The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: A PET, histological and biochemical study
Parkinson's disease (PD) is diagnosed when striatal dopamine (DA) loss exceeds a certain threshold and the cardinal motor features become apparent. The presymptomatic compensatory mechanisms underlying the lack of motor manifestations despite progressive striatal depletion are not well understo...
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| Format: | Article |
| Language: | English |
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Elsevier
2012-10-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996112002045 |
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| author | J. Blesa C. Pifl M.A. Sánchez-González C. Juri M.A. García-Cabezas R. Adánez E. Iglesias M. Collantes I. Peñuelas J.J. Sánchez-Hernández M.C. Rodríguez-Oroz C. Avendaño O. Hornykiewicz C. Cavada J.A. Obeso |
| author_facet | J. Blesa C. Pifl M.A. Sánchez-González C. Juri M.A. García-Cabezas R. Adánez E. Iglesias M. Collantes I. Peñuelas J.J. Sánchez-Hernández M.C. Rodríguez-Oroz C. Avendaño O. Hornykiewicz C. Cavada J.A. Obeso |
| author_sort | J. Blesa |
| collection | DOAJ |
| description | Parkinson's disease (PD) is diagnosed when striatal dopamine (DA) loss exceeds a certain threshold and the cardinal motor features become apparent. The presymptomatic compensatory mechanisms underlying the lack of motor manifestations despite progressive striatal depletion are not well understood. Most animal models of PD involve the induction of a severe dopaminergic deficit in an acute manner, which departs from the typical, chronic evolution of PD in humans. We have used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administered to monkeys via a slow intoxication protocol to produce a more gradual development of nigral lesion. Twelve control and 38 MPTP-intoxicated monkeys were divided into four groups. The latter included monkeys who were always asymptomatic, monkeys who recovered after showing mild parkinsonian signs, and monkeys with stable, moderate and severe parkinsonism. We found a close correlation between cell loss in the substantia nigra pars compacta (SNc) and striatal dopaminergic depletion and the four motor states. There was an overall negative correlation between the degree of parkinsonism (Kurlan scale) and in vivo PET (18F-DOPA Ki and 11C-DTBZ binding potential), as well as with TH-immunoreactive cell counts in SNc, striatal dopaminergic markers (TH, DAT and VMAT2) and striatal DA concentration. This intoxication protocol permits to establish a critical threshold of SNc cell loss and dopaminergic innervation distinguishing between the asymptomatic and symptomatic parkinsonian stages. Compensatory changes in nigrostriatal dopaminergic activity occurred in the recovered and parkinsonian monkeys when DA depletion was at least 88% of control, and accordingly may be considered too late to explain compensatory mechanisms in the early asymptomatic period. Our findings suggest the need for further exploration of the role of non-striatal mechanisms in PD prior to the development of motor features. |
| first_indexed | 2024-12-18T02:07:00Z |
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| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-18T02:07:00Z |
| publishDate | 2012-10-01 |
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| series | Neurobiology of Disease |
| spelling | doaj.art-9692e153e7e5499f86109e3d7ad3e3d92022-12-21T21:24:34ZengElsevierNeurobiology of Disease1095-953X2012-10-014817991The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: A PET, histological and biochemical studyJ. Blesa0C. Pifl1M.A. Sánchez-González2C. Juri3M.A. García-Cabezas4R. Adánez5E. Iglesias6M. Collantes7I. Peñuelas8J.J. Sánchez-Hernández9M.C. Rodríguez-Oroz10C. Avendaño11O. Hornykiewicz12C. Cavada13J.A. Obeso14Movement Disorders Group, Neurosciences Division, CIMA, and Department of Neurology and Neurosurgery, Clínica Universidad de Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Carlos III, Ministerio de Ciencia e Innovación, SpainCenter for Brain Research, Medical University of Vienna, AustriaDepartamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria IdiPAZ, Madrid, SpainMovement Disorders Group, Neurosciences Division, CIMA, and Department of Neurology and Neurosurgery, Clínica Universidad de Navarra, Pamplona, Spain; Department of Neurology, Pontificia Universidad Catolica de Chile, Santiago, ChileDepartamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria IdiPAZ, Madrid, SpainMovement Disorders Group, Neurosciences Division, CIMA, and Department of Neurology and Neurosurgery, Clínica Universidad de Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Carlos III, Ministerio de Ciencia e Innovación, SpainMovement Disorders Group, Neurosciences Division, CIMA, and Department of Neurology and Neurosurgery, Clínica