Use of catechol-O-methyltransferase inhibition to minimize L-3,4-dihydroxyphenylalanine-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydrop yridine-lesioned macaque

• Published in: The European journal of neuroscience Vol. 37; no. 5; pp. 831 - 838
• Main Authors: Huot, Philippe, Johnston, Tom H, Snoeren, Tessa, Koprich, James B, Hill, Michael P, Fox, Susan H, Brotchie, Jonathan M
• Format: Journal Article
• Language: English
• Published: 01-03-2013
• Subjects: Basal ganglia; Catechol O-methyltransferase; Central nervous system diseases; Cynomolgus; Data processing; Dopamine; Dyskinesia; Levodopa; Lipoproteins (low density); Macaca; Movement disorders; Nervous system; Neurodegenerative diseases; Parkinson's disease
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.12093

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-tetrahydrop yridine. 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 similar to 170 min and the ON-time after LDl alone ( similar to 98 min) was not significantly different to vehicle ( similar to 37 min). In combination with LDl, entacapone significantly increased the ON-time (5, 15 and 45 mg/kg being similar to 123, similar to 148 and similar to 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 similar to 56% with LDh, it was only similar to 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. This study was conducted in the 1-methyl-4-phenyl-1,2,3,6-tetrahydrop yridine-lesioned macaque model of Parkinson's disease. The animals were administered entacapone in combination with a low, sub-threshold, dose of L-3,4-dihydroxyphenylalanine (L-DOPA), as well as a standard, higher, dose of L-DOPA, alone. The combination of entacapone and low dose L-DOPA led to a reversal of parkinsonism comparable to that achieved with a high dose of L-DOPA, while eliciting significantly less dyskinesia.