| Abstract | Adenosine A2A receptor antagonists provide a promising nondopaminergic approach to the treatment of Parkinson's disease (PD). Initial clinical trials of A2A antagonists targeted PD patients who had already developed treatment complications known as L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in an effort to improve symptoms while reducing existing LID. The goal of this study is to explore the effect of A2A antagonists and targeted A2A receptor depletion on the actual development of sensitized responses to L-DOPA in mouse models of LID in PD. Hemiparkinsonian mice (unilaterally lesioned with 6-OHDA) were treated daily for 3 weeks with a low dose of L-DOPA (2 mg/kg) preceded by a low dose of selective A2A antagonist (KW-6002 [(E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione] at 0.03 or 0.3 mg/kg, or SCH58261 [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine] at 0.03 mg/kg) or vehicle intraperitoneally. In control mice, contralateral rotational responses to daily L-DOPA gradually increased over the initial week before reaching a persistent maximum. Both A2A antagonists inhibited the development of sensitized contralateral turning, with KW-6002 pretreatment reducing the sensitized rotational responses by up to threefold. The development of abnormal involuntary movements (a measure of LID) as well as rotational responses was attenuated by the postnatal depletion of forebrain A2A receptors in conditional (Cre/loxP system) knock-out mice. These pharmacological and genetic data provide evidence that striatal A2A receptors play an important role in the neuroplasticity underlying behavioral sensitization to L-DOPA, supporting consideration of early adjunctive therapy with an A2A antagonist to reduce the risk of LID in PD. |
| Authors | Danqing Xiao, Elena Bastia, Yue-Hang Xu, Caroline L Benn, Jang-Ho J Cha, Tracy S Peterson, Jiang-Fan Chen, Michael A Schwarzschild
(Affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.)
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| Journal | The Journal of neuroscience : the official journal of the Society for Neuroscience
(J Neurosci)
Vol. 26
Issue 52
Pg. 13548-55
(Dec 27 2006)
ISSN: 1529-2401 United States |
| PMID | 17192438
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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| Chemical References |
- Levodopa
- Purines
- Receptor, Adenosine A2A
- Oxidopamine
- istradefylline
|
| Topics |
- Animals
- Dyskinesia, Drug-Induced
(drug therapy, metabolism)
- Levodopa
(pharmacology, therapeutic use, toxicity)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Oxidopamine
(toxicity)
- Parkinsonian Disorders
(chemically induced, drug therapy, metabolism)
- Prosencephalon
(drug effects, metabolism, physiology)
- Purines
(pharmacology, therapeutic use)
- Receptor, Adenosine A2A
(antagonists & inhibitors, genetics, physiology)
|
