Document Detail


The effects of a selective dopamine D2 receptor agonist on behavioral and pathological outcome in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated squirrel monkeys.
MedLine Citation:
PMID:  15980058     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In this study, we investigated antiparkinsonian activity of the novel, highly selective dopamine D(2) receptor agonist sumanirole compared with two clinically effective dopaminergic therapies in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson's disease. Squirrel monkeys were rendered parkinsonian by chronic administration of MPTP and subsequently dosed with vehicle, L-DOPA plus carbidopa (L-DOPA), ropinirole, or sumanirole over a duration of 8 weeks. Antiparkinsonian effects measured with a parkinsonian primate rating scale (PPRS) showed that sumanirole elicited improved functional outcome compared with vehicle. The dopamine D2/D3 agonist ropinirole improved behavioral outcome similar to sumanirole, whereas L-DOPA treatment yielded the most significant symptomatic improvement. The relative rank of therapies that elicited normalization of PPRS was L-DOPA > sumanirole; ropinirole did not normalize PPRS in any of the treated monkeys. Dyskinesias were present with L-DOPA treatment but were not observed in sumanirole-, ropinirole-, or placebo-treated primates. Pathologically, all MPTP-treated animals displayed neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta and reactive astrocytosis. Neurons immunoreactive with antibodies to the nuclear transcription factor DeltaFosB were most significantly increased in the striatum of L-DOPA-treated monkeys. These results suggest that sumanirole can exert antiparkinsonian effects similar to L-DOPA without the behavioral and morphological consequences of the latter.
Authors:
Diane T Stephenson; Martin D Meglasson; Mark A Connell; Mary A Childs; Eva Hajos-Korcsok; Marina E Emborg
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2005-06-24
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  314     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2005 Sep 
Date Detail:
Created Date:  2005-08-22     Completed Date:  2005-10-21     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1257-66     Citation Subset:  IM    
Affiliation:
Pfizer Global Research and Development, Groton, CT 06340, USA. diane.t.stephenson@pfizer.com
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MeSH Terms
Descriptor/Qualifier:
Animals
Basal Ganglia / pathology
Benzimidazoles / pharmacokinetics,  therapeutic use*
Biogenic Monoamines / cerebrospinal fluid
Dopamine Agonists / therapeutic use*
Levodopa / therapeutic use
MPTP Poisoning / drug therapy*,  pathology,  psychology
Male
Motor Activity / drug effects
Receptors, Dopamine D2 / agonists*
Saimiri
Substantia Nigra / pathology
Grant Support
ID/Acronym/Agency:
P51RR000167/RR/NCRR NIH HHS; R01-NS40578/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Benzimidazoles; 0/Biogenic Monoamines; 0/Dopamine Agonists; 0/Levodopa; 0/Receptors, Dopamine D2; 0/U 95666E

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