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.
Eur J Neurosci
; 37(5): 831-8, 2013 Mar.
Article
en En
| MEDLINE
| ID: mdl-23281915
ABSTRACT
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 â¼170 min and the ON-time after LDl alone (â¼98 min) was not significantly different to vehicle (â¼37 min). In combination with LDl, entacapone significantly increased the ON-time (5, 15 and 45 mg/kg being â¼123, â¼148 and â¼180 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 â¼56% with LDh, it was only â¼31% 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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Levodopa
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Intoxicación por MPTP
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Discinesia Inducida por Medicamentos
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Inhibidores de Catecol O-Metiltransferasa
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Antiparkinsonianos
Límite:
Animals
Idioma:
En
Revista:
Eur J Neurosci
Asunto de la revista:
NEUROLOGIA
Año:
2013
Tipo del documento:
Article
País de afiliación:
Canadá