Toward a primate model of L-dopa-unresponsive parkinsonism mimicking striatonigral degeneration.
Identifieur interne : 001279 ( PubMed/Curation ); précédent : 001278; suivant : 001280Toward a primate model of L-dopa-unresponsive parkinsonism mimicking striatonigral degeneration.
Auteurs : I. Ghorayeb [France] ; P O Fernagut ; I. Aubert ; E. Bezard ; W. Poewe ; G K Wenning ; F. TisonSource :
- Movement disorders : official journal of the Movement Disorder Society [ 0885-3185 ] ; 2000.
English descriptors
- KwdEn :
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Antiparkinson Agents (pharmacology), Brain Mapping, Corpus Striatum (drug effects), Corpus Striatum (pathology), Corpus Striatum (physiopathology), Diagnosis, Differential, Disease Models, Animal, Dopamine (metabolism), Levodopa (pharmacology), Macaca fascicularis, Male, Multiple System Atrophy (chemically induced), Multiple System Atrophy (pathology), Multiple System Atrophy (physiopathology), Nerve Degeneration (chemically induced), Nerve Degeneration (pathology), Nerve Degeneration (physiopathology), Neurotoxins, Nitro Compounds, Parkinson Disease, Secondary (chemically induced), Parkinson Disease, Secondary (pathology), Parkinson Disease, Secondary (physiopathology), Propionates, Striatonigral Degeneration (chemically induced), Striatonigral Degeneration (pathology), Striatonigral Degeneration (physiopathology).
- MESH :
- chemical , metabolism : Dopamine.
- chemical , pharmacology : Antiparkinson Agents, Levodopa.
- chemical : 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Neurotoxins, Nitro Compounds, Propionates.
- chemically induced : Multiple System Atrophy, Nerve Degeneration, Parkinson Disease, Secondary, Striatonigral Degeneration.
- drug effects : Corpus Striatum.
- pathology : Corpus Striatum, Multiple System Atrophy, Nerve Degeneration, Parkinson Disease, Secondary, Striatonigral Degeneration.
- physiopathology : Corpus Striatum, Multiple System Atrophy, Nerve Degeneration, Parkinson Disease, Secondary, Striatonigral Degeneration.
- Animals, Brain Mapping, Diagnosis, Differential, Disease Models, Animal, Macaca fascicularis, Male.
Abstract
We developed a primate model of striatonigral degeneration (SND), the neuropathology underlying levodopa-unresponsive parkinsonism associated with multiple systemic atrophy (MSA-P), by sequential systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3-nitropropionic acid (3NP) in a Macaca fascicularis monkey. L-Dopa-responsive parkinsonian features emerged after MPTP injections. Subsequent chronic 3NP administration aggravated the motor symptoms and abolished the L-dopa response. In vivo magnetic resonance imaging revealed bilateral striatal lesions. Histopathologically, there was severe dopaminergic cell loss in the substantia nigra pars compacta compared with the control monkey. Furthermore, we observed circumscribed areas of severe neuronal degeneration in the motor striatum. These changes were absent in the control monkey, and they were associated with diffuse metabolic failure as demonstrated by cytochrome oxidase histochemistry. The striatal pathology predominantly involved output pre-pro-enkephalin A- and substance P-containing cells, whereas somatostatin (NADPH-diaphorase)-containing interneurons were relatively spared. Our model therefore reproduced levodopa-unresponsive parkinsonism and SND-like pathologic changes characteristic of MSA-P. The double-lesion primate model of SND may serve as a preclinical test-bed for the evaluation of novel therapeutic strategies in MSA-P.
PubMed: 10830420
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<front><div type="abstract" xml:lang="en">We developed a primate model of striatonigral degeneration (SND), the neuropathology underlying levodopa-unresponsive parkinsonism associated with multiple systemic atrophy (MSA-P), by sequential systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3-nitropropionic acid (3NP) in a Macaca fascicularis monkey. L-Dopa-responsive parkinsonian features emerged after MPTP injections. Subsequent chronic 3NP administration aggravated the motor symptoms and abolished the L-dopa response. In vivo magnetic resonance imaging revealed bilateral striatal lesions. Histopathologically, there was severe dopaminergic cell loss in the substantia nigra pars compacta compared with the control monkey. Furthermore, we observed circumscribed areas of severe neuronal degeneration in the motor striatum. These changes were absent in the control monkey, and they were associated with diffuse metabolic failure as demonstrated by cytochrome oxidase histochemistry. The striatal pathology predominantly involved output pre-pro-enkephalin A- and substance P-containing cells, whereas somatostatin (NADPH-diaphorase)-containing interneurons were relatively spared. Our model therefore reproduced levodopa-unresponsive parkinsonism and SND-like pathologic changes characteristic of MSA-P. The double-lesion primate model of SND may serve as a preclinical test-bed for the evaluation of novel therapeutic strategies in MSA-P.</div>
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