DOCSLIB.ORG

[18F]FPEB Binding to Metabotropic Glutamate Receptor Subtype

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
[18F]FPEB Binding to Metabotropic Glutamate Receptor Subtype Dupont et al. Translational Psychiatry (2021) 11:66 https://doi.org/10.1038/s41398-020-01152-2 Translational Psychiatry ARTICLE Open Access Study of influence of the glutamatergic concentration of [18F]FPEB binding to metabotropic glutamate receptor subtype 5 with N-acetylcysteine challenge in rats and SRM/PET study in human healthy volunteers Anne-Claire Dupont 1,2, Sophie Serrière2, Laurent Barantin 2, Johnny Vercouillie 2,3, Clovis Tauber2, Valérie Gissot 3, Sylvie Bodard2, Gabrielle Chicheri2,SylvieChalon 2, Pr Frédérique Bonnet-Brilhault2,4, Pr Maria-Joao Santiago-Ribeiro2,3,5 and Nicolas Arlicot 1,2,3 Abstract Altered glutamate signaling is thought to be involved in a myriad of psychiatric disorders. Positron emission tomography (PET) imaging with [18F]FPEB allows assessing dynamic changes in metabotropic glutamate receptor 5 (mGluR5) availability underlying neuropathological conditions. The influence of endogenous glutamatergic levels into receptor binding has not been well established yet. The purpose of this study was to explore the [18F]FPEB binding regarding to physiological fluctuations or acute changes of glutamate synaptic concentrations by a translational approach; a PET/MRS imaging study in 12 healthy human volunteers combined to a PET imaging after an N- 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; acetylcysteine (NAc) pharmacological challenge in rodents. No significant differences were observed with small-animal PET in the test and retest conditions on the one hand and the NAc condition on the other hand for any regions. To test for an interaction of mGuR5 density and glutamatergic concentrations in healthy subjects, we correlated the [18F] FPEB BPND with Glu/Cr, Gln/Cr, Glx/Cr ratios in the anterior cingulate cortex VOI; respectively, no significance correlation has been revealed (Glu/Cr: r = 0.51, p = 0.09; Gln/Cr: r = −0.46, p = 0.13; Glx/Cr: r = −0.035, p = 0.92).These data suggest that the in vivo binding of [18F]FPEB to an allosteric site of the mGluR5 is not modulated by endogenous glutamate in vivo. Thus, [18F]FPEB appears unable to measure acute fluctuations in endogenous levels of glutamate. Introduction dysfunction. Indeed, glutamate is only removed from the Glutamate, the most abundant neurotransmitter in the synaptic cleft thanks to two major astrocytic transporters, central nervous system (CNS), is primarily involved in the namely GLT-1 (EAAT2) and GLAST (EAAT1), regulating synaptic excitatory activity1. Thus, it intervenes in several receptor’s excitability3. Alterations of this glutamatergic brain functions such as memory, learning, behavior, and homeostasis may lead to various neurological and psychia- – movement2. However, when present at an excessive con- tric disorders4 9. Due to their substantial role in brain centration, glutamate may contribute to neuronal functions, elucidating the mechanism underlying glutamate receptor’s action would clarify glutamate’s role in physiolo- gical and pathological conditions. There are two main Correspondence: Nicolas Arlicot ([email protected]) classes of glutamate receptors: (i) the ionotropic receptors 1Service de Radiopharmacie, CHRU de Tours, 37044 Tours, France 2UMR 1253, iBrain, Université de Tours, Inserm, Tours, France (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid Full list of author information is available at the end of the article © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Dupont et al. Translational Psychiatry (2021) 11:66 Page 2 of 10 receptor (AMPA), Kainate receptor and N-methyl-d-aspar- concentration of PET radiotracer23. Hence, several tate receptor (NMDA)), involved in the fast-acting radiotracers targeting mGluR5 allosteric binding sites excitatory effects and, (ii) the metabotropic receptors have been proposed to investigate in vivo glutamate (mGluR), mainly implicated in the modulation of the neurotransmission by PET. The first suitable tracer for glutamatergic neurotransmission. Those metabotropic both preclinical and clinical use, namely [11C]ABP688, glutamate receptors are classified into three subtypes, was developed in 200624. Despite its favorable character- based on both their structure and functions: group I istics, its major limitation remains the short half-life of its (mGluR1 and mGluR5), group II (mGluR2 and mGluR3), radioisotope (about 20 min), limiting its use to centers with and group III (mGluR4, and mGluR6–8). The mGluR a cyclotron on site. Therefore, and to get around this belong to the G-protein coupled receptors (GPCRs), which drawback, two