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Parkinson Disease: HELP
Articles by Erwan Bezard
Based on 62 articles published since 2008
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Between 2008 and 2019, E. Bezard wrote the following 62 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial Experimental reappraisal of continuous dopaminergic stimulation against L-dopa-induced dyskinesia. 2013

Bezard, Erwan. · ·Mov Disord · Pubmed #23143999.

ABSTRACT: -- No abstract --

2 Review Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy. 2017

Obeso, J A / Stamelou, M / Goetz, C G / Poewe, W / Lang, A E / Weintraub, D / Burn, D / Halliday, G M / Bezard, E / Przedborski, S / Lehericy, S / Brooks, D J / Rothwell, J C / Hallett, M / DeLong, M R / Marras, C / Tanner, C M / Ross, G W / Langston, J W / Klein, C / Bonifati, V / Jankovic, J / Lozano, A M / Deuschl, G / Bergman, H / Tolosa, E / Rodriguez-Violante, M / Fahn, S / Postuma, R B / Berg, D / Marek, K / Standaert, D G / Surmeier, D J / Olanow, C W / Kordower, J H / Calabresi, P / Schapira, A H V / Stoessl, A J. ·HM CINAC, Hospital Universitario HM Puerta del Sur, Mostoles, Madrid, Spain. · Universidad CEU San Pablo, Madrid, Spain. · CIBERNED, Madrid, Spain. · Department of Neurology, Philipps University, Marburg, Germany. · Parkinson's Disease and Movement Disorders Department, HYGEIA Hospital and Attikon Hospital, University of Athens, Athens, Greece. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA. · Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. · Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto, Canada. · Department of Medicine, University of Toronto, Toronto, Canada. · Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Parkinson's Disease and Mental Illness Research, Education and Clinical Centers (PADRECC and MIRECC), Corporal Michael J. Crescenz Veteran's Affairs Medical Center, Philadelphia, Pennsylvania, USA. · Medical Sciences, Newcastle University, Newcastle, UK. · Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia. · School of Medical Sciences, University of New South Wales and Neuroscience Research Australia, Sydney, Australia. · Université de Bordeaux, Institut des Maladies Neurodégénératives, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, Institut des Maladies Neurodégénératives, Bordeaux, France. · China Academy of Medical Sciences, Institute of Lab Animal Sciences, Beijing, China. · Departments of Neurology, Pathology, and Cell Biology, the Center for Motor Neuron Biology and Disease, Columbia University, New York, New York, USA. · Columbia Translational Neuroscience Initiative, Columbia University, New York, New York, USA. · Institut du Cerveau et de la Moelle épinière - ICM, Centre de NeuroImagerie de Recherche - CENIR, Sorbonne Universités, UPMC Univ Paris 06, Inserm U1127, CNRS UMR 7225, Paris, France. · Groupe Hospitalier Pitié-Salpêtrière, Paris, France. · Clinical Sciences Department, Newcastle University, Newcastle, UK. · Department of Nuclear Medicine, Aarhus University, Aarhus, Denmark. · Human Neurophysiology, Sobell Department, UCL Institute of Neurology, London, UK. · Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. · Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA. · Morton and Gloria Shulman Movement Disorders Centre and the Edmond J Safra Program in Parkinson's disease, Toronto Western Hospital, University of Toronto, Toronto, Canada. · Movement Disorders and Neuromodulation Center, Department of Neurology, University of California-San Francisco, San Francisco, California, USA. · Parkinson's Disease Research, Education and Clinical Center, San Francisco Veterans Affairs Medical Center, San Francisco, California, USA. · Veterans Affairs Pacific Islands Health Care System, Honolulu, Hawaii, USA. · Parkinson's Institute, Sunnyvale, California, USA. · Institute of Neurogenetics, University of Luebeck, Luebeck, Germany. · Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. · Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA. · Department of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Canada. · Department of Neurology, Universitätsklinikum Schleswig-Holstein, Christian Albrechts University Kiel, Kiel, Germany. · Department of Medical Neurobiology, Institute of Medical Research Israel-Canada, Jerusalem, Israel. · Edmond and Lily Safra Center for Brain Sciences, The Hebrew University, Jerusalem, Israel. · Department of Neurosurgery, Hadassah University Hospital, Jerusalem, Israel. · Parkinson's Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Barcelona, Spain. · Department of Medicine, Universitat de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Barcelona, Spain. · Movement Disorders Clinic, Clinical Neurodegenerative Research Unit, Mexico City, Mexico. · Instituto Nacional de Neurología y Neurocirugía, Mexico City, Mexico. · Department of Neurology, Columbia University Medical Center, New York, New York, USA. · Department of Neurology, McGill University, Montreal General Hospital, Montreal, Quebec, Canada. · Klinik für Neurologie, UKSH, Campus Kiel, Christian-Albrechts-Universität, Kiel, Germany. · Institute for Neurodegenerative Disorders, New Haven, Connecticut, USA. · Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA. · Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. · Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, New York, USA. · Research Center for Brain Repair, Rush University Medical Center, Chicago, Illinois, USA. · Neuroscience Graduate Program, Rush University Medical Center, Chicago, Illinois, USA. · Neurological Clinic, Department of Medicine, Hospital Santa Maria della Misericordia, University of Perugia, Perugia, Italy. · Laboratory of Neurophysiology, Santa Lucia Foundation, IRCCS, Rome, Italy. · University Department of Clinical Neurosciences, UCL Institute of Neurology, University College London, London, UK. · Pacific Parkinson's Research Centre, Division of Neurology & Djavadf Mowafaghian Centre for Brain Health, University of British Columbia, British Columbia, Canada. · Vancouver Coastal Health, Vancouver, British Columbia, Canada. ·Mov Disord · Pubmed #28887905.

ABSTRACT: This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

3 Review Experimental animal models of Parkinson's disease: A transition from assessing symptomatology to α-synuclein targeted disease modification. 2017

Ko, Wai Kin D / Bezard, Erwan. ·Motac Neuroscience Ltd, Manchester, United Kingdom. Electronic address: d.ko@motac.com. · Motac Neuroscience Ltd, Manchester, United Kingdom; Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France. ·Exp Neurol · Pubmed #28764902.

