 expression in activated cerebrovenular endothelium within substance P (SP), neurokinin B (NKB), and the tachykinin/ and adjacent to the infarct. NK1 expression was absent from neurokinin receptors (NK1, NK2, and NK3) after middle cerebral activated astroglia or microglia. The differential ischemia-induced artery occlusion (MCAO) in the rat. Our analysis by quantitative plasticity of the tachykinin system in distinct inhibitory and exci- in situ hybridization, immunohistochemistry, and confocal mi- tatory cerebrocortical circuits suggests that it may be involved in croscopy was concentrated on cerebrocortical areas that sur- the balance of endogenous neuroprotection and neurotoxicity by vive primary infarction but undergo secondary damage. Here, enhancing GABAergic inhibitory circuits or by facilitating SP-encoding preprotachykinin-A and NK1 mRNA levels and glutamate-mediated hyperexcitability.
    [Show full text]
  • Review Article Blocking Neurogenic Inflammation for the Treatment of Acute Disorders of the Central Nervous System
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Crossref Hindawi Publishing Corporation International Journal of Inflammation Volume 2013, Article ID 578480, 16 pages http://dx.doi.org/10.1155/2013/578480 Review Article Blocking Neurogenic Inflammation for the Treatment of Acute Disorders of the Central Nervous System Kate Marie Lewis, Renée Jade Turner, and Robert Vink Adelaide Centre for Neuroscience Research, School of Medical Sciences, The University of Adelaide, North Terrace, SA 5005, Australia Correspondence should be addressed to Robert Vink; [email protected] Received 6 February 2013; Accepted 8 May 2013 Academic Editor: Christopher D. Buckley Copyright © 2013 Kate Marie Lewis et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Classical inflammation is a well-characterized secondary response to many acute disorders of the central nervous system. However, in recent years, the role of neurogenic inflammation in the pathogenesis of neurological diseases has gained increasing attention, with a particular focus on its effects on modulation of the blood-brain barrier BBB. The neuropeptide substance P has been shown to increase blood-brain barrier permeability following acute injury to the brain and is associated with marked cerebral edema. Its release has also been shown to modulate classical inflammation. Accordingly, blocking substance P NK1 receptors may provide a novel alternative treatment to ameliorate the deleterious effects of neurogenic inflammation in the central nervous system. The purpose of this paper is to provide an overview of the role of substance P and neurogenic inflammation in acute injury to the central nervous system following traumatic brain injury, spinal cord injury, stroke, and meningitis.
    [Show full text]
  • Calcitonin Gene-Related Peptide Regulates Expression of Neurokinin1 Receptors by Rat Spinal Neurons
    1816 • The Journal of Neuroscience, March 1, 2003 • 23(5):1816–1824 Calcitonin Gene-Related Peptide Regulates Expression of Neurokinin1 Receptors by Rat Spinal Neurons Virginia S. Seybold,1 Kenneth E. McCarson,2 Paul G. Mermelstein,1 Rachel D. Groth,1 and Lia G. Abrahams1 1Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, and 2Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160 Although neurokinin 1 (NK1) receptors contribute to hyperalgesia, and their expression is increased in the spinal cord during peripheral inflammation, little is known regarding the signaling molecules and the second messenger pathways that they activate in regulating the expression of the NK1 receptor gene. Because the promoter region of the NK1 receptor contains a cAMP response element (CRE), we tested the hypothesis that calcitonin gene-related peptide (CGRP) regulates the expression of NK1 receptors via a pathway involving activation of the transcription factor cAMP response element binding protein (CREB). Experiments were conducted on primary cultures of neonatal rat spinal neurons. Treatment of cultures with CGRP for 8–24 hr increased 125I-substance P binding on spinal neurons; the increase in binding was preceded by an elevation in NK1 receptor mRNA. The CGRP-induced change in 125I-substance P binding was concentration-dependent and was inhibited by the antagonist CGRP8–37. CGRP increased phosphorylated CREB immunoreactivity and CRE-dependent transcription in neurons, indicating the involvement of the transcription factor CREB. Evidence that CGRP increased cAMP levels in spinal neurons and that the protein kinase A inhibitor H89 attenuated CGRP-induced CRE-dependent transcription suggests that the intracellular pathway stimulated by CGRP leads to activation of protein kinase A.