fluorinated radiotracers have recently been represent the largest class of drug targets, accounting for developed: [18F]PSS232 and [18F]FPEB. [18F]FPEB (3-[(18) more than 40% of marketed drugs10. Among them, F]fluoro-5-(2-pyridinylethynyl)benzonitrile) is a negative metabotropic glutamate receptors subtype 5 (mGluR5) modulator of the mGluR5 allosteric sites with an excellent 2+ have been demonstrated to play crucial roles in synaptic pharmacological profile with a human mGluR5 Ca Ic50 11,12 plasticity and neuronal development , and have espe- flux of 0.66 nM, a Ki in rats of 0.20 nM, and a logP value of cially emerged as a promising target for a broad range of 2.825. Thanks to its favorable reversible kinetics, a high neurological disorders. Widely expressed and mainly specificity, and the absence of brain radiometabolites26, postsynaptic throughout the cerebral cortex, corpus [18F]FPEB has been widely used to study in vivo dysfunc- striatum, hippocampus, olfactory bulb, caudate nucleus, tional glutamate transmission associated with neu- nucleus accumbens but also in non-neuronal cells includ- ropsychiatric including Parkinson’s disease (PD)27,major ing astrocytes and microglia, mGluR5 have been implicated depressive disorder28, addictions (alcohol)29, and autism30. in the pathogenesis of numerous psychiatric, neurological, The lack of sleep31 or smoking or a treatment by gluta- – and neurodevelopmental disorders including schizophre- mate modulators32 36 could disturb glutamate balance and nia, addiction, anxiety, depression, PD, fragile X syndrome knowledge is lacking as to whether these endogenous – (FXS), or autism spectrum disorders (ASD)2,13 17 Firstly, fluctuations could hold sway over the mGluR5 allosteric drug development programs targeting mGluR5 were binding. Numerous studies with [11C]ABP688 or [18F] interested in the orthosteric site of the receptor. However, PSS232 radiotracers based on pharmacological challenges recent findings have clearly demonstrated that allosteric that modulate endogenous glutamate levels attempted to modulators that interact with binding sites distinct from provide insight into glutamate receptor availability for sev- – the endogenous agonist glutamate had better potential. eral PET mGluR5 radioligands37 40, but only one investi- Indeed, they exhibit numerous advantages including higher gated whether [18F]FPEB could detect ketamine-induced subtype selectivity, better blood‐brain-barrier penetration, changes in mGluR5 in healthy subjects41.Conflicting results and absence of desensitization which is caused by were highlighted regarding both tracers and animal species. orthosteric ligands after repeated administrations18,19.An One PET study showed that pharmacological challenge allosteric modulator can potentiate glutamate response in with N-acetylcysteine (NAc), known to indirectly increase the case of positive allosteric modulator (PAM) or reduce extrasynaptic glutamate release through activation of the glutamate response in the case of negative allosteric cystine-glutamate antiporter (xc-)32, produced a decrease in modulator (NAM)18. NAMs (e.g., basimglurant, mavoglur- the binding of [11C]ABP688 in baboons42. In contrast, ant, and dipraglurant) were the first mGluR5 allosteric repeated studies in both rats39 and Rhesus monkeys40 – modulators evaluated into clinical trials19 22. showed no effect of pharmacological challenge on [11C] In relation to these therapeutic trials, intense efforts ABP688 binding. Therefore, assessing the [18F]FPEB bind- have been made to develop biomarkers and companion ing behavior with glutamate shift concentration seems to be tests, including for noninvasive techniques allowing glu- valuable regarding its large use in clinical trials. The pur- tamatergic transmission imaging. poseofthepresentstudywasthereforetoexplorethe Positron emission tomography (PET) utilizes positron sensitivity of [18F]FPEB binding to fluctuations of glutamate emitter labeled compound to provide valuable informa- synaptic concentrations using a translational approach. We tion about the target availability under normal and firstly used a combined PET/magnetic resonance spectro- pathological conditions,
Load more

Recommended publications
  • Mglur5 Modulation As a Treatment for Parkinson's Disease