ABSTRACT: With the understanding that α-synuclein plays a major role in the pathogenesis of Parkinson's disease (PD), novel animal models have been developed for conducting preclinical research in screening novel disease modifying therapies. Advancements in research techniques in α-synuclein targeted disease modification have utilised methods such as viral mediated expression of human α-synuclein, as well as the inoculation of pathogenic α-synuclein species from Lewy Bodies of PD patients, for accurately modelling progressive self-propagating neurodegeneration. In applying these cutting-edge research tools with sophisticated trial designs in preclinical drug trials, a useful platform has emerged for developing candidate agents with disease modifying actions, promising a greater chance of success for clinical translation. In this article, we describe the transition of well-established animal models of PD symptomatology to newly developed models of PD pathogenesis, with specific focus on methods of viral-mediated and inoculation of pathogenic α-synuclein, that aim to aid scientific translation of neuroprotective strategies.

4 Review Impulse control disorders and levodopa-induced dyskinesias in Parkinson's disease: an update. 2017

Voon, Valerie / Napier, T Celeste / Frank, Michael J / Sgambato-Faure, Veronique / Grace, Anthony A / Rodriguez-Oroz, Maria / Obeso, Jose / Bezard, Erwan / Fernagut, Pierre-Olivier. ·Department of Psychiatry and Behavioural and Clinical Neurosciences Institute, University of Cambridge, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK. Electronic address: vv247@cam.ac.uk. · Departments of Pharmacology and Psychiatry, Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA. · Department of Cognitive, Linguistic and Psychological Sciences and Department of Psychiatry and Human Behavior, Brown Institute for Brain Science, Providence, RI, USA. · Institut des Sciences Cognitives Marc Jeannerod, CNRS, Bron, France; Université Claude Bernard Lyon 1, Villeurbanne, France. · Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA, USA. · Biodonostia Health Research Institute, University Hospital Donostia, and Basque Center on Cognition, Brain and Language, San Sebastián, Spain; Ikerbasque-Basque Foundation for Science, Bilbao, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto Carlos III, Spain. · Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto Carlos III, Spain; HM Centro Integral de Neurociencias, HM Puerta del Sur, Mostoles and Centro de Estudios Universitarios-San Pablo University, Madrid, Spain. · Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; Centre National de la Recherche Scientifique, Institut des Maladies Neurodégénératives, Bordeaux, France. ·Lancet Neurol · Pubmed #28229895.

ABSTRACT: Dopaminergic medications used in the treatment of patients with Parkinson's disease are associated with motor and non-motor behavioural side-effects, such as dyskinesias and impulse control disorders also known as behavioural addictions. Levodopa-induced dyskinesias occur in up to 80% of patients with Parkinson's after a few years of chronic treatment. Impulse control disorders, including gambling disorder, binge eating disorder, compulsive sexual behaviour, and compulsive shopping occur in about 17% of patients with Parkinson's disease on dopamine agonists. These behaviours reflect the interactions of the dopaminergic medications with the individual's susceptibility, and the underlying neurobiology of Parkinson's disease. Parkinsonian rodent models show enhanced reinforcing effects of chronic dopaminergic medication, and a potential role for individual susceptibility. In patients with Parkinson's disease and impulse control disorders, impairments are observed across subtypes of decisional impulsivity, possibly reflecting uncertainty and the relative balance of rewards and losses. Impairments appear to be more specific to decisional than motor impulsivity, which might reflect differences in ventral and dorsal striatal engagement. Emerging evidence suggests impulse control disorder subtypes have dissociable correlates, which indicate that individual susceptibility predisposes towards the expression of different behavioural subtypes and neurobiological substrates. Therapeutic interventions to treat patients with Parkinson's disease and impulse control disorders have shown efficacy in randomised controlled trials. Large-scale studies are warranted to identify individual risk factors and novel therapeutic targets for these diseases. Mechanisms underlying impulse control disorders and dyskinesias could provide crucial insights into other behavioural symptoms in Parkinson's disease and addictions in the general population.

5 Review Protein aggregation and neurodegeneration in prototypical neurodegenerative diseases: Examples of amyloidopathies, tauopathies and synucleinopathies. 2017

Bourdenx, Mathieu / Koulakiotis, Nikolaos Stavros / Sanoudou, Despina / Bezard, Erwan / Dehay, Benjamin / Tsarbopoulos, Anthony. ·Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. · GAIA Research Center, Bioanalytical Department, The Goulandris Natural History Museum, Kifissia 14562, Greece. · National and Kapodistrian University of Athens Medical School, Department of Internal Medicine, 75 Mikras Asias Street, Athens 11527, Greece. · Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. Electronic address: benjamin.dehay@u-bordeaux.fr. · GAIA Research Center, Bioanalytical Department, The Goulandris Natural History Museum, Kifissia 14562, Greece; National and Kapodistrian University of Athens Medical School, Department of Pharmacology, 75 Mikras Asias Street, Athens 11527, Greece. Electronic address: atsarbop@med.uoa.gr. ·Prog Neurobiol · Pubmed #26209472.

ABSTRACT: Alzheimer's and Parkinson's diseases are the most prevalent neurodegenerative diseases that generate important health-related direct and indirect socio-economic costs. They are characterized by severe neuronal losses in several disease-specific brain regions associated with deposits of aggregated proteins. In Alzheimer's disease, β-amyloid peptide-containing plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated microtubule-associated protein tau are the two main neuropathological lesions, while Parkinson's disease is defined by the presence of Lewy Bodies that are intraneuronal proteinaceous cytoplasmic inclusions. α-Synuclein has been identified as a major protein component of Lewy Bodies and heavily implicated in the pathogenesis of Parkinson's disease. In the past few years, evidence has emerged to explain how these aggregate-prone proteins can undergo spontaneous self-aggregation, propagate from cell to cell, and mediate neurotoxicity. Current research now indicates that oligomeric forms are probably the toxic species. This article discusses recent progress in the understanding of the pathogenesis of these diseases, with a focus on the underlying mechanisms of protein aggregation, and emphasizes the pathophysiological molecular mechanisms leading to cellular toxicity. Finally, we present the putative direct link between β-amyloid peptide and tau in causing toxicity in Alzheimer's disease as well as α-synuclein in Parkinson's disease, along with some of the most promising therapeutic strategies currently in development for those incurable neurodegenerative disorders.

