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The novel adenosine A(2a) receptor antagonist ST1535 potentiates the effects of a threshold dose of L-DOPA in MPTP treated common marmosets

Research output: Contribution to journalArticle

S Rose, M J Jackson, L A Smith, K Stockwell, L Johnson, P Carminati, P Jenner

Original languageEnglish
Pages (from-to)82 - 87
Number of pages6
JournalEuropean Journal of Pharmacology
Volume546
Issue number1-3
DOIs
Publication statusPublished - 28 Sep 2006

King's Authors

Abstract

Adenosine A(2a) receptor antagonists may represent a novel non-dopaminergic approach to the treatment of Parkinson's disease. However, there is little information available on their ability to reverse motor deficits in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride (MPTP)treated primates. We have studied the effects of the novel A(2a) receptor antagonist 2-butyl-9-methyl-8-(2H-1,2,3-triazol 2-yl)-9 H-purin-6-ylamine (ST1535) alone and in combination with L-3, 4-dihydroxyphenylalanine (L-DOPA) in MPTP-treated common marmosets. ST1535 (10, 20 and 40 mg/kg, p.o.) when administered alone to MPTP-treated common marmosets produced a dose related increase in locomotor motor activity and tended to reverse motor disability. Treatment with a threshold dose of L-DOPA (2.5 mg/kg, p.o.) produced an increase in locomotor activity and again tended to reverse motor disability. When L-DOPA (2.5 mg/kg, p.o.) was administered in combination with ST1535 (20 mg/kg, p.o.), there was an enhancement in the intensity and duration of the effect Of L-DOPA (2.5 mg/kg, p.o.) in reversing motor deficits as shown by both a further increase in locomotor activity and reversal of motor disability. The combination Of L-DOPA (2.5 mg/kg, p.o.) plus ST1535 (20 mg/kg, p.o.) significantly increased "on time" in these animals. These data substantiate the evidence that adenosine A(2a) receptor antagonists are able to reverse motor deficits in a highly predictive model of clinical efficacy in Parkinson's disease. The data suggests that ST1535 will be an effective anti-parkinsonian agent in combination with L-DOPA and allow a reduction in L-DOPA usage in the treatment of Parkinson's disease. (c) 2006 Elsevier B.V. All rights reserved

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