Universidad de Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Carlos III, Ministerio de Ciencia e Innovación, SpainSmall Animal Imaging Research Unit, Center for Applied Medical Research (CIMA) and Clínica Universidad de Navarra, Pamplona, Spain; Department of Nuclear Medicine, Clínica Universidad de Navarra, Pamplona, SpainSmall Animal Imaging Research Unit, Center for Applied Medical Research (CIMA) and Clínica Universidad de Navarra, Pamplona, Spain; Department of Nuclear Medicine, Clínica Universidad de Navarra, Pamplona, SpainDepartamento de Medicina Preventiva y Salud Pública, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, SpainMovement Disorders Group, Neurosciences Division, CIMA, and Department of Neurology and Neurosurgery, Clínica Universidad de Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Carlos III, Ministerio de Ciencia e Innovación, SpainDepartamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria IdiPAZ, Madrid, SpainCenter for Brain Research, Medical University of Vienna, AustriaDepartamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria IdiPAZ, Madrid, SpainMovement Disorders Group, Neurosciences Division, CIMA, and Department of Neurology and Neurosurgery, Clínica Universidad de Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Carlos III, Ministerio de Ciencia e Innovación, Spain; Corresponding author at: CIMA-Neurociencias, Universidad de Navarra, Pío XII, 55, Pamplona 31008, Spain. Fax: +34 948 19 47 15.Parkinson's disease (PD) is diagnosed when striatal dopamine (DA) loss exceeds a certain threshold and the cardinal motor features become apparent. The presymptomatic compensatory mechanisms underlying the lack of motor manifestations despite progressive striatal depletion are not well understood. Most animal models of PD involve the induction of a severe dopaminergic deficit in an acute manner, which departs from the typical, chronic evolution of PD in humans. We have used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administered to monkeys via a slow intoxication protocol to produce a more gradual development of nigral lesion. Twelve control and 38 MPTP-intoxicated monkeys were divided into four groups. The latter included monkeys who were always asymptomatic, monkeys who recovered after showing mild parkinsonian signs, and monkeys with stable, moderate and severe parkinsonism. We found a close correlation between cell loss in the substantia nigra pars compacta (SNc) and striatal dopaminergic depletion and the four motor states. There was an overall negative correlation between the degree of parkinsonism (Kurlan scale) and in vivo PET (18F-DOPA Ki and 11C-DTBZ binding potential), as well as with TH-immunoreactive cell counts in SNc, striatal dopaminergic markers (TH, DAT and VMAT2) and striatal DA concentration. This intoxication protocol permits to establish a critical threshold of SNc cell loss and dopaminergic innervation distinguishing between the asymptomatic and symptomatic parkinsonian stages. Compensatory changes in nigrostriatal dopaminergic activity occurred in the recovered and parkinsonian monkeys when DA depletion was at least 88% of control, and accordingly may be considered too late to explain compensatory mechanisms in the early asymptomatic period. Our findings suggest the need for further exploration of the role of non-striatal mechanisms in PD prior to the development of motor features.http://www.sciencedirect.com/science/article/pii/S0969996112002045MPTP monkeyParkinson's diseasePETAAADCompensatory mechanisms |
| spellingShingle | J. Blesa C. Pifl M.A. Sánchez-González C. Juri M.A. García-Cabezas R. Adánez E. Iglesias M. Collantes I. Peñuelas J.J. Sánchez-Hernández M.C. Rodríguez-Oroz C. Avendaño O. Hornykiewicz C. Cavada J.A. Obeso The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: A PET, histological and biochemical study Neurobiology of Disease MPTP monkey Parkinson's disease PET AAAD Compensatory mechanisms |
| title | The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: A PET, histological and biochemical study |
| title_full | The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: A PET, histological and biochemical study |
| title_fullStr | The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: A PET, histological and biochemical study |
| title_full_unstemmed | The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: A PET, histological and biochemical study |
| title_short | The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: A PET, histological and biochemical study |
| title_sort | nigrostriatal system in the presymptomatic and symptomatic stages in the mptp monkey model a pet histological and biochemical study |
| topic | MPTP monkey Parkinson's disease PET AAAD Compensatory mechanisms |
| url | http://www.sciencedirect.com/science/article/pii/S0969996112002045 |
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