6 Review Targeting α-synuclein: Therapeutic options. 2016

Dehay, Benjamin / Decressac, Mickael / Bourdenx, Mathieu / Guadagnino, Irene / Fernagut, Pierre-Olivier / Tamburrino, Anna / Bassil, Fares / Meissner, Wassilios G / Bezard, Erwan. ·Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. · CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. · Telethon Institute of Genetics and Medicine, Pozzuoli, Italy. · Department of Neurology, University Hospital Bordeaux, Bordeaux, France. ·Mov Disord · Pubmed #26926119.

ABSTRACT: The discovery of the central role of α-synuclein (αSyn) in the pathogenesis of Parkinson's disease (PD) has powered, in the last decade, the emergence of novel relevant models of this condition based on viral vector-mediated expression of the disease-causing protein or inoculation of toxic species of αSyn. Although the development of these powerful tools and models has provided considerable insights into the mechanisms underlying neurodegeneration in PD, it has also been translated into the expansion of the landscape of preclinical therapeutic strategies. Much attention is now brought to the proteotoxic mechanisms induced by αSyn and how to block them using strategies inspired by intrinsic cellular pathways such as the enhancement of cellular clearance by the lysosomal-autophagic system, through proteasome-mediated degradation or through immunization. The important effort undertaken by several laboratories and consortia to tackle these issues and identify novel targets warrants great promise for the discovery not only of neuroprotective approaches but also of restorative strategies for PD and other synucleinopathies. In this viewpoint, we summarize the latest advances in this new area of PD research and will discuss promising approaches and ongoing challenges. © 2016 International Parkinson and Movement Disorder Society.

7 Review Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease. 2015

Bastide, Matthieu F / Meissner, Wassilios G / Picconi, Barbara / Fasano, Stefania / Fernagut, Pierre-Olivier / Feyder, Michael / Francardo, Veronica / Alcacer, Cristina / Ding, Yunmin / Brambilla, Riccardo / Fisone, Gilberto / Jon Stoessl, A / Bourdenx, Mathieu / Engeln, Michel / Navailles, Sylvia / De Deurwaerdère, Philippe / Ko, Wai Kin D / Simola, Nicola / Morelli, Micaela / Groc, Laurent / Rodriguez, Maria-Cruz / Gurevich, Eugenia V / Quik, Maryka / Morari, Michele / Mellone, Manuela / Gardoni, Fabrizio / Tronci, Elisabetta / Guehl, Dominique / Tison, François / Crossman, Alan R / Kang, Un Jung / Steece-Collier, Kathy / Fox, Susan / Carta, Manolo / Angela Cenci, M / Bézard, Erwan. ·Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France. · Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France; Department of Neurology, University Hospital Bordeaux, France. · Laboratory of Neurophysiology, Fondazione Santa Lucia, IRCCS, Rome, Italy. · Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy. · Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. · Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden. · Department of Neurology, Columbia University, New York, USA. · Pacific Parkinson's Research Centre and National Parkinson Foundation Centre of Excellence, University of British Columbia, Vancouver, Canada. · Department of Biomedical Sciences, Section of Neuropsychopharmacology, Cagliari University, 09124 Cagliari, Italy. · Univ. de Bordeaux, Institut Interdisciplinaire de neurosciences, UMR 5297, 33000 Bordeaux, France; CNRS, Institut Interdisciplinaire de neurosciences, UMR 5297, 33000 Bordeaux, France. · Department of Neurology, Hospital Universitario Donostia and Neuroscience Unit, Bio Donostia Research Institute, San Sebastian, Spain. · Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. · Center for Health Sciences, SRI International, CA 94025, USA. · Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy. · Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milano, Italy. · Department of Biomedical Sciences, Physiology Section, Cagliari University, Cagliari, Italy. · Motac Neuroscience Ltd, Manchester, UK. · Michigan State University, College of Human Medicine, Department of Translational Science and Molecular Medicine & The Udall Center of Excellence in Parkinson's Disease Research, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA. · Morton & Gloria Shulman Movement Disorders Center, Toronto Western Hospital, Toronto, Ontario M4T 2S8, Canada. · Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France; Motac Neuroscience Ltd, Manchester, UK. Electronic address: erwan.bezard@u-bordeaux.fr. ·Prog Neurobiol · Pubmed #26209473.

ABSTRACT: Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinson's disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms.

8 Review Why bother using non-human primate models of cognitive disorders in translational research? 2015

Camus, Sandrine / Ko, Wai Kin D / Pioli, Elsa / Bezard, Erwan. ·Motac Neuroscience Ltd, Manchester, United Kingdom. · Motac Neuroscience Ltd, Manchester, United Kingdom; Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France. ·Neurobiol Learn Mem · Pubmed #26135120.

ABSTRACT: Although everyone would agree that successful translation of therapeutic candidates for central nervous disorders should involve non-human primate (nhp) models of cognitive disorders, we are left with the paucity of publications reporting either the target validation or the actual preclinical testing in heuristic nhp models. In this review, we discuss the importance of nhps in translational research, highlighting the advances in technological/methodological approaches for 'bridging the gap' between preclinical and clinical experiments. In this process, we acknowledge that nhps remain a vital tool for the investigation of complex cognitive functions, given their resemblance to humans in aspects of behaviour, anatomy and physiology. The recent improvements made for a suitable nhp model in cognitive research, including new surrogates of disease and application of innovative methodological approaches, are continuous strides for reaching efficient translation for human benefit. This will ultimately aid the development of innovative treatments against the current and future threat of neurological and psychiatric disorders to the global population.

