Targeting adenosine A2A receptors in Parkinson's disease.
The adenosine A2A receptor has emerged as an attractive non-dopaminergic target in the pursuit of improved therapy for Parkinson's disease (PD), based in part on its unique CNS distribution. It is highly enriched in striatopallidal neurons and can form functional heteromeric complexes with other G-protein-coupled receptors, including dopamine D2, metabotropic glutamate mGlu5 and adenosine A1 receptors. Blockade of the adenosine A2A receptor in striatopallidal neurons reduces postsynaptic effects of dopamine depletion, and in turn lessens the motor deficits of PD. A2A antagonists might partially improve not only the symptoms of PD but also its course, by slowing the underlying neurodegeneration and reducing the maladaptive neuroplasticity that complicates standard 'dopamine replacement' treatments. Thus, we review here a prime example of translational neuroscience, through which antagonism of A2A receptors has now entered the arena of clinical trials with realistic prospects for advancing PD therapeutics.
Schwarzschild
Michael A
MA
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA 02129, USA. michaels@helix.mgh.harvard.edu
Agnati
Luigi
L
Fuxe
Kjell
K
Chen
Jiang-Fan
JF
Morelli
Micaela
M
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008959:Models, Neurological; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism
D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D043705:Receptor, Adenosine A2A