    [Show full text]
  • Anti-Tachykinin Receptor 2 (T6075)
    Anti-Tachykinin Receptor 2 produced in rabbit, affinity isolated antibody Catalog Number T6075 Product Description respiratory tract and proved more potent than the Anti-Tachykinin Receptor 2 is produced in rabbit using peptide antagonist (MEN 10376), indicating their as immunogen a synthetic peptide conjugated to KLH. greater therapeutic potential as antiasthmatic agents. The peptide corresponds to the C-terminus of human tachykinin receptor 2. The antibody is affinity-purified Tachykinin receptor 2 is expressed in trachea, lung, using the immunizing peptide immobilized on agarose. and gastrointestinal tract. ESTs have been isolated from human heart/melanocyte/uterus, prostate, and Anti-Tachykinin Receptor 2 specifically recognizes uterus libraries. human tachykinin receptor 2 by immunohistochemistry with formalin-fixed, paraffin-embedded tissues and Reagent immunocytochemistry. Not tested for other uses. The Supplied as a solution of 1 mg/mL in phosphate human receptor has 85% homology with mouse and rat buffered saline, pH 7.7, containing 0.01% sodium azide. genes. Other species reactivity has not been confirmed. Precautions and Disclaimer Three classes of tachykinin receptors have been This product is for R&D use only, not for drug, characterized, the NK-1, NK-2, and NK-3. The NK-1 household, or other uses. Please consult the Material receptor preferentially binds substance P, the NK-2 Safety Data Sheet for information regarding hazards receptor binds neurokinin A, and the NK-3 receptor and safe handling practices recognizes neurokinin B. These peptides are involved in nociception and neuroimmunomodulation, and in the Storage/Stability development of diseases such as bronchial asthma, For continuous use, store at 2-8 °C for up to one month.
    [Show full text]
  • A Lack of Functional NK1 Receptors Explains Most, but Not All, Abnormal Behaviours of NK1R-/- Mice1
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by UCL Discovery Genes, Brain and Behavior (2015) 14: 189–199 doi: 10.1111/gbb.12195 A lack of functional NK1 receptors explains most, but not all, abnormal behaviours of NK1R-/- mice1 A. J. Porter†, K. Pillidge†,Y.C.Tsai†,J.A. the greater impulsivity of NK1R-/- mice depended on Dudley‡,S.P.Hunt‡,S.N.Peirson§,L.A. an interaction between a functional deficit of NK1R Brown§ and S. C. Stanford∗,† and other (possibly environmental and/or epigenetic) factors. †Department of Neuroscience, Physiology and Pharmacology, Keywords: 5-Choice Serial Reaction-Time Task, ADHD, atten- ‡Department of Cell and Developmental Biology, University tion, diurnal motor rhythm, epigenetics, hyperactivity, impul- College London, London, and §Department of Clinical sivity, NK1 receptor, perseveration, TACR1 gene Neurosciences (Nuffield Laboratory of Ophthalmology), Received 31 July 2014, revised 21 October 2014 and revised 4 University of Oxford, John Radcliffe Hospital, Oxford, UK December 2014, accepted for publication 11 December 2014 1A.J.P., K.P.,Y.C.T. (unregulated procedures, only), J.A.D. (training, only), and S.C.S. designed and performed the experiments. L.A.B. and S.N.P.developed the activity sensors and associated software. S.P.H.developed the NK1R-/- mouse. Mice with functional ablation of the substance P-preferring A.J.P.and S.C.S. analysed the data. A.J.P.and S.C.S. wrote the (NK1) receptor gene (NK1R-/-) (de Felipe et al. 1998) express manuscript (with input from other authors).