9 Review Targeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations. 2015

Dehay, Benjamin / Bourdenx, Mathieu / Gorry, Philippe / Przedborski, Serge / Vila, Miquel / Hunot, Stephane / Singleton, Andrew / Olanow, C Warren / Merchant, Kalpana M / Bezard, Erwan / Petsko, Gregory A / Meissner, Wassilios G. ·Institute of Neurodegenerative Diseases, University of Bordeaux, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux, France. · Research Unit of Theoretical & Applied Economics, University of Bordeaux, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5113, 33608 Pessac, France. · Departments of Neurology, Pathology and Cell Biology, and the Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA. · Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas, 08035 Barcelona, Spain. · Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, 08193 Bellaterra, Barcelona, Spain. · Catalan Institution for Research and Advanced Studies, 08010 Barcelona, Spain. · ICM, Paris, France; Sorbonne Universités. · UPMC Université Paris 06, UM 75, ICM, Paris, France. · CNRS, UMR 7225, ICM, Paris, France. · Inserm, U 1127, ICM, Paris, France. · Molecular Genetics Section and Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD20892, USA. · Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY 10032, USA. · TransThera Consulting Co., Zionsville, IN, 46077, USA. · Department of Neurology and Feil Family Brain and Mind research Institute, Weill Cornell Medical College, New York NY 10021, USA. ·Lancet Neurol · Pubmed #26050140.

ABSTRACT: Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the α-synuclein protein in the form of Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease. Most cases occur sporadically, but mutations in several genes, including SNCA, which encodes α-synuclein, are associated with disease development. The discovery and development of therapeutic strategies to block cell death in Parkinson's disease has been limited by a lack of understanding of the mechanisms driving neurodegeneration. However, increasing evidence of multiple pivotal roles of α-synuclein in the pathogenesis of Parkinson's disease has led researchers to consider the therapeutic potential of several strategies aimed at reduction of α-synuclein toxicity. We critically assess the potential of experimental therapies targeting α-synuclein, and discuss steps that need to be taken for target validation and drug development.

10 Review Slowing of neurodegeneration in Parkinson's disease and Huntington's disease: future therapeutic perspectives. 2014

Schapira, Anthony H V / Olanow, C Warren / Greenamyre, J Timothy / Bezard, Erwan. ·Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK. Electronic address: a.schapira@ucl.ac.uk. · Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY, USA. · Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15260, USA. · Université de Bordeaux, Institut des Maladies Neurodégénératives, 33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, 33000 Bordeaux, France. ·Lancet · Pubmed #24954676.

ABSTRACT: Several important advances have been made in our understanding of the pathways that lead to cell dysfunction and death in Parkinson's disease and Huntington's disease. These advances have been informed by both direct analysis of the post-mortem brain and by study of the biological consequences of the genetic causes of these diseases. Some of the pathways that have been implicated so far include mitochondrial dysfunction, oxidative stress, kinase pathways, calcium dysregulation, inflammation, protein handling, and prion-like processes. Intriguingly, these pathways seem to be important in the pathogenesis of both diseases and have led to the identification of molecular targets for candidate interventions designed to slow or reverse their course. We review some recent advances that underlie putative therapies for neuroprotection in Parkinson's disease and Huntington's disease, and potential targets that might be exploited in the future. Although we will need to overcome important hurdles, especially in terms of clinical trial design, we propose several target pathways that merit further study. In Parkinson's disease, these targets include agents that might improve mitochondrial function or increase degradation of defective mitochondria, kinase inhibitors, calcium channel blockers, and approaches that interfere with the misfolding, templating, and transmission of α-synuclein. In Huntington's disease, strategies might also be directed at mitochondrial bioenergetics and turnover, the prevention of protein dysregulation, disruption of the interaction between huntingtin and p53 or huntingtin-interacting protein 1 to reduce apoptosis, and interference with expression of mutant huntingtin at both the nucleic acid and protein levels.

11 Review Multiple system atrophy: a prototypical synucleinopathy for disease-modifying therapeutic strategies. 2014

Fernagut, Pierre-Olivier / Dehay, Benjamin / Maillard, Aline / Bezard, Erwan / Perez, Paul / Pavy-Le Traon, Anne / Rascol, Olivier / Foubert-Samier, Alexandra / Tison, François / Meissner, Wassilios G. ·Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France. · CHU de Bordeaux, Unité de Soutien Méthodologique à la Recherche Clinique (USMR), Pôle de santé publique, Bordeaux, France. · Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; Service de Neurologie, CHU de Bordeaux, F-33604 Pessac, France. · Centre de référence atrophie multisystématisée, CHU de Toulouse, Toulouse, France. · Centre de référence atrophie multisystématisée, CHU de Toulouse, Toulouse, France; Department of Clinical Pharmacology, University Hospital and University of Toulouse 3, Toulouse, France; Department of Neurosciences, University Hospital and University of Toulouse 3, Toulouse, France; INSERM UMR825 and CIC9302, Toulouse, France. · Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; Service de Neurologie, CHU de Bordeaux, F-33604 Pessac, France; Centre de référence atrophie multisystématisée, CHU de Bordeaux, Pessac, France. · Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; Service de Neurologie, CHU de Bordeaux, F-33604 Pessac, France; Centre de référence atrophie multisystématisée, CHU de Bordeaux, Pessac, France. Electronic address: wassilios.meissner@chu-bordeaux.fr. ·Neurobiol Dis · Pubmed #24727096.

