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

• 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: Oxford Blackwell Publishing Ltd 01-03-2013; Blackwell
• Subjects: 1-methyl-4-phenyl-1; 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine; 4-dihydroxyphenylalanine; 6-tetrahydropyridine; Animals; Antiparkinson Agents - administration & dosage; Antiparkinson Agents - therapeutic use; Antiparkinson Agents - toxicity; Biological and medical sciences; Catechol O-Methyltransferase Inhibitors; catechol-O-methyltransferase inhibition; Catechols - administration & dosage; Catechols - therapeutic use; Drug Therapy, Combination; dyskinesia; Dyskinesia, Drug-Induced - drug therapy; entacapone; Female; Fundamental and applied biological sciences. Psychology; L-3; Levodopa - administration & dosage; Levodopa - therapeutic use; Levodopa - toxicity; L‐3,4‐dihydroxyphenylalanine; Macaca fascicularis; macaque; Male; MPTP Poisoning - drug therapy; Nitriles - administration & dosage; Nitriles - therapeutic use; Vertebrates: nervous system and sense organs; macaque; Methyltransferases; Enzyme; catechol-O-methyltransferase inhibition; Transferases; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Entacapone; Catechol O-methyltransferase; Lesion; L-3,4-dihydroxyphenylalanine; Dopa; dyskinesia
• 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‐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.
This study was conducted in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐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.