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      Relationship between the Appearance of Symptoms and the Level of Nigrostriatal Degeneration in a Progressive 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Macaque Model of Parkinson's Disease

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          Abstract

          The concept of a threshold of dopamine (DA) depletion for onset of Parkinson's disease symptoms, although widely accepted, has, to date, not been determined experimentally in nonhuman primates in which a more rigorous definition of the mechanisms responsible for the threshold effect might be obtained. The present study was thus designed to determine (1) the relationship between Parkinsonian symptom appearance and level of degeneration of the nigrostriatal pathway and (2) the concomitant presynaptic and postsynaptic striatal response to the denervation, in monkeys treated chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine according to a regimen that produces a progressive Parkinsonian state. The kinetics of the nigrostriatal degeneration described allow the determination of the critical thresholds associated to symptom appearance, these were a loss of 43.2% of tyrosine hydroxylase-immunopositive neurons at the nigral level and losses of 80.3 and 81.6% DA transporter binding and DA content, respectively, at the striatal level. Our data argue against the concept that an increase in DA metabolism could act as an efficient adaptive mechanism early in the disease progress. Surprisingly, the D 2-like DA receptor binding showed a biphasic regulation in relation to the level of striatal dopaminergic denervation, i.e., an initial decrease in the presymptomatic period was followed by an upregulation of postsynaptic receptors commencing when striatal dopaminergic homeostasis is broken. Further in vivofollow-up of the kinetics of striatal denervation in this, and similar, experimental models is now needed with a view to developing early diagnosis tools and symptomatic therapies that might enhance endogenous compensatory mechanisms.

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          Author and article information

          Journal
          J Neurosci
          J. Neurosci
          jneuro
          jneurosci
          J. Neurosci
          The Journal of Neuroscience
          Society for Neuroscience
          0270-6474
          1529-2401
          1 September 2001
          : 21
          : 17
          : 6853-6861
          Affiliations
          [ 1 ]Manchester Movement Disorder Laboratory, Division of Neuroscience, School of Biological Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom,
          [ 2 ]Basal Gang, Laboratoire de Neurophysiologie, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5543, UniversitéVictor Segalen, 33076 Bordeaux Cedex, France,
          [ 3 ]Institut National de la Santé et de la Recherche Médicale U316, Laboratoire de Biophysique Médicale et Pharmaceutique, 37200 Tours, France, and
          [ 4 ]Motac Neuroscience Ltd., Manchester M13 9XX, United Kingdom
          Article
          PMC6763089 PMC6763089 6763089 5588
          10.1523/JNEUROSCI.21-17-06853.2001
          6763089
          11517273
          eebcd066-ee44-4385-af28-0bf1a22f7f73
          Copyright © 2001 Society for Neuroscience
          History
          : 11 April 2001
          : 4 June 2001
          : 19 June 2001
          Categories
          ARTICLE
          Behavioral/Systems
          Custom metadata
          5.00

          substantia nigra,early D2dopaminergic receptor upregulation,dopaminergic homeostasis,threshold for symptom appearance,striatum,compensatory mechanisms

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