    mGluR5 modulation as a treatment for Parkinson’s disease Kyle Farmer A thesis submitted to the Faculty of Graduate & Postdoctoral Affairs in partial fulfillment of requirements of the degree of Doctor of Philosophy in Neuroscience Carleton University Ottawa, ON Copyright © 2018 – Kyle Farmer ii Space Abstract Parkinson’s disease is an age related neurodegenerative disease. Current treatments do not reverse the degenerative course; rather they merely manage symptom severity. As such there is an urgent need to develop novel neuroprotective therapeutics. There is an additional need to stimulate and promote inherent neuro-recovery processes. Such processes could maximize the utilization of the existing dopamine neurons, and/or recruit alternate neuronal pathways to promote recovery. This thesis investigates the therapeutic potential of the mGluR5 negative allosteric modulator CTEP in a 6-hydroxydopamine mouse model of Parkinson’s disease. We found that CTEP caused a modest reduction in the parkinsonian phenotype after only 1 week of treatment. When administered for 12 weeks, CTEP was able to completely reverse any parkinsonian behaviours and resulted in full dopaminergic striatal terminal re-innervation. Furthermore, restoration of the striatal terminals resulted in normalization of hyperactive neurons in both the striatum and the motor cortex. The beneficial effects within the striatum iii were associated with an increase in activation of mTOR and p70s6K activity. Accordingly, the beneficial effects of CTEP can be blocked if co-administered with the mTOR complex 1 inhibitor, rapamycin. In contrast, CTEP had differential effects in the motor cortex, promoting ERK1/2 and CaMKIIα instead of mTOR. Together these data suggest that modulating mGluR5 with CTEP may have clinical significance in treating Parkinson’s disease.
    [Show full text]
  • Abstract Book – Oral Sessions
    Sunday, June 21, 2015 12:00 p.m. - 1:15 p.m. Latin American Psychopharmacology Update: INNOVATIVE TREATMENTS IN PSYCHIATRY INNOVATIVE TREATMENTS IN PSYCHIATRY Flavio Kapczinski, The University of Texas Health Science Center at Houston Overall Abstract In this panel, we will propose innovative treatments in psychiatry and recent literature findings will be summarized. The effective pharmacological treatment of psychiatric diseases and development of new therapeutic entities has been a long-standing challenge. Despite the complexity and heterogeneity of psychiatric disorders, basic and clinical research studies and technological advancements in genomics, biomarkers, and imaging have begun to elucidate the pathophysiology of etiological complexity of psychiatric diseases and to identify efficacious new agents (Tcheremissine et al. 2014). Many psychiatric illnesses are associated with neuronal atrophy, characterized by loss of synaptic connections, increase of inflammatory markers like TNF-α and DAMPS (damage-associate molecular patterns,- cell free (ccf) DNA, heat shock proteins HSP70, HSP90, and HSP60, and cytochrome C), decrease of neurotrophic factors, increase of oxidative stress, mitochondrial dysfunction and apoptosis (Fries et al., 2012; Pfaffenseller et al., 2014). Also, neurocognitive impairment and poor psychosocial functioning has been related to a psychiatric disease. Therefore, trying to discover new therapeutic targets that act in these pathways can help to develop new treatment or improve the treatment of these serious diseases.
    [Show full text]
  • Metabotropic Glutamate Receptors
    mGluR Metabotropic glutamate receptors mGluR (metabotropic glutamate receptor) is a type of glutamate receptor that are active through an indirect metabotropic process. They are members of thegroup C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatoryneurotransmitter. The mGluRs perform a variety of functions in the central and peripheral nervous systems: mGluRs are involved in learning, memory, anxiety, and the perception of pain. mGluRs are found in pre- and postsynaptic neurons in synapses of the hippocampus, cerebellum, and the cerebral cortex, as well as other parts of the brain and in peripheral tissues. Eight different types of mGluRs, labeled mGluR1 to mGluR8, are divided into groups I, II, and III. Receptor types are grouped based on receptor structure and physiological activity. www.MedChemExpress.com 1 mGluR Agonists, Antagonists, Inhibitors, Modulators & Activators (-)-Camphoric acid (1R,2S)-VU0155041 Cat. No.: HY-122808 Cat. No.: HY-14417A (-)-Camphoric acid is the less active enantiomer (1R,2S)-VU0155041, Cis regioisomer of VU0155041, is of Camphoric acid. Camphoric acid stimulates a partial mGluR4 agonist with an EC50 of 2.35 osteoblast differentiation and induces μM. glutamate receptor expression. Camphoric acid also significantly induced the activation of NF-κB and AP-1. Purity: ≥98.0% Purity: ≥98.0% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10 mM × 1 mL, 100 mg Size: 10 mM × 1 mL, 5 mg, 10 mg, 25 mg (2R,4R)-APDC (R)-ADX-47273 Cat. No.: HY-102091 Cat. No.: HY-13058B (2R,4R)-APDC is a selective group II metabotropic (R)-ADX-47273 is a potent mGluR5 positive glutamate receptors (mGluRs) agonist.