ABSTRACT: Despite active fundamental, translational and clinical research, no therapeutic intervention has yet shown convincing effects on disease progression in Parkinson's disease (PD) patients. Indeed, several disease-modification trials failed or proved to be inconclusive due to lack of consistency between clinical rating scales and putative surrogate markers of disease progression, or confounding symptomatic effects of the tested compound. Multiple system atrophy (MSA) is a rapidly progressing orphan disorder leading to severe motor disability within a few years. Together with PD and dementia with Lewy bodies (DLB), MSA belongs to the synucleinopathies, a group of neurodegenerative disorders characterized by the abnormal accumulation of alpha-synuclein. Crucial milestones have been reached for successfully conducting clinical intervention trials in a large number of patients with MSA. In this personal view, we will review evidence, and discuss why MSA could prove the most relevant clinical model for assessing treatments that target mechanisms operating in all synucleinopathies.

12 Review Lysosomal impairment in Parkinson's disease. 2013

Dehay, Benjamin / Martinez-Vicente, Marta / Caldwell, Guy A / Caldwell, Kim A / Yue, Zhenyue / Cookson, Mark R / Klein, Christine / Vila, Miquel / Bezard, Erwan. ·Institute of Neurodegenerative Diseases, University of Bordeaux Segalen, Centre National de Recherche Scientifique Unité Mixte de Recherche 5293, Bordeaux, France. benjamin.dehay@u-bordeaux2.fr ·Mov Disord · Pubmed #23580333.

ABSTRACT: Impairment of autophagy-lysosomal pathways (ALPs) is increasingly regarded as a major pathogenic event in neurodegenerative diseases, including Parkinson's disease (PD). ALP alterations are observed in sporadic PD brains and in toxic and genetic rodent models of PD-related neurodegeneration. In addition, PD-linked mutations and post-translational modifications of α-synuclein impair its own lysosomal-mediated degradation, thereby contributing to its accumulation and aggregation. Furthermore, other PD-related genes, such as leucine-rich repeat kinase-2 (LRRK2), parkin, and phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), have been mechanistically linked to alterations in ALPs. Conversely, mutations in lysosomal-related genes, such as glucocerebrosidase (GBA) and lysosomal type 5 P-type ATPase (ATP13A2), have been linked to PD. New data offer mechanistic molecular evidence for such a connection, unraveling a causal link between lysosomal impairment, α-synuclein accumulation, and neurotoxicity. First, PD-related GBA deficiency/mutations initiate a positive feedback loop in which reduced lysosomal function leads to α-synuclein accumulation, which, in turn, further decreases lysosomal GBA activity by impairing the trafficking of GBA from the endoplasmic reticulum-Golgi to lysosomes, leading to neurodegeneration. Second, PD-related mutations/deficiency in the ATP13A2 gene lead to a general lysosomal impairment characterized by lysosomal membrane instability, impaired lysosomal acidification, decreased processing of lysosomal enzymes, reduced degradation of lysosomal substrates, and diminished clearance of autophagosomes, collectively contributing to α-synuclein accumulation and cell death. According to these new findings, primary lysosomal defects could potentially account for Lewy body formation and neurodegeneration in PD, laying the groundwork for the prospective development of new neuroprotective/disease-modifying therapeutic strategies aimed at restoring lysosomal levels and function.

13 Review Animal models of Parkinson's disease: limits and relevance to neuroprotection studies. 2013

Bezard, Erwan / Yue, Zhenyu / Kirik, Deniz / Spillantini, Maria Grazia. ·University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. erwan.bezard@u-bordeaux2.fr ·Mov Disord · Pubmed #22753348.

ABSTRACT: Over the last two decades, significant strides has been made toward acquiring a better knowledge of both the etiology and pathogenesis of Parkinson's disease (PD). Experimental models are of paramount importance to obtain greater insights into the pathogenesis of the disease. Thus far, neurotoxin-based animal models have been the most popular tools employed to produce selective neuronal death in both in vitro and in vivo systems. These models have been commonly referred to as the pathogenic models. The current trend in modeling PD revolves around what can be called the disease gene-based models or etiologic models. The value of utilizing multiple models with a different mechanism of insult rests on the premise that dopamine-producing neurons die by stereotyped cascades that can be activated by a range of insults, from neurotoxins to downregulation and overexpression of disease-related genes. In this position article, we present the relevance of both pathogenic and etiologic models as well as the concept of clinically relevant designs that, we argue, should be utilized in the preclinical development phase of new neuroprotective therapies before embarking into clinical trials.

14 Review New animal models of Parkinson's disease. 2011

Dehay, Benjamin / Bezard, Erwan. ·Université Victor Ségalen-Bordeaux II, Centre National de la Recherche Scientifique, Institute of Neurodegenerative Diseases, Bordeaux, France. benjamin.dehay@u-bordeaux2.fr ·Mov Disord · Pubmed #22046592.

ABSTRACT: BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder mainly characterized by the loss of dopaminergic neurons from the substantia nigra pars compacta and the presence, in the affected brain regions, of protein inclusions named Lewy Bodies. Despite the fact that numerous mutations causing hereditary forms of Parkinson's disease have been identified in the last decade, current transgenic animal models do not adequately reproduce cardinal features of the human disease. Altogether, the animal models derived of human mutations indicate that the nigrostriatal degenerative process results from the combination of several mechanisms that implicate mitochondrial dysfunction, oxidative damage, and protein degradation impairment. METHODS AND RESULTS: We performed a literature search between 2008 and 2010. DISCUSSION: The absence of adequate in vivo experimental models of Parkinson's disease has severe repercussions for therapeutic intervention success for this incurable neurodegenerative disorder. The present nonexhaustive review looks at invertebrate and mammalian models of Parkinson's disease generated in the last three years.

15 Review Molecular mechanisms of l-DOPA-induced dyskinesia. 2011

Fisone, Gilberto / Bezard, Erwan. ·Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden. ·Int Rev Neurobiol · Pubmed #21907084.

ABSTRACT: Parkinson's disease (PD), a common neurodegenerative disorder caused by the loss of the dopaminergic input to the basal ganglia, is commonly treated with l-DOPA. Use of this drug, however, is severely limited by the development of dystonic and choreic motor complications, or dyskinesia. This chapter describes the molecular mechanisms implicated in the emergence and manifestation of l-DOPA-induced dyskinesia (LID). Particular emphasis is given to the role played in this condition by abnormalities in signal transduction at the level of the medium spiny neurons (MSNs) of the striatum, which are the principal target of l-DOPA. Recent evidence pointing to pre-synaptic dysregulation is also discussed.

