Document Detail


Use of catechol-O-methyltransferase inhibition to minimize L-3,4-dihydroxyphenylalanine-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque.
MedLine Citation:
PMID:  23281915     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia is a complication of dopaminergic treatment in Parkinson's disease. Lowering the L-DOPA dose reduces dyskinesia but also reduces the antiparkinsonian benefit. A therapy that could enhance the antiparkinsonian action of low-dose L-DOPA (LDl) without exacerbating dyskinesia would thus be of considerable therapeutic benefit. This study assessed whether catechol-O-methyltransferase (COMT) inhibition, as an add-on to LDl, might be a means to achieve this goal. Cynomolgus macaques were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Dyskinesia was established by chronic treatment with L-DOPA. Two doses of L-DOPA were identified - high-dose L-DOPA (LDh), which provided good antiparkinsonian benefit but was compromised by disabling dyskinesia, and LDl, which was sub-threshold for providing significant antiparkinsonian benefit, without dyskinesia. LDh and LDl were administered in acute challenges in combination with vehicle and, for LDl, with the COMT inhibitor entacapone (5, 15 and 45 mg/kg). The duration of antiparkinsonian benefit (ON-time), parkinsonism and dyskinesia were determined. The ON-time after LDh was ∼170 min and the ON-time after LDl alone (∼98 min) was not significantly different to vehicle (∼37 min). In combination with LDl, entacapone significantly increased the ON-time (5, 15 and 45 mg/kg being ∼123, ∼148 and ∼180 min, respectively). The ON-time after LDl/entacapone 45 mg/kg was not different to that after LDh. However, whereas the percentage ON-time that was compromised by disabling dyskinesia was ∼56% with LDh, it was only ∼31% with LDl/entacapone 45 mg/kg. In addition to the well-recognized action of COMT inhibition to reduce wearing-OFF, the data presented suggest that COMT inhibition in combination with low doses of L-DOPA has potential as a strategy to alleviate dyskinesia.
Authors:
Philippe Huot; Tom H Johnston; Tessa Snoeren; James B Koprich; Michael P Hill; Susan H Fox; Jonathan M Brotchie
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-03
Journal Detail:
Title:  The European journal of neuroscience     Volume:  37     ISSN:  1460-9568     ISO Abbreviation:  Eur. J. Neurosci.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-04     Completed Date:  2013-08-16     Revised Date:  2013-11-25    
Medline Journal Info:
Nlm Unique ID:  8918110     Medline TA:  Eur J Neurosci     Country:  France    
Other Details:
Languages:  eng     Pagination:  831-8     Citation Subset:  IM    
Copyright Information:
© 2013 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antiparkinson Agents / administration & dosage,  therapeutic use,  toxicity*
Catechol O-Methyltransferase / antagonists & inhibitors*
Catechols / administration & dosage,  therapeutic use
Drug Therapy, Combination
Dyskinesia, Drug-Induced / drug therapy*
Female
Levodopa / administration & dosage,  therapeutic use,  toxicity*
MPTP Poisoning / drug therapy*
Macaca fascicularis
Male
Nitriles / administration & dosage,  therapeutic use
Chemical
Reg. No./Substance:
0/Antiparkinson Agents; 0/Catechols; 0/Nitriles; 46627O600J/Levodopa; 4975G9NM6T/entacapone; EC 2.1.1.6/Catechol O-Methyltransferase

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