    [Show full text]
  • Draft COMP Agenda 16-18 January 2018
    12 January 2018 EMA/COMP/818236/2017 Inspections, Human Medicines Pharmacovigilance and Committees Committee for Orphan Medicinal Products (COMP) Draft agenda for the meeting on 16-18 January 2018 Chair: Bruno Sepodes – Vice-Chair: Lesley Greene 16 January 2018, 09:00-19:30, room 2F 17 January 2018, 08:30-19:30, room 2F 18 January 2018, 08:30-18:30, room 2F Health and safety information In accordance with the Agency’s health and safety policy, delegates are to be briefed on health, safety and emergency information and procedures prior to the start of the meeting. Disclaimers Some of the information contained in this agenda is considered commercially confidential or sensitive and therefore not disclosed. With regard to intended therapeutic indications or procedure scopes listed against products, it must be noted that these may not reflect the full wording proposed by applicants and may also vary during the course of the review. Additional details on some of these procedures will be published in the COMP meeting reports once the procedures are finalised. Of note, this agenda is a working document primarily designed for COMP members and the work the Committee undertakes. Note on access to documents Some documents mentioned in the agenda cannot be released at present following a request for access to documents within the framework of Regulation (EC) No 1049/2001 as they are subject to on- going procedures for which a final decision has not yet been adopted. They will become public when adopted or considered public according to the principles stated in the Agency policy on access to documents (EMA/127362/2006).
    [Show full text]
  • Hierarchical Mechanistic Modelling of Clinical Pharmacokinetic Data
    Hierarchical mechanistic modelling of clinical pharmacokinetic data A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Medical and Human Sciences 2015 Thierry Wendling Manchester Pharmacy School Contents List of Figures ........................................................................................................ 6 List of Tables .......................................................................................................... 9 List of abbreviations ............................................................................................ 10 Abstract ................................................................................................................ 13 Declaration ........................................................................................................... 14 Copyright ............................................................................................................. 14 Acknowledgements .............................................................................................. 15 Chapter 1: General introduction ...................................................................... 16 1.1. Modelling and simulation in drug development ........................................ 17 1.1.1. The drug development process .......................................................... 17 1.1.2. The role of pharmacokinetic and pharmacodynamic modelling in drug development ..................................................................................................
    [Show full text]
  • Brain Metabolic Profile After Intranasal Vs. Intraperitoneal Clomipramine
    International Journal of Molecular Sciences Article Brain Metabolic Profile after Intranasal vs. Intraperitoneal Clomipramine Treatment in Rats with Ultrasound Model of Depression Olga Abramova 1,2, Yana Zorkina 1,2,* , Timur Syunyakov 2,3 , Eugene Zubkov 1, Valeria Ushakova 1,2, Artemiy Silantyev 1, Kristina Soloveva 2, Olga Gurina 1, Alexander Majouga 4, Anna Morozova 1,2 and Vladimir Chekhonin 1,5 1 V. Serbsky National Medical Research Centre of Psychiatry and Narcology, 119034 Moscow, Russia; [email protected] (O.A.); [email protected] (E.Z.); [email protected] (V.U.); [email protected] (A.S.); [email protected] (O.G.); [email protected] (A.M.); [email protected] (V.C.) 2 Mental-Health Clinic No. 1 Named after N.A. Alekseev, 117152 Moscow, Russia; [email protected] (T.S.); [email protected] (K.S.) 3 Federal State Budgetary Institution Research Zakusov Institute of Pharmacology, 125315 Moscow, Russia 4 Drug Delivery Systems Laboratory, D. Mendeleev University of Chemical Technology of Russia, Miusskaya pl. 9, 125047 Moscow, Russia; [email protected] 5 Department of Medical Nanobiotechnology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia * Correspondence: [email protected]; Tel.: +7-916-588-4851 Citation: Abramova, O.; Zorkina, Y.; Abstract: Background: Molecular mechanisms of depression remain unclear. The brain metabolome Syunyakov, T.; Zubkov, E.; Ushakova, after antidepressant therapy is poorly understood and had not been performed for different routes V.; Silantyev, A.; Soloveva, K.; Gurina, of drug administration before the present study. Rats were exposed to chronic ultrasound stress O.; Majouga, A.; Morozova, A.; et al. and treated with intranasal and intraperitoneal clomipramine.