16 Review Contribution of pre-synaptic mechanisms to L-DOPA-induced dyskinesia. 2011

Carta, M / Bezard, E. ·Neurobiology Unit, Department of Experimental Medical Science, Lund University, BMC A11, Solvegatan 17, 22184 Lund, Sweden. manolocarta@unica.it ·Neuroscience · Pubmed #21840375.

ABSTRACT: Positron emission tomography (PET) imaging studies have shown that peak-dose dyskinesia is associated to abnormally high levels of synaptic dopamine (DA) in the caudate-putamen of dyskinetic L-DOPA-treated patients. High striatal extracellular DA levels have also been found in dyskinetic 6-OHDA-lesioned rats as compared to non-dyskinetic ones, suggesting that extracellular DA levels may play a key role in the induction of dyskinesia. In this article we review the evidences pointing to the serotonin system as the primary cause for the abnormally high levels of L-DOPA-derived extracellular DA in Parkinson's disease, and we discuss the feasibility of a therapeutic approach targeting this system.

17 Review A tale on animal models of Parkinson's disease. 2011

Bezard, Erwan / Przedborski, Serge. ·Insitute of Neurodegenerative Diseases, Université Victor Ségalen-Bordeaux II, Centre National de la Recherche Scientifique, Bordeaux, France. ·Mov Disord · Pubmed #21626544.

ABSTRACT: Parkinson's disease is a neurodegenerative disorder whose cardinal manifestations are due primarily to a profound deficit in brain dopamine. Since the 1980s, several therapeutic strategies have been discovered to treat the symptoms of this neurological disorder, but as of yet, none halts or retards the neurodegenerative process. In an attempt to shed light on the neurobiology of Parkinson's disease, a number of experimental models have been developed, especially during the last 25 years. They come essentially in 3 flavors: pharmacological (eg, reserpine), toxic (eg, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), and genetic (eg, transgenic synuclein mice). These models can also be recast as etiologic, pathogenic, and symptomatic/pathophysiologic, as each may contribute to our understanding of the cause, the mechanisms, and the treatment of Parkinson's disease. In this review, we will discuss the question of Parkinson's disease models, starting from the period when this journal was born to today. During this journey of 25 years, we will discuss both the significant contributions of the Parkinson's disease models and hurdles that remain to be overcome to one day cure this neurological disease.

18 Review Priorities in Parkinson's disease research. 2011

Meissner, Wassilios G / Frasier, Mark / Gasser, Thomas / Goetz, Christopher G / Lozano, Andres / Piccini, Paola / Obeso, José A / Rascol, Olivier / Schapira, Anthony / Voon, Valerie / Weiner, David M / Tison, François / Bezard, Erwan. ·Service de Neurologie et Centre de référence atrophie multisystématisée, CHU de Bordeaux, Avenue Magellan F-33604 Pessac France. wassilios.meissner@chu-bordeaux.fr ·Nat Rev Drug Discov · Pubmed #21532567.

ABSTRACT: The loss of dopaminergic neurons in the substantia nigra pars compacta leads to the characteristic motor symptoms of Parkinson's disease: bradykinesia, rigidity and resting tremors. Although these symptoms can be improved using currently available dopamine replacement strategies, there is still a need to improve current strategies of treating these symptoms, together with a need to alleviate non-motor symptoms of the disease. Moreover, treatments that provide neuroprotection and/or disease-modifying effects remain an urgent unmet clinical need. This Review describes the most promising biological targets and therapeutic agents that are currently being assessed to address these treatment goals. Progress will rely on understanding genetic mutations or susceptibility factors that lead to Parkinson's disease, better translation between preclinical animal models and clinical research, and improving the design of future clinical trials.

19 Review Dopamine receptors and L-dopa-induced dyskinesia. 2009

Berthet, Amandine / Bezard, Erwan. ·Université Victor-Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France. ·Parkinsonism Relat Disord · Pubmed #20123563.

ABSTRACT: In the majority of Parkinson's disease patients, chronic dopamine replacement therapy leads to involuntary aimless movements known as l-dopa-induced dyskinesia. While mechanisms involved in dyskinesia occurrence are still unclear, dopamine receptors undoubtedly have a central role in their pathophysiology. Here we review current knowledge and evidence for their involvement in dyskinesia genesis and manifestation. We propose that an anti-dyskinetic strategy should target the D1/D3 signalling cascade, as targeting D2 receptor signalling seems to inherently convey anti-therapeutic effects deleterious to patients. As more molecular tools are made available, we will better understand the role of each receptor and its associated signalling cascade in Parkinson's disease and L-dopa-induced dyskinesia, hopefully in a way amenable to patients.

20 Review Chronic dopaminergic stimulation in Parkinson's disease: from dyskinesias to impulse control disorders. 2009

Voon, Valerie / Fernagut, Pierre-Olivier / Wickens, Jeff / Baunez, Christelle / Rodriguez, Manuel / Pavon, Nancy / Juncos, Jorge L / Obeso, José A / Bezard, Erwan. ·Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, UK. voonval@gmail.com ·Lancet Neurol · Pubmed #19909912.

ABSTRACT: Dopamine is an essential neurotransmitter for many brain functions, and its dysfunction has been implicated in both neurological and psychiatric disorders. Parkinson's disease is an archetypal disorder of dopamine dysfunction characterised by motor, cognitive, behavioural, and autonomic symptoms. While effective for motor symptoms, dopamine replacement therapy is associated not only with motor side-effects, such as levodopa-induced dyskinesia, but also behavioural side-effects such as impulse control disorders (eg, pathological gambling and shopping, binge eating, and hypersexuality), punding (ie, abnormal repetitive non-goal oriented behaviours), and compulsive medication use. We review clinical features, overlapping molecular mechanisms, and a specific cognitive mechanism of habit learning that might underlie these behaviours. We integrate these mechanisms with the emerging view of the basal ganglia as a distributive system involved in the selection and facilitation of movements, acts, and emotions.

