Adenosine A2A receptor antagonists exert motor and neuroprotective effects by distinct cellular mechanisms.
OBJECTIVE
To investigate whether the motor and neuroprotective effects of adenosine A(2A) receptor (A(2A)R) 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 A(2A)R knock-out mice coupled with flow cytometric analyses and intracerebroventricular injection to determine the contribution of A(2A)Rs in forebrain neurons and glial cells to A(2A)R antagonist-mediated motor and neuroprotective effects.


RESULTS
The selective deletion of A(2A)Rs in forebrain neurons abolished the motor stimulant effects of the A(2A)R antagonist KW-6002 but did not affect acute MPTP neurotoxicity. Intracerebroventricular administration of KW-6002 into forebrain A(2A)R knock-out mice reinstated protection against acute MPTP-induced dopaminergic neurotoxicity and attenuated MPTP-induced striatal microglial and astroglial activation.


CONCLUSIONS
A(2A)R 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.
Yu
Liqun
L
Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.
Shen
Hai-Ying
HY
Coelho
Joana E
JE
Araújo
Inês M
IM
Huang
Qing-Yuan
QY
Day
Yuan-Ji
YJ
Rebola
Nelson
N
Canas
Paula M
PM
Rapp
Erica Kirsten
EK
Ferrara
Jarrod
J
Taylor
Darcie
D
Müller
Christa E
CE
Linden
Joel
J
Cunha
Rodrigo A
RA
Chen
Jiang-Fan
JF
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D020267:MPTP Poisoning / Q000188:drug therapy / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D043705:Receptor, Adenosine A2A / Q000172:deficiency / Q000502:physiology
D058917:Adenosine A2 Receptor Antagonists; D018696:Neuroprotective Agents; D011687:Purines; D043705:Receptor, Adenosine A2A; C111599:istradefylline