    [Show full text]
  • GPCR/G Protein
    Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com GPCR/G Protein G Protein Coupled Receptors (GPCRs) perceive many extracellular signals and transduce them to heterotrimeric G proteins, which further transduce these signals intracellular to appropriate downstream effectors and thereby play an important role in various signaling pathways. G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). In unstimulated cells, the state of G alpha is defined by its interaction with GDP, G beta-gamma, and a GPCR. Upon receptor stimulation by a ligand, G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell. These effects include activating the MAPK and PI3K pathways, as well as inhibition of the Na+/H+ exchanger in the plasma membrane, and the lowering of intracellular Ca2+ levels. Most human GPCRs can be grouped into five main families named; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secretin, forming the GRAFS classification system. A series of studies showed that aberrant GPCR Signaling including those for GPCR-PCa, PSGR2, CaSR, GPR30, and GPR39 are associated with tumorigenesis or metastasis, thus interfering with these receptors and their downstream targets might provide an opportunity for the development of new strategies for cancer diagnosis, prevention and treatment. At present, modulators of GPCRs form a key area for the pharmaceutical industry, representing approximately 27% of all FDA-approved drugs. References: [1] Moreira IS. Biochim Biophys Acta. 2014 Jan;1840(1):16-33.
    [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]
  • Title Page Metabolism and Disposition of the Metabotropic Glutamate
    DMD Fast Forward. Published on June 17, 2013 as DOI: 10.1124/dmd.112.050716 DMD FastThis article Forward. has not been Published copyedited onand Juneformatted. 17, The 2013 final versionas doi:10.1124/dmd.112.050716 may differ from this version. DMD#50716 Title Page Metabolism and disposition of the metabotropic glutamate receptor 5 antagonist (mGluR5) mavoglurant (AFQ056) in healthy subjects Downloaded from Markus Walles, Thierry Wolf, Yi Jin, Michael Ritzau, Luc Alexis Leuthold, Joel Krauser, dmd.aspetjournals.org Hans-Peter Gschwind, David Carcache, Matthias Kittelmann, Magdalena Ocwieja, Mike Ufer, Ralph Woessner, Abhijit Chakraborty and Piet Swart at ASPET Journals on September 27, 2021 Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Basel Switzerland (M.W., T.W., Y.J., L.A.L., J. K. H.-P.G, R.W., A.C., P.S.) Analytical Sciences, Novartis Institutes for Biomedical Research, Basel, Switzerland (M.R.) Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Basel, Switzerland (M.K., D.C.) Clinical Science & Innovation Novartis Institutes for Biomedical Research, Basel, Switzerland (M.O.) Translational Medicine, Novartis Institutes for Biomedical Research, Basel, Switzerland (M.U.) 1 Copyright 2013 by the American Society for Pharmacology and Experimental Therapeutics. DMD Fast Forward. Published on June 17, 2013 as DOI: 10.1124/dmd.112.050716 This article has not been copyedited and formatted. The final version may differ from this version. DMD#50716 Running Title Page Running title:
    [Show full text]
  • Emerging Preclinical Pharmacological Targets for Parkinson's Disease
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 20 Emerging preclinical pharmacological targets for Parkinson’s disease Sandeep Vasant More1 and Dong-Kug Choi1 1 Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, South Korea Correspondence to: Dong-Kug Choi, email: [email protected] Keywords: dopaminergic, Parkinson’s disease, pharmacological targets, neuroprotection, preclinical Received: October 08, 2015 Accepted: February 08, 2016 Published: March 15, 2016 ABSTRACT Parkinson’s disease (PD) is a progressive neurological condition caused by the degeneration of dopaminergic neurons in the basal ganglia. It is the most prevalent form of Parkinsonism, categorized by cardinal features such as bradykinesia, rigidity, tremors, and postural instability. Due to the multicentric pathology of PD involving inflammation, oxidative stress, excitotoxicity, apoptosis, and protein aggregation, it has become difficult to pin-point a single therapeutic target and evaluate its potential application. Currently available drugs for treating PD provide only symptomatic relief and do not decrease or avert disease progression resulting in poor patient satisfaction and compliance. Significant amount of understanding concerning the pathophysiology of PD has offered a range of potential targets for PD. Several emerging targets including AAV-hAADC gene therapy, phosphodiesterase-4, potassium channels, myeloperoxidase, acetylcholinesterase, MAO-B, dopamine, A2A, mGlu5, and 5-HT- 1A/1B receptors are in different stages of clinical development. Additionally, alternative interventions such as deep brain stimulation, thalamotomy, transcranial magnetic stimulation, and gamma knife surgery, are also being developed for patients with advanced PD. As much as these therapeutic targets hold potential to delay the onset and reverse the disease, more targets and alternative interventions need to be examined in different stages of PD.