21 Review Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms. 2009

Rodriguez-Oroz, Maria C / Jahanshahi, Marjan / Krack, Paul / Litvan, Irene / Macias, Raúl / Bezard, Erwan / Obeso, José A. ·Department of Neurology, Clinica Universitaria and Medical School and Neuroscience, CIMA, University of Navarra, Pamplona, Spain. ·Lancet Neurol · Pubmed #19909911.

ABSTRACT: A dopaminergic deficiency in patients with Parkinson's disease (PD) causes abnormalities of movement, behaviour, learning, and emotions. The main motor features (ie, tremor, rigidity, and akinesia) are associated with a deficiency of dopamine in the posterior putamen and the motor circuit. Hypokinesia and bradykinesia might have a dual anatomo-functional basis: hypokinesia mediated by brainstem mechanisms and bradykinesia by cortical mechanisms. The classic pathophysiological model for PD (ie, hyperactivity in the globus pallidus pars interna and substantia nigra pars reticulata) does not explain rigidity and tremor, which might be caused by changes in primary motor cortex activity. Executive functions (ie, planning and problem solving) are also impaired in early PD, but are usually not clinically noticed. These impairments are associated with dopamine deficiency in the caudate nucleus and with dysfunction of the associative and other non-motor circuits. Apathy, anxiety, and depression are the main psychiatric manifestations in untreated PD, which might be caused by ventral striatum dopaminergic deficit and depletion of serotonin and norepinephrine. In this Review we discuss the motor, cognitive, and psychiatric manifestations associated with the dopaminergic deficiency in the early phase of the parkinsonian state and the different circuits implicated, and we propose distinct mechanisms to explain the wide clinical range of PD symptoms at the time of diagnosis.

22 Review Priming for l-dopa-induced dyskinesia in Parkinson's disease: a feature inherent to the treatment or the disease? 2009

Nadjar, Agnès / Gerfen, Charles R / Bezard, Erwan. ·Universite Victor Segalen-Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, CNRS UMR 5227, 146 Rue Leo Saignat, Bordeaux 33076, France. ·Prog Neurobiol · Pubmed #18938208.

ABSTRACT: Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson's disease ultimately experienced by the vast majority of patients. This article does not review the increased understanding of dyskinesia pathophysiology we have seen during the past few years but, instead, specifically focuses upon the very first molecular events thought to be responsible for the establishment of dyskinesia and generally grouped under the term of "priming". Priming is classically defined as the process by which the brain becomes sensitized such that administration of a dopaminergic therapy modifies the response to subsequent dopaminergic treatments. In this way, over time, with repeated treatment, the chance of dopaminergic stimulation eliciting dyskinesia is increased and once dyskinesia has been established, the severity of dyskinesia increases. In this opinion review, however, we aim at strongly opposing the common view of priming. We propose, and hopefully will demonstrate, that priming does not exist per se but is the direct and intrinsic consequence of the loss of dopamine innervation of the striatum (and other target structures), meaning that the first injections of dopaminergic drugs only exacerbate those mechanisms (sensitization) but do not induce them. Chronicity and pulsatility of subsequent dopaminergic treatment only exacerbates the likelihood of developing dyskinesia.

23 Clinical Trial A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson's Disease. 2016

Tison, François / Keywood, Charlotte / Wakefield, Mark / Durif, Franck / Corvol, Jean-Christophe / Eggert, Karla / Lew, Mark / Isaacson, Stuart / Bezard, Erwan / Poli, Sonia-Maria / Goetz, Christopher G / Trenkwalder, Claudia / Rascol, Olivier. ·Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France. francois.tison@chu-bordeaux.fr. · CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. francois.tison@chu-bordeaux.fr. · Service de Neurologie, CHU de Bordeaux, Bordeaux, France. francois.tison@chu-bordeaux.fr. · NS-Park/FCRIN Network, UMS 015, Toulouse, France. francois.tison@chu-bordeaux.fr. · Addex Pharma SA, Plan Les Ouates, Switzerland. · NS-Park/FCRIN Network, UMS 015, Toulouse, France. · Neurology Service, A, Hôpital Gabriel Montpied, Clermont Ferrand, France. · Sorbonne Universités and UPMC Univ Paris 06, INSERM UMRS-1127 and CIC-1422; CNRS UMR-7225; AP-HP; and ICM, Hôpital Pitié-Salpêtrière, Paris, France. · Universitätsklinikum Giessen und Marburg, Klinik für Neurologie, Marburg, Germany. · Department of Neurology USC/Keck School of Medicine, Los Angeles, California, USA. · Parkinson's Disease and Movement Disorders Center of Boca Raton, Boca Raton, Florida, USA. · Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France. · CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. · Rush University Medical Center, Dept. of Neurological Sciences, Movement Disorder Section, Chicago, Illinois, USA. · Paracelsus Elena Klinik, centre for Parkinson's Disease & Movement Disorders, Kassel, Germany. · CIC9302, Departments of Clinical Pharmacology and Neurosciences and NeuroToul COEN Center; INSERM, University Hospital of Toulouse and University of Toulouse 3, Toulouse, France. ·Mov Disord · Pubmed #27214664.

