Adenosine A2A receptor antagonists exert motor and neuroprotective effects by distinct cellular mechanisms
Liqun Yu
Department of Neurology, Boston University School of Medicine, Boston, MA
Search for more papers by this authorHai-Ying Shen
Department of Neurology, Boston University School of Medicine, Boston, MA
Search for more papers by this authorJoana E. Coelho
Department of Neurology, Boston University School of Medicine, Boston, MA
Search for more papers by this authorInês M. Araújo BS
Center for Neuroscience of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Search for more papers by this authorQing-Yuan Huang
Department of Neurology, Boston University School of Medicine, Boston, MA
Search for more papers by this authorYuan-Ji Day
Department of Internal Medicine, University of Virginia, Charlottesville, VA
Search for more papers by this authorNelson Rebola
Center for Neuroscience of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Search for more papers by this authorPaula M. Canas
Center for Neuroscience of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Search for more papers by this authorErica Kirsten Rapp BS
Department of Neurology, Boston University School of Medicine, Boston, MA
Search for more papers by this authorJarrod Ferrara BS
Department of Neurology, Boston University School of Medicine, Boston, MA
Search for more papers by this authorDarcie Taylor BS
Department of Neurology, Boston University School of Medicine, Boston, MA
Search for more papers by this authorChrista E. Müller
Pharmaceutical Sciences Bonn, Pharmaceutical Chemistry I, Pharmaceutical Institute, University of Bonn, Bonn, Germany
Search for more papers by this authorJoel Linden
Department of Internal Medicine, University of Virginia, Charlottesville, VA
Search for more papers by this authorRodrigo A. Cunha
Center for Neuroscience of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Search for more papers by this authorCorresponding Author
Jiang-Fan Chen
Department of Neurology, Boston University School of Medicine, Boston, MA
Department of Neurology, Boston University School of Medicine, 715 Albany Street, E301, Boston, MA 02118Search for more papers by this authorLiqun Yu
Department of Neurology, Boston University School of Medicine, Boston, MA
Search for more papers by this authorHai-Ying Shen
Department of Neurology, Boston University School of Medicine, Boston, MA
Search for more papers by this authorJoana E. Coelho
Department of Neurology, Boston University School of Medicine, Boston, MA
Search for more papers by this authorInês M. Araújo BS
Center for Neuroscience of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Search for more papers by this authorQing-Yuan Huang
Department of Neurology, Boston University School of Medicine, Boston, MA
Search for more papers by this authorYuan-Ji Day
Department of Internal Medicine, University of Virginia, Charlottesville, VA
Search for more papers by this authorNelson Rebola
Center for Neuroscience of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Search for more papers by this authorPaula M. Canas
Center for Neuroscience of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Search for more papers by this authorErica Kirsten Rapp BS
Department of Neurology, Boston University School of Medicine, Boston, MA
Search for more papers by this authorJarrod Ferrara BS
Department of Neurology, Boston University School of Medicine, Boston, MA
Search for more papers by this authorDarcie Taylor BS
Department of Neurology, Boston University School of Medicine, Boston, MA
Search for more papers by this authorChrista E. Müller
Pharmaceutical Sciences Bonn, Pharmaceutical Chemistry I, Pharmaceutical Institute, University of Bonn, Bonn, Germany
Search for more papers by this authorJoel Linden
Department of Internal Medicine, University of Virginia, Charlottesville, VA
Search for more papers by this authorRodrigo A. Cunha
Center for Neuroscience of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Search for more papers by this authorCorresponding Author
Jiang-Fan Chen
Department of Neurology, Boston University School of Medicine, Boston, MA
Department of Neurology, Boston University School of Medicine, 715 Albany Street, E301, Boston, MA 02118Search for more papers by this authorAbstract
Objective
To investigate whether the motor and neuroprotective effects of adenosine A2A receptor (A2AR) antagonists are mediated by distinct cell types in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease.
Methods
We used the forebrain A2AR knock-out mice coupled with flow cytometric analyses and intracerebroventricular injection to determine the contribution of A2ARs in forebrain neurons and glial cells to A2AR antagonist-mediated motor and neuroprotective effects.
Results
The selective deletion of A2ARs in forebrain neurons abolished the motor stimulant effects of the A2AR antagonist KW-6002 but did not affect acute MPTP neurotoxicity. Intracerebroventricular administration of KW-6002 into forebrain A2AR knock-out mice reinstated protection against acute MPTP-induced dopaminergic neurotoxicity and attenuated MPTP-induced striatal microglial and astroglial activation.
Interpretation
A2AR activity in forebrain neurons is critical to the control of motor activity, whereas brain cells other than forebrain neurons (likely glial cells) are important components for protection against acute MPTP toxicity. Ann Neurol 2008
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