    [Show full text]
  • AHRQ Healthcare Horizon Scanning System – Status Update
    AHRQ Healthcare Horizon Scanning System – Status Update Horizon Scanning Status Update: January 2015 Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov Contract No. HHSA290-2010-00006-C Prepared by: ECRI Institute 5200 Butler Pike Plymouth Meeting, PA 19462 January 2015 Statement of Funding and Purpose This report incorporates data collected during implementation of the Agency for Healthcare Research and Quality (AHRQ) Healthcare Horizon Scanning System by ECRI Institute under contract to AHRQ, Rockville, MD (Contract No. HHSA290-2010-00006-C). The findings and conclusions in this document are those of the authors, who are responsible for its content, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. A novel intervention may not appear in this report simply because the System has not yet detected it. The list of novel interventions in the Horizon Scanning Status Update Report will change over time as new information is collected. This should not be construed as either endorsements or rejections of specific interventions. As topics are entered into the System, individual target technology reports are developed for those that appear to be closer to diffusion into practice in the United States. A representative from AHRQ served as a Contracting Officer’s Technical Representative and provided input during the implementation of the horizon scanning system. AHRQ did not directly participate in the horizon scanning, assessing the leads or topics, or provide opinions regarding potential impact of interventions.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9,636,316 B2 Cohen Et Al
    USOO9636316B2 (12) United States Patent (10) Patent No.: US 9,636,316 B2 Cohen et al. (45) Date of Patent: May 2, 2017 (54) BACLOFENAND ACAMPROSATE BASED (58) Field of Classification Search THERAPY OF NEUROLOGICAL DISORDERS CPC ... A61K 31/197; A61K 31/445; A61K 31/42: A61K 31/44; A61K 31/195; A61 K (71) Applicant: PHARNEXT, Issy les Moulineaux (FR) 31/185; A61K 31/138: A61K 31/164 (72) Inventors: Daniel Cohen, Saint Cloud (FR); Ilya USPC ................................. 514/567, 555, 568, 665 Chumakov, Vaux-le-Penil (FR); See application file for complete search history. Serguei Nabirochkin, Chatenay-Malabry (FR); Emmanuel Vial, Paris (FR); Mickael Guedj. Paris (56) References Cited (FR) U.S. PATENT DOCUMENTS (73) Assignee: PHARNEXT, Issy les Moulineaux (FR) 6,391922 B1 5/2002 Fogel 8,741,886 B2 6, 2014 Cohen et al. Notice: Subject to any disclaimer, the term of this 2001, 0004640 A1 6/2001 Inada et al. (*) 2001 OO23246 A1 9, 2001 Barritault et al. patent is extended or adjusted under 35 2004.0102525 A1 5, 2004 KOZachuk U.S.C. 154(b) by 0 days. 2008. O18851.0 A1 8, 2008 Yoshino 2009 OO69419 A1 3/2009 Jandeleit et al. (21) Appl. No.: 14/861,169 2009/O197958 A1 8/2009 Sastry et al. 2011 O230659 A1 9/2011 Tsukamoto et al. (22) Filed: Sep. 22, 2015 2012fO27083.6 A1 10, 2012 Cohen et al. (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2016/OOOO736A1 Jan. 7, 2016 EP 1 S63 846 8, 2005 EP 1837 O34 9, 2007 WO WO O1, 58.476 8, 2001 WO WO O3,OOT993 1, 2003 Related U.S.
    [Show full text]