ABSTRACT: BACKGROUND: The metabotropic glutamate receptor 5-negative allosteric modulator dipraglurant reduces levodopa-induced dyskinesia in the MPTP-macaque model. The objective of this study was to assess the safety, tolerability (primary objective), and efficacy (secondary objective) of dipraglurant on levodopa-induced dyskinesia in Parkinson's disease (PD). METHODS: The study was a phase 2A double-blind, placebo-controlled, randomized (2:1), 4-week, parallel-group, multicenter dose-escalation (from 50 mg once daily to 100 mg 3 times daily) clinical trial involving 76 PD subjects with moderate to severe levodopa-induced dyskinesia. Safety and tolerability were assessed based on clinical and biological examination and adverse events recording. Secondary efficacy outcome measures included the modified Abnormal Involuntary Movement Scale, UPDRS, and diaries. Pharmacokinetics were measured at 3 visits following a single dose. RESULTS: Fifty-two patients were exposed to dipraglurant and 24 to placebo. There were no major safety concerns. Two subjects did not complete the study because of adverse events. Most frequent adverse events included dyskinesia, dizziness, nausea, and fatigue. Dipraglurant significantly reduced peak dose dyskinesia (modified Abnormal Involuntary Movement Scale) on day 1 (50 mg, 20%; P = 0.04) and on day 14 (100 mg, 32%; P =0 .04) and across a 3-hour postdose period on day 14 (P = 0.04). There was no evidence of worsening of parkinsonism. Dipraglurant was rapidly absorbed (tmax = 1 hour). The 100-mg dose led to a mean Cmax of 1844 ng/mL on day 28. CONCLUSIONS: Dipraglurant proved to be safe and well tolerated in its first administration to PD patients. Its efficacy in reversing levodopa-induced dyskinesia warrants further investigations in a larger number of patients. © 2016 International Parkinson and Movement Disorder Society.

24 Article In utero delivery of rAAV2/9 induces neuronal expression of the transgene in the brain: towards new models of Parkinson's disease. 2017

Chansel-Debordeaux, L / Bourdenx, M / Dovero, S / Grouthier, V / Dutheil, N / Espana, A / Groc, L / Jimenez, C / Bezard, E / Dehay, B. ·University de Bordeaux, Institut des Maladies Neurodégénératives Bordeaux, France. · CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France. · CHU Bordeaux, Service de Biologie de la reproduction-CECOS, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France. · University de Bordeaux, Interdisciplinary Institute for Neuroscience, Bordeaux, France. · CNRS, Institut Interdisciplinaire de Neurosciences, Bordeaux, France. ·Gene Ther · Pubmed #28853717.

ABSTRACT: Animal models are essential tools for basic pathophysiological research as well as validation of therapeutic strategies for curing human diseases. However, technical difficulties associated with classical transgenesis approaches in rodent species higher than Mus musculus have prevented this long-awaited development. The availability of viral-mediated gene delivery systems in the past few years has stimulated the production of viruses with unique characteristics. For example, the recombinant adeno-associated virus serotype 9 (rAAV2/9) crosses the blood-brain barrier, is capable of transducing developing cells and neurons after intravenous injection and mediates long-term transduction. Whilst post-natal delivery is technically straightforward, in utero delivery bears the potential of achieving gene transduction in neurons at embryonic stages during which the target area is undergoing development. To test this possibility, we injected rAAV2/9 carrying either A53T mutant human α-synuclein or green fluorescent protein, intracerebroventricularly in rats at embryonic day 16.5. We observed neuronal transgene expression in most regions of the brain at 1 and 3 months after birth. This proof-of-concept experiment introduces a new opportunity to model brain diseases in rats.

25 Article Decreased Rhes mRNA levels in the brain of patients with Parkinson's disease and MPTP-treated macaques. 2017

Napolitano, Francesco / Booth Warren, Emily / Migliarini, Sara / Punzo, Daniela / Errico, Francesco / Li, Qin / Thiolat, Marie-Laure / Vescovi, Angelo Luigi / Calabresi, Paolo / Bezard, Erwan / Morelli, Micaela / Konradi, Christine / Pasqualetti, Massimo / Usiello, Alessandro. ·Ceinge Biotecnologie Avanzate, Naples, Italy. · Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy. · Department of Pharmacology, Vanderbilt University, Nashville, TN, United States of America. · Department of Biology Unit of Cell and Developmental Biology, University of Pisa, Pisa, Italy. · Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, Luigi Vanvitelli, Italy. · Motac Neuroscience, UK-M15 6WE, Manchester, United Kingdom. · Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China. · Université de Bordeaux, Institut des Maladies Neurodégénératives,Bordeaux, France. · Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, Institut des Maladies Neurodégénératives, Bordeaux, France. · IRCSS Casa Sollievo della Sofferenza, ISBReMIT-Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, San Giovanni Rotondo, Italy. · Department of Medicine, University of Perugia and Clinica Neurologica, Santa Maria della Misericordia Hospital, Perugia, Italy. · National Research Council of Italy (CNR), Neuroscience Institute, Cagliari, Italy. · Department of Biomedical Sciences, section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy. · Center for Neuroscience and Cognitive Systems, Istituto Italiano di Tecnologia, Rovereto, TN, Italy. · Neuroscience Institute, National Research Council (CNR), Pisa, Italy. ·PLoS One · Pubmed #28742811.

ABSTRACT: In rodent and human brains, the small GTP-binding protein Rhes is highly expressed in virtually all dopaminoceptive striatal GABAergic medium spiny neurons, as well as in large aspiny cholinergic interneurons, where it is thought to modulate dopamine-dependent signaling. Consistent with this knowledge, and considering that dopaminergic neurotransmission is altered in neurological and psychiatric disorders, here we sought to investigate whether Rhes mRNA expression is altered in brain regions of patients with Parkinson's disease (PD), Schizophrenia (SCZ), and Bipolar Disorder (BD), when compared to healthy controls (about 200 post-mortem samples). Moreover, we performed the same analysis in the putamen of non-human primate Macaca Mulatta, lesioned with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Overall, our data indicated comparable Rhes mRNA levels in the brain of patients with SCZ and BD, and their respective healthy controls. In sharp contrast, the putamen of patients suffering from PD showed a significant 35% reduction of this transcript, compared to healthy subjects. Interestingly, in line with observations obtained in humans, we found 27% decrease in Rhes mRNA levels in the putamen of MPTP-treated primates. Based on the established inhibitory influence of Rhes on dopamine-related responses, we hypothesize that its striatal downregulation in PD patients and animal models of PD might represent an adaptive event of the dopaminergic system to functionally counteract the reduced nigrostriatal innervation.

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