Deletion of adenosine A₁ or A(₂A) receptors reduces L-3,4-dihydroxyphenylalanine-induced dyskinesia in a model of Parkinson's disease.

Abstract

Adenosine A(₂A) receptor antagonism provides a promising approach to developing nondopaminergic therapy for Parkinson's disease (PD). Clinical trials of A(₂A) antagonists have targeted PD patients with L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in an effort to improve parkinsonian symptoms. The role of adenosine in the development of LID is little known, especially regarding its actions via A₁ receptors. We aimed to examine the effects of genetic deletion and pharmacological blockade of A₁ and/or A(₂A) receptors on the development of LID, on the induction of molecular markers of LID including striatal preprodynorphin and preproenkephalin (PPE), and on the integrity of dopaminergic nigrostriatal neurons in hemiparkinsonian mice. Following a unilateral 6-hydroxydopamine lesion A₁, A(₂A) and double A₁-A(₂A) knockout (KO) and wild-type littermate mice, and mice pretreated with caffeine (an antagonist of both A₁ and A(₂A) receptors) or saline were treated daily for 18-21 days with a low dose of L-DOPA. Total abnormal involuntary movements (AIMs, a measure of LID) were significantly attenuated (p<0.05) in A₁ and A(₂A) KOs, but not in A₁-A(₂A) KOs and caffeine-pretreated mice. An elevation of PPE mRNA ipsilateral to the lesion in WT mice was reduced in all KO mice. In addition, neuronal integrity assessed by striatal dopamine content was similar in all KOs and caffeine-pretreated mice following 6-hydroxydopamine lesioning. Our findings raise the possibility that A₁ or A(₂A) receptors blockade might also confer a disease-modifying benefit of reduced risk of disabling LID, whereas the effect of their combined inactivation is less clear.

• Authors: Danqing Xiao, Jared J Cassin, Brian Healy, Thomas C Burdett, Jiang-Fan Chen, Bertil B Fredholm, Michael A Schwarzschild
• Journal: Brain research (Brain Res) Vol. 1367 Pg. 310-8 (Jan 07 2011) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 20828543 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2010 Elsevier B.V. All rights reserved.

Chemical References

• Adrenergic Agents
• Antiparkinson Agents
• Enkephalins
• Protein Precursors
• Purinergic P1 Receptor Antagonists
• RNA, Messenger
• Receptor, Adenosine A1
• Receptor, Adenosine A2A
• pre-prodynorphin
• Caffeine
• Levodopa
• Dynorphins
• Oxidopamine
• preproenkephalin

Topics

• Adrenergic Agents (toxicity)
• Animals
• Antiparkinson Agents (adverse effects)
• Caffeine (administration & dosage)
• Corpus Striatum (drug effects)
• Disease Models, Animal
• Dynorphins (genetics, metabolism)
• Dyskinesia, Drug-Induced (etiology, genetics, prevention & control)
• Enkephalins (genetics, metabolism)
• Gene Expression Regulation (drug effects)
• Levodopa (adverse effects)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Oxidopamine (toxicity)
• Parkinson Disease (drug therapy, etiology, genetics)
• Protein Precursors (genetics, metabolism)
• Purinergic P1 Receptor Antagonists (administration & dosage)
• RNA, Messenger (metabolism)
• Receptor, Adenosine A1 (deficiency)
• Receptor, Adenosine A2A (deficiency)
• Statistics, Nonparametric
• Time Factors