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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.
J Neurosci. 2001 Sep 01; 21(17):6853-61.JN

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 vivo follow-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.

Authors+Show Affiliations

Manchester Movement Disorder Laboratory, Division of Neuroscience, School of Biological Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom. erwan.bezard@umr5543.u-bordeaux2.frNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11517273

Citation

Bezard, E, et al. "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." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 21, no. 17, 2001, pp. 6853-61.
Bezard E, Dovero S, Prunier C, et al. 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. J Neurosci. 2001;21(17):6853-61.
Bezard, E., Dovero, S., Prunier, C., Ravenscroft, P., Chalon, S., Guilloteau, D., Crossman, A. R., Bioulac, B., Brotchie, J. M., & Gross, C. E. (2001). 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. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 21(17), 6853-61.
Bezard E, et al. 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. J Neurosci. 2001 Sep 1;21(17):6853-61. PubMed PMID: 11517273.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Bezard,E, AU - Dovero,S, AU - Prunier,C, AU - Ravenscroft,P, AU - Chalon,S, AU - Guilloteau,D, AU - Crossman,A R, AU - Bioulac,B, AU - Brotchie,J M, AU - Gross,C E, PY - 2001/8/23/pubmed PY - 2001/9/21/medline PY - 2001/8/23/entrez SP - 6853 EP - 61 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 21 IS - 17 N2 - 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 vivo follow-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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/11517273/Relationship_between_the_appearance_of_symptoms_and_the_level_of_nigrostriatal_degeneration_in_a_progressive_1_methyl_4_phenyl_1236_tetrahydropyridine_lesioned_macaque_model_of_Parkinson's_disease_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=11517273 DB - PRIME DP - Unbound Medicine ER -