    [Show full text]
  • Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells Amy Sue Bogard University of Tennessee Health Science Center
    University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 12-2013 Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells Amy Sue Bogard University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Medical Cell Biology Commons, and the Medical Molecular Biology Commons Recommended Citation Bogard, Amy Sue , "Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells" (2013). Theses and Dissertations (ETD). Paper 330. http://dx.doi.org/10.21007/etd.cghs.2013.0029. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Biomedical Sciences Track Molecular Therapeutics and Cell Signaling Research Advisor Rennolds Ostrom, Ph.D. Committee Elizabeth Fitzpatrick, Ph.D. Edwards Park, Ph.D. Steven Tavalin, Ph.D. Christopher Waters, Ph.D. DOI 10.21007/etd.cghs.2013.0029 Comments Six month embargo expired June 2014 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/330 Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells A Dissertation Presented for The Graduate Studies Council The University of Tennessee Health Science Center In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy From The University of Tennessee By Amy Sue Bogard December 2013 Copyright © 2013 by Amy Sue Bogard.
    [Show full text]
  • Research Article Complex and Multidimensional Lipid Raft Alterations in a Murine Model of Alzheimer’S Disease
    SAGE-Hindawi Access to Research International Journal of Alzheimer’s Disease Volume 2010, Article ID 604792, 56 pages doi:10.4061/2010/604792 Research Article Complex and Multidimensional Lipid Raft Alterations in a Murine Model of Alzheimer’s Disease Wayne Chadwick, 1 Randall Brenneman,1, 2 Bronwen Martin,3 and Stuart Maudsley1 1 Receptor Pharmacology Unit, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA 2 Miller School of Medicine, University of Miami, Miami, FL 33124, USA 3 Metabolism Unit, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA Correspondence should be addressed to Stuart Maudsley, [email protected] Received 17 May 2010; Accepted 27 July 2010 Academic Editor: Gemma Casadesus Copyright © 2010 Wayne Chadwick et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Various animal models of Alzheimer’s disease (AD) have been created to assist our appreciation of AD pathophysiology, as well as aid development of novel therapeutic strategies. Despite the discovery of mutated proteins that predict the development of AD, there are likely to be many other proteins also involved in this disorder. Complex physiological processes are mediated by coherent interactions of clusters of functionally related proteins. Synaptic dysfunction is one of the hallmarks of AD. Synaptic proteins are organized into multiprotein complexes in high-density membrane structures, known as lipid rafts. These microdomains enable coherent clustering of synergistic signaling proteins.
    [Show full text]
  • Repertoires of G Protein-Coupled Receptors for Ciona-Specific Neuropeptides
    Repertoires of G protein-coupled receptors for Ciona-specific neuropeptides Akira Shiraishia, Toshimi Okudaa, Natsuko Miyasakaa, Tomohiro Osugia, Yasushi Okunob, Jun Inouec, and Honoo Satakea,1 aBioorganic Research Institute, Suntory Foundation for Life Sciences, 619-0284 Kyoto, Japan; bDepartment of Biomedical Intelligence, Graduate School of Medicine, Kyoto University, 606-8507 Kyoto, Japan; and cMarine Genomics Unit, Okinawa Institute of Science and Technology Graduate University, 904-0495 Okinawa, Japan Edited by Thomas P. Sakmar, The Rockefeller University, New York, NY, and accepted by Editorial Board Member Jeremy Nathans March 11, 2019 (received for review September 26, 2018) Neuropeptides play pivotal roles in various biological events in the conservesagreaternumberofneuropeptide homologs than proto- nervous, neuroendocrine, and endocrine systems, and are corre- stomes (e.g., Caenorhabditis elegans and Drosophila melanogaster) lated with both physiological functions and unique behavioral and other invertebrate deuterostomes (7–13), confirming the evo- traits of animals. Elucidation of functional interaction between lutionary and phylogenetic relatedness of ascidians to vertebrates. neuropeptides and receptors is a crucial step for the verification of The second group includes Ciona-specific novel neuropeptides, their biological roles and evolutionary processes. However, most namely Ci-NTLPs, Ci-LFs, and Ci-YFV/Ls (SI Appendix,Fig. receptors for novel peptides remain to be identified. Here, we S1 and Table S1), which share neither consensus motifs nor se- show the identification of multiple G protein-coupled receptors quence similarity with any other peptides (8, 9). The presence of (GPCRs) for species-specific neuropeptides of the vertebrate sister both homologous and species-specific neuropeptides highlights this group, Ciona intestinalis Type A, by combining machine learning phylogenetic relative of vertebrates as a prominent model organism and experimental validation.
    [Show full text]