The Adenosine A2A-Receptor Antagonist Istradefylline Enhances the Motor Response of l-DOPA Without Worsening Dyskinesia in MPTP-Treated Common Marmosets
The adenosine A2A-receptor antagonist istradefylline decreases OFF time in patients with Parkinson’s disease who are already treated with optimal doses of dopaminergic medication but can cause an increase in non-troublesome dyskinesia. Preclinical experiments have shown that A2A antagonists are most...
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doaj-c06ff4334a9f480c94ce2931d1f2fc212020-11-25T01:26:21ZengElsevierJournal of Pharmacological Sciences1347-86132014-01-011244480485The Adenosine A2A-Receptor Antagonist Istradefylline Enhances the Motor Response of l-DOPA Without Worsening Dyskinesia in MPTP-Treated Common MarmosetsShin-ichi Uchida0Tomomi Tashiro1Mika Kawai-Uchida2Akihisa Mori3Peter Jenner4Tomoyuki Kanda5Development Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, JapanDevelopment Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, JapanDevelopment Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, JapanStrategic Product Portfolio Department, Kyowa Hakko Kirin Co., Ltd., Tokyo 100-8185, JapanNeurodegenerative Diseases Research Centre, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, King’s College, London WC2R 2LS, UKDevelopment Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan; Corresponding author. tomoyuki.kanda@kyowa-kirin.co.jpThe adenosine A2A-receptor antagonist istradefylline decreases OFF time in patients with Parkinson’s disease who are already treated with optimal doses of dopaminergic medication but can cause an increase in non-troublesome dyskinesia. Preclinical experiments have shown that A2A antagonists are most effective in potentiating motor function when combined with submaximal doses of l-DOPA. However, the effects of combining istradefylline with sub-optimal l-DOPA treatment on established dyskinesia have not been studied. We now examine the effects of acute and repeated administration of istradefylline on dyskinesia in MPTP-treated common marmosets previously primed to exhibit involuntary movements by prior exposure to l-DOPA. In these animals, single dose acute oral administration of istradefylline (10 mg/kg) enhanced and prolonged the anti-parkinsonian effects of a sub-optimal dose of l-DOPA (2.5 mg/kg). The chronic co-administration of istradefylline (10 mg/kg) with l-DOPA (2.5 mg/kg) for 21 days did not worsen the severity of existing dyskinesia. Rather, the severity of dyskinesia tended to be reduced over the 21-day treatment period. These results suggest that istradefylline can be used to potentiate the effects of sub-optimal doses of l-DOPA in the treatment of Parkinson’s disease without causing or worsening dyskinesia. Keywords:: anti-parkinsonian, adenosine A2A-receptor antagonist, l-DOPA, dyskinesia, MPTPhttp://www.sciencedirect.com/science/article/pii/S1347861319301707 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shin-ichi Uchida Tomomi Tashiro Mika Kawai-Uchida Akihisa Mori Peter Jenner Tomoyuki Kanda |
spellingShingle |
Shin-ichi Uchida Tomomi Tashiro Mika Kawai-Uchida Akihisa Mori Peter Jenner Tomoyuki Kanda The Adenosine A2A-Receptor Antagonist Istradefylline Enhances the Motor Response of l-DOPA Without Worsening Dyskinesia in MPTP-Treated Common Marmosets Journal of Pharmacological Sciences |
author_facet |
Shin-ichi Uchida Tomomi Tashiro Mika Kawai-Uchida Akihisa Mori Peter Jenner Tomoyuki Kanda |
author_sort |
Shin-ichi Uchida |
title |
The Adenosine A2A-Receptor Antagonist Istradefylline Enhances the Motor Response of l-DOPA Without Worsening Dyskinesia in MPTP-Treated Common Marmosets |
title_short |
The Adenosine A2A-Receptor Antagonist Istradefylline Enhances the Motor Response of l-DOPA Without Worsening Dyskinesia in MPTP-Treated Common Marmosets |
title_full |
The Adenosine A2A-Receptor Antagonist Istradefylline Enhances the Motor Response of l-DOPA Without Worsening Dyskinesia in MPTP-Treated Common Marmosets |
title_fullStr |
The Adenosine A2A-Receptor Antagonist Istradefylline Enhances the Motor Response of l-DOPA Without Worsening Dyskinesia in MPTP-Treated Common Marmosets |
title_full_unstemmed |
The Adenosine A2A-Receptor Antagonist Istradefylline Enhances the Motor Response of l-DOPA Without Worsening Dyskinesia in MPTP-Treated Common Marmosets |
title_sort |
adenosine a2a-receptor antagonist istradefylline enhances the motor response of l-dopa without worsening dyskinesia in mptp-treated common marmosets |
publisher |
Elsevier |
series |
Journal of Pharmacological Sciences |
issn |
1347-8613 |
publishDate |
2014-01-01 |
description |
The adenosine A2A-receptor antagonist istradefylline decreases OFF time in patients with Parkinson’s disease who are already treated with optimal doses of dopaminergic medication but can cause an increase in non-troublesome dyskinesia. Preclinical experiments have shown that A2A antagonists are most effective in potentiating motor function when combined with submaximal doses of l-DOPA. However, the effects of combining istradefylline with sub-optimal l-DOPA treatment on established dyskinesia have not been studied. We now examine the effects of acute and repeated administration of istradefylline on dyskinesia in MPTP-treated common marmosets previously primed to exhibit involuntary movements by prior exposure to l-DOPA. In these animals, single dose acute oral administration of istradefylline (10 mg/kg) enhanced and prolonged the anti-parkinsonian effects of a sub-optimal dose of l-DOPA (2.5 mg/kg). The chronic co-administration of istradefylline (10 mg/kg) with l-DOPA (2.5 mg/kg) for 21 days did not worsen the severity of existing dyskinesia. Rather, the severity of dyskinesia tended to be reduced over the 21-day treatment period. These results suggest that istradefylline can be used to potentiate the effects of sub-optimal doses of l-DOPA in the treatment of Parkinson’s disease without causing or worsening dyskinesia. Keywords:: anti-parkinsonian, adenosine A2A-receptor antagonist, l-DOPA, dyskinesia, MPTP |
url |
http://www.sciencedirect.com/science/article/pii/S1